Nucleic acids, proteins, and antibodies

Abstract

The present invention relates to novel proteins. More specifically, isolated nucleic acid molecules are provided encoding novel polypeptides. Novel polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human polynucleotides and/or polypeptides, and antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to these novel polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further relates to methods and/or compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

Description

STATEMENT UNDER 37 C.F.R. §1.77(b)(4)

[0001] This application refers to a “Sequence Listing” listed below, which is provided as an electronic document on two identical compact discs (CD-R), labeled “Copy 1” and “Copy 2.” These compact discs each contain the following files, which are hereby incorporated in their entirety herein:

	File	Size in	Date of
Document	Name	bytes	Creation
Sequence Listing	PJZO2_seqList.txt	2,365,610	Jan. 15, 2001
V Viewer Setup File	SetupDLL.exe	695,808	Dec. 19, 2000
V Viewer Help	v.cnt	7,984	Jan. 05, 2001
File Controller
V Viewer Program	v.exe	753,664	Dec. 19, 2000
File
V Viewer Help File	v.hlp	447,766	Jan. 05, 2001

[0002] The Sequence Listing may be viewed on an IBM-PC machine running the MS-Windows operating system by using the V viewer software, licensed by HGS, Inc., included on the compact discs (see World Wide Web URL: http://www.fileviewer.com).

FIELD OF THE INVENTION

[0003] The present invention relates to novel proteins. More specifically, isolated nucleic acid molecules are provided encoding novel polypeptides. Novel polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human polynucleotides and/or polypeptides, and antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to these novel polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further relates to methods and/or compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

BACKGROUND OF THE INVENTION

[0004] The brain regulates every aspect of human behavior and physiology, from movement, heart rate, blood pressure, and body temperature, to language, emotion, and memories. The prominence of the nervous system among other bodily systems is evidenced by the disproportionate amount of resources consumed by the brain. While comprising only 2% of the body's weight, the brain consumes 20% of the body's oxygen, 25% of the body's glucose, and receives 15% of the cardiac output (see Circulation and energy metabolism of the brain. In: Siegel G, Agranoff B, Albers R W, and Molinoff P, eds. Basic Neurochemistry: molecular, cellular, and medical aspects. 4th ed. New York: Raven Press (1989)).

[0005] The nervous system is organized into the central nervous system (CNS; comprising the brain and spinal cord), and the peripheral nervous system (PNS; comprising the network of nerves that connects the brain and spinal cord to the rest of the body). The basic functional units of the CNS and PNS are neurons, usually composed of dendrites (branching specializations which receive input from other neurons), a cell body (containing the machinery to sustain cellular functions), and an axon (which transmits electrical signals to other neurons or muscle cells). Electrical impulses, propagated along axons by voltage-gated ion channels, are converted to chemical signals at junctions between neurons called synapses. Calcium-mediated exocytosis of storage vesicles in the axon terminal leads to neurotransmitter release into the synaptic cleft. The signaling molecules passively diffuse to the postsynaptic membrane and bind to neurotransmitter-specific receptor proteins. Depending on the type of receptor activated, neurotransmitter binding can have a variety of effects on the postsynaptic cell, including activation of second messenger biocehmical cascades and modulation of ion channel permeability. These biochemical and biophysical changes influence the subsequent behavior of the neuron, for example making the cell more or less excitable to incoming signals.

[0006] The elaborate circuitry of the adult nervous system arises through an interaction between genetically programmed growth patterns and environmental influences. During embryonic development, neural connections are formed via the programmed extension of axons under the influence of local molecular cues. Through post-natal development, this coarse pattern of connections is refined based on specific interactions between the child and the environment. It is believed that there are critical periods of neural development in childhood, during which environmental stimulation has a more profound effect on nervous system organization than during adulthood. For example, it is known that sensory deprivation in early childhood (such as blindness or deafness), leads to measurable differences in brain organization (see, for examples, Roder et al., Nature 400(6740):162-6 (1999); Buchel et al., Brain 121 (Pt 3):409-19 (1998)).

[0007] Because of its integral role in human behavior and physiology, disorders of the nervous system are among the most debilitating diseases known. Since the adult nervous system has very limited ability to regenerate, neural injury due to illness or trauma can produce life-long impairments. About half of all spinal cord injuries result in permenant loss of movement and sensation in the arms and legs (quadriplegia). Similarly, up to 30% of stroke survivors are left permanently disabled (American Heart Association 2000 Heart and Stroke Statistical Update, Dallas, Tex. (1999)). Methods of promoting neural tissue regeneration—for example, to repair spinal cord injuries or brain tissue damage—is a major focus of modern neurobiology. However, currently there is no effective way to repair damaged adult neural tissues.

[0008] A number of neurological conditions, including schizophrenia, depression, and myesthenia gravis, involve impaired or inappropriate synaptic communication between neurons. Drug therapies designed to correct the synaptic chemical imbalances underlying these disorders, such as dopamine receptor antagonists for schizophrenia and serotonin uptake inhibitors for depression, have had varying degrees of success, at the cost of sometimes serious side-effects.

[0009] The immune system is suspected to play a role in some neurological disorders and conditions. For example, multiple sclerosis, which is characterized by sensory impairments (tingling, numbness, dizziness, loss of vision) and motor impairments (tremor, weakness, loss of coordination), is thought to be an autoimmune disorder in which immune cells destroy the insulating myelin sheath covering axons. In addition, the inflammatory immune response can be a serious complication of brain injury (e.g. trauma and stroke), spinal cord damage, and infection (e.g. encephalitis and meningitis), and may be a common pathological mechanism in many other neurological disorders (Hays, Curr. Pharm. Des. 4:335-48 (1998); Halliday et al., Clin. Exp. Pharmacol. Physiol. 27:1-8 (2000)).

[0010] The field of neurobiology is only beginning to uncover the biological basis of neurological diseases. In fact, in most cases the underlying cause or causes remain poorly understood. Thus, the discovery of new human nervous system-associated polynucleotides, the polypeptides encoded by them, and antibodies that immunospecifically bind these polypeptides, satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, prevention and/or prognosis of neurological diseases, disorders, and/or conditions, including, but not limited to, neuropsychiatric disorders, neurodegenerative diseases, vascular disorders, developmental disorders, infections, and neoplastic disorders.

SUMMARY OF THE INVENTION

[0011] The present invention relates to novel proteins. More specifically, isolated nucleic acid molecules are provided encoding novel polypeptides. Novel polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human polynucleotides and/or polypeptides, and antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to these novel polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further relates to methods and/or compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

DETAILED DESCRIPTION

[0012] Tables

[0013] Table 1A summarizes some of the polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) and contig nucleotide sequence identifier (SEQ ID NO:X)) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby. The first column provides the gene number in the application for each clone identifier. The second column provides a unique clone identifier, “Clone ID NO:Z”, for a cDNA clone related to each contig sequence disclosed in Table 1A. The third column provides a unique contig identifier, “Contig ID:” for each of the contig sequences disclosed in Table 1A. The fourth column provides the sequence identifier, “SEQ ID NO:X”, for each of the contig sequences disclosed in Table 1A. The fifth column, “ORF (From-To)”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:X that delineate the preferred open reading frame (ORF) that encodes the amino acid sequence shown in the sequence listing and referenced in Table 1A as SEQ ID NO:Y (column 6). Column 7 lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y). Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4; 181-186 (1988)); specifically, the Genetics Computer Group (GCG) implementation of this algorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group (GCG), Madison, Wis.). This method returns a measure of the probability that a given residue is found on the surface of the protein. Regions where the antigenic index score is greater than 0.9 over at least 6 amino acids are indicated in Table 1A as “Predicted Epitopes”. In particular embodiments, polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly. Column 8, “Tissue Distribution” shows the expression profile of tissue, cells, and/or cell line libraries which express the polynucleotides of the invention. The first number in column 8 (preceding the colon), represents the tissue/cell source identifier code corresponding to the key provided in Table 4. Expression of these polynucleotides was not observed in the other tissues and/or cell libraries tested. For those identifier codes in which the first two letters are not “AR”, the second number in column 8 (following the colon), represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ ID NO:X) was identified in the tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are “AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of 33P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after “[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression. Column 9 provides the chromosomal location of polynucleotides corresponding to SEQ ID NO:X. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Given a presumptive chromosomal location, disease locus association was determined by comparison with the Morbid Map, derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM™. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). If the putative chromosomal location of the Query overlaps with the chromosomal location of a Morbid Map entry, an OMIM identification number is disclosed in column 10 labeled “OMIM Disease Reference(s)”. A key to the OMIM reference identification numbers is provided in Table 5.

[0014] Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, “Clone ID NO:Z”, for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, “SEQ ID NO:X”, for each contig sequence. The third column provides a unique contig identifier, “Contig ID:” for each contig sequence. The fourth column, provides a BAC identifier “BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, “SEQ ID NO:B” for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, “Exon From-To”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).

[0015] Table 2 summarizes homology and features of some of the polypeptides of the invention. The first column provides a unique clone identifier, “Clone ID NO:Z”, corresponding to a cDNA clone disclosed in Table 1A. The second column provides the unique contig identifier, “Contig ID:” corresponding to contigs in Table 1A and allowing for correlation with the information in Table 1A. The third column provides the sequence identifier, “SEQ ID NO:X”, for the contig polynucleotide sequence. The fourth column provides the analysis method by which the homology/identity disclosed in the Table was determined. Comparisons were made between polypeptides encoded by the polynucleotides of the invention and either a non-redundant protein database (herein referred to as “NR”), or a database of protein families (herein referred to as “PFAM”) as further described below. The fifth column provides a description of the PFAM/NR hit having a significant match to a polypeptide of the invention. Column six provides the accession number of the PFAM/NR hit disclosed in the fifth column. Column seven, “Score/Percent Identity”, provides a quality score or the percent identity, of the hit disclosed in columns five and six. Columns 8 and 9, “NT From” and “NT To” respectively, delineate the polynucleotides in “SEQ ID NO:X” that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth and sixth columns. In specific embodiments polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by a polynucleotide in SEQ ID NO:X as delineated in columns 8 and 9, or fragments or variants thereof.

[0016] Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention. The first column provides a unique clone identifier, “Clone ID”, for a cDNA clone related to contig sequences disclosed in Table 1A. The second column provides the sequence identifier, “SEQ ID NO:X”, for contig sequences disclosed in Table 1A. The third column provides the unique contig identifier, “Contig ID:”, for contigs disclosed in Table 1A. The fourth column provides a unique integer ‘a’ where ‘a’ is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, and the fifth column provides a unique integer ‘b’ where ‘b’ is any integer between 15 and the final nucleotide of SEQ ID NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a +14. For each of the polynucleotides shown as SEQ ID NO:X, the uniquely defined integers can be substituted into the general formula of a-b, and used to describe polynucleotides which may be preferably excluded from the invention. In certain embodiments, preferably excluded from the invention are at least one, two, three, four, five, ten, or more of the polynucleotide sequence(s) having the accession number(s) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone).

[0017] Table 4 provides a key to the tissue/cell source identifier code disclosed in Table 1A, column 8. Column 1 provides the tissue/cell source identifier code disclosed in Table 1A, Column 8. Columns 2-5 provide a description of the tissue or cell source. Codes corresponding to diseased tissues are indicated in column 6 with the word “disease”. The use of the word “disease” in column 6 is non-limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ). Furthermore, tissues and/or cells lacking the “disease” designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder. In numerous cases where the tissue/cell source is a library, column 7 identifies the vector used to generate the library.

[0018] Table 5 provides a key to the OMIM reference identification numbers disclosed in Table 1A, column 10. OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 9, as determined using the Morbid Map database.

[0019] Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application.

[0020] Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers and vector information relating to these cDNA libraries.

[0021] Table 8 provides a physical characterization of clones encompassed by the invention. The first column provides the unique clone identifier, “Clone ID NO:Z”, for certain cDNA clones of the invention, as described in Table 1A. The second column provides the size of the cDNA insert contained in the corresponding cDNA clone.

[0022] Definitions

[0023] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[0024] In the present invention, “isolated” refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered “by the hand of man” from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be “isolated” because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide. The term “isolated” does not refer to genomic or cDNA libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic DNA preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide/sequences of the present invention.

[0025] As used herein, a “polynucleotide” refers to a molecule having a nucleic acid sequence encoding SEQ ID NO:Y or a fragment or variant thereof, a nucleic acid sequence contained in SEQ ID NO:X (as described in column 3 of Table 1A) or the complement thereof, a cDNA sequence contained in Clone ID NO:Z (as described in column 2 of Table 1A and contained within a library deposited with the ATCC); a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B or a fragment or variant thereof; or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B or the complement thereof. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5′ and 3′ untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence. Moreover, as used herein, a “polypeptide” refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA).

[0026] In the present invention, “SEQ ID NO:X” was often generated by overlapping sequences contained in multiple clones (contig analysis). A representative clone containing all or most of the sequence for SEQ ID NO:X is deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library. As shown, for example, in column 2 of Table 1A, each clone is identified by a cDNA Clone ID (identifier generally referred to herein as Clone ID NO:Z). Each Clone ID is unique to an individual clone and the Clone ID is all the information needed to retrieve a given clone from the HGS library. Furthermore, certain clones disclosed in this application have been deposited with the ATCC on Oct. 5, 2000, having the ATCC designation numbers PTA 2574 and PTA 2575; and on Jan. 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2. In addition to the individual cDNA clone deposits, most of the cDNA libraries from which the clones were derived were deposited at the American Type Culture Collection (hereinafter “ATCC”). Table 7 provides a list of the deposited cDNA libraries. One can use the Clone ID NO:Z to determine the library source by reference to Tables 6 and 7. Table 7 lists the deposited cDNA libraries by name and links each library to an ATCC Deposit. Library names contain four characters, for example, “HTWE.” The name of a cDNA clone (Clone ID) isolated from that library begins with the same four characters, for example “HTWEP07”. As mentioned below, Table 1A correlates the Clone ID names with SEQ ID NO:X. Thus, starting with an SEQ ID NO:X, one can use Tables 1, 6 and 7 to determine the corresponding Clone ID, which library it came from and which ATCC deposit the library is contained in. Furthermore, it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein. The ATCC is located at 10801 University Boulevard, Manassas, Va. 20110-2209, USA. The ATCC deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.

[0027] In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).

[0028] A “polynucleotide” of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, or the complement thereof (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained in Clone ID NO:Z (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA clones deposited with the ATCC, described herein), and/or the polynucleotide sequence delineated in column 6 of Table 1B or the complement thereof. “Stringent hybridization conditions” refers to an overnight incubation at 42 degree C. in a solution comprising 50% formamide, 5×SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5× Denhardt's solution, 10% dextran sulfate, and 20 μg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1×SSC at about 65 degree C.

[0029] Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions. Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature. For example, lower stringency conditions include an overnight incubation at 37 degree C. in a solution comprising 6×SSPE (20×SSPE=3M NaCl; 0.2M NaH2PO4; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50 degree C. with 1×SSPE, 0.1% SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5×SSC).

[0030] Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.

[0031] Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as any 3′ terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of “polynucleotide,” since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone generated using oligo dT as a primer).

[0032] The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. “Modified” bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA and RNA; thus, “polynucleotide” embraces chemically, enzymatically, or metabolically modified forms.

[0033] The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids. The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

[0034] “SEQ ID NO:X” refers to a polynucleotide sequence described, for example, in Tables 1A or 2, while “SEQ ID NO:Y” refers to a polypeptide sequence described in column 6 of Table 1A. SEQ ID NO:X is identified by an integer specified in column 4 of Table 1A. The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID NO:X. “Clone ID NO:Z” refers to a cDNA clone described in column 2 of Table 1A.

[0035] “A polypeptide having functional activity” refers to a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) protein. Such functional activities include, but are not limited to, biological activity, antigenicity [ability to bind (or compete with a polypeptide for binding) to an anti-polypeptide antibody], immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide.

[0036] The polypeptides of the invention can be assayed for functional activity (e.g. biological activity) using or routinely modifying assays known in the art, as well as assays described herein. Specifically, one of skill in the art may routinely assay nervous system polypeptides (including fragments and variants) of the invention for activity using assays as described in Examples 24, 34, 37, 48, and 59.

[0037] “A polypeptide having biological activity” refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).

[0038] Table 1A summarizes some of the polynucleotides encompassed by the invention (including contig sequences (SEQ ID NO:X) and clones (Clone ID NO:Z) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.

[0039] Polynucleotides and Polypeptides of the Invention

TABLE 1A
					AA		Tissue Distribution
					SEQ		Library code: count		OMIM
Gene		Contig	SEQ ID	ORF	ID		(see Table IV for Library	Cytologic	Disease
No:	Clone ID NO: Z	ID:	NO: X	(From-To)	NO: Y	Predicted Epitopes	Codes)	Band	Reference(s):
1	HTPAD46	1048901	11	1567-1148	609		AR061: 0, AR089: 0
							L0794: 4, H0039: 2,
							S0358: 1, H0013: 1,
							H0575: 1, L0770: 1,
							L0769: 1 and L0749: 1.
		503313	335	103-309	933	His-50 to Leu-69.
2	HCWFF88	1092566	12	628-227	610		AR089: 15, AR061: 6
							H0305: 2
		506577	336	41-187	934	Pro-1 to Gly-6,
						Ala-41 to Leu-47.
3	HSSAX53	1198889	13	209-361	611		H0135: 1 and H0063:
							1.
		507509	337	209-361	935
4	HCEPH71	522739	14	3-410	612	Val-1 to Lys-8,	AR089: 1, AR061: 1
						Pro-36 to Lys-41,	H0052: 1 and T0067:
						Gln-49 to Lys-57,	1.
						Ser-63 to Ser-70,
						Asp-79 to Gln-92,
						Asn-103 to Thr-122.
5	HTEDF74	1083405	15	2-970	613	Pro-37 to Trp-53,	AR061: 3, AR089: 2
						Arg-56 to Pro-62.	L0731: 2, H0341: 1,
							H0392: 1, H0038: 1,
							H0641: 1, L0803: 1 and
							H0445: 1.
		522982	338	3-575	936	Pro-20 to Trp-36,
						Arg-39 to Pro-45,
						Gly-62 to Glu-69,
						Asp-77 to Lys-82,
						Pro-87 to Ala-93.
6	HTTEK47	1134534	16	2-1009	614	Val-21 to Pro-27.	AR061: 8, AR089: 6
							L0439: 5, H0622: 3,
							H0040: 2, L0794: 2,
							L0805: 2, L0758: 2,
							L0803: 1, L0375: 1,
							L0659: 1, L0789: 1,
							L0665: 1, H0579: 1,
							L0750: 1, L0779: 1,
							L0777: 1, L0752: 1 and
							L0755: 1.
		573649	339	2-349	937	Leu-13 to Val-18,
						Thr-37 to Lys-46.
7	HTOBE75	1163883	17	149-1075	615	Arg-36 to Gln-44,	AR061: 2, AR089: 1
						Ser-49 to Gln-57,	H0038: 3, L0748: 3,
						Lys-276 to Cys-286.	L0659: 2, L0743: 2,
							L0744: 2, H0486: 1,
							H0421: 1, H0024: 1,
							H0031: 1, H0272: 1,
							L0662: 1, L0384: 1,
							L0809: 1 and L0779: 1.
		591896	340	1-414	938
8	HCFAT05	1156310	18	1-747	616	Leu-21 to Gln-29,	AR061: 1, AR089: 1
						Ala-95 to Gly-101,	H0556: 2, H0634: 1,
						Arg-163 to Gln-172,	L0766: 1 and H0422: 1.
						Ser-183 to Glu-202,
						Thr-219 to Ser-226,
						Thr-231 to Ser-238.
		592118	341	2-490	939	Arg-1 to His-11,
						Ser-18 to Gly-27,
						Gly-36 to Gly-44,
						Asp-97 to Phe-103,
						Pro-127 to Gly-132.
9	HFIAH37	1189001	19	69-872	617	Lys-65 to Thr-71,	AR089: 7, AR061: 1
						Lys-104 to Gly-109,	H0457: 2, H0529: 2,
						Lys-116 to His-122,	H0561: 1, H0521: 1,
						Asn-140 to Asp-146,	S0192: 1 and L0600: 1.
						Lys-184 to Lys-203,
						Glu-205 to Asn-239,
						Ala-256 to Phe-267.
		615597	342	70-375	940	Lys-65 to Thr-71.
10	HFTDF15	1084887	20	475-672	618		AR089: 3, AR061: 2
							H0563: 1 and H0123:
							1.
		657020	343	129-254	941
11	HPFCU80	1017593	21	341-3	619		AR089: 16, AR061: 13
							H0163: 3 and H0169:
							1.
		685294	344	162-341	942
12	HSVAW49	1153916	22	767-501	620	Pro-19 to Thr-24,	AR061: 9, AR089: 7
						Thr-78 to Lys-89.	H0309: 1
		689674	345	44-208	943	Glu-21 to Glu-27.
13	HWHQC94	1116463	23	2-916	621		AR089: 2, AR061: 1
							L0665: 4, S0132: 2,
							L0438: 2, L0439: 2,
							L0596: 2, H0542: 2,
							H0543: 2, S0114: 1,
							H0614: 1, H0592: 1,
							H0587: 1, S0280: 1,
							H0253: 1, H0581: 1,
							H0457: 1, H0012: 1,
							H0083: 1, H0687: 1,
							H0290: 1, H0622: 1,
							H0135: 1, S0150: 1,
							L0796: 1, L0646: 1,
							L0643: 1, L0764: 1,
							L0773: 1, L0649: 1,
							L0659: 1, L0663: 1,
							H0658: 1, H0555: 1,
							H0478: 1, L0752: 1,
							L0599: 1 and H0506: 1.
		715096	346	1-627	944	Trp-62 to Pro-67.
14	HRSMD49	1065458	24	166-342	622	Phe-16 to Trp-24,	AR089: 3, AR061: 2
						Leu-30 to Val-37,	H0394: 1 and L0589:
						Phe-41 to Ile-49.	1.
		723025	347	190-456	945	Gln-36 to Ile-46,
						Ser-55 to Phe-65,
						Ser-67 to Lys-78.
15	HFTDY67	1151220	25	1527-1	623	Asn-64 to Pro-73,	AR089: 89, AR061: 75
						Asp-83 to Glu-94,	S0002: 2, H0521: 2,
						Leu-144 to Pro-153,	S0360: 1, H0123: 1,
						Glu-162 to Thr-167,	S0250: 1, L0654: 1,
						Asp-178 to Ser-189,	S0152: 1, L0740: 1 and
						Gly-197 to Leu-210,	L0749: 1.
						Pro-217 to Pro-222,
						Arg-234 to Asp-251,
						Gly-279 to Phe-293,
						Asp-357 to Gly-367,
						Gly-379 to Val-396,
						Glu-421 to Met-426,
						Asn-441 to Leu-447,
						Glu-467 to Trp-474.
		745221	348	1-228	946	Gly-23 to Phe-37.
16	HYABL89	1090733	26	247-417	624		AR089: 1, AR061: 1
							S0114: 1, H0583: 1 and
							H0013: 1.
		786157	349	246-416	947
17	HCUEV29	1137791	27	3-569	625	Glu-18 to Val-28,	AR089: 1, AR061: 1
						Pro-31 to Glu-47,	H0457: 15, H0271: 11,
						Glu-88 to Asp-94,	H0494: 7, H0521: 7,
						Ser-154 to Lys-178.	H0141: 6, H0255: 6,
							S0434: 6, L0758: 5,
							S0354: 4, S0358: 4,
							S0278: 4, H0179: 4,
							L0771: 4, L0783: 4,
							H0436: 4, H0556: 3,
							H0069: 3, H0618: 3,
							L0776: 3, L0659: 3,
							H0435: 3, H0661: 2,
							S0418: 2, S0420: 2,
							H0580: 2, S0222: 2,
							H0486: 2, H0013: 2,
							H0581: 2, H0083: 2,
							H0266: 2, S0003: 2,
							H0424: 2, S0036: 2,
							H0090: 2, H0038: 2,
							H0634: 2, H0616: 2,
							S0344: 2, S0002: 2,
							L0770: 2, L0646: 2,
							L0662: 2, L0381: 2,
							L0655: 2, L0809: 2,
							L0666: 2, L0665: 2,
							S0216: 2, H0703: 2,
							H0547: 2, H0593: 2,
							H0670: 2, H0539: 2,
							S0027: 2, L0748: 2,
							L0439: 2, L0751: 2,
							L0591: 2, H0543: 2,
							H0624: 1, H0650: 1,
							H0656: 1, S0116: 1,
							H0484: 1, H0402: 1,
							S0376: 1, S0444: 1,
							S0360: 1, S0045: 1,
							S0046: 1, H0619: 1,
							S6026: 1, H0261: 1,
							H0438: 1, H0586: 1,
							H0559: 1, H0101: 1,
							H0427: 1, H0036: 1,
							T0048: 1, H0318: 1,
							S0474: 1, H0421: 1,
							H0052: 1, H0205: 1,
							H0231: 1, L0738: 1,
							H0150: 1, H0081: 1,
							T0010: 1, H0416: 1,
							T0006: 1, H0213: 1,
							H0598: 1, H0135: 1,
							H0040: 1, H0087: 1,
							H0264: 1, H0488: 1,
							H0623: 1, H0334: 1,
							H0561: 1, S0440: 1,
							L0369: 1, L0769: 1,
							L0667: 1, L0773: 1,
							L0648: 1, L0364: 1,
							L0766: 1, L0649: 1,
							L0375: 1, L0378: 1,
							L0806: 1, L0653: 1,
							L0657: 1, L0636: 1,
							S0052: 1, S0428: 1,
							H0702: 1, S0374: 1,
							L0438: 1, S0328: 1,
							S0330: 1, H0710: 1,
							S0146: 1, S0406: 1,
							H0576: 1, H0631: 1,
							S3014: 1, L0779: 1,
							L0759: 1, H0445: 1,
							S0436: 1, S0011: 1,
							S0026: 1, S0242: 1 and
							H0506: 1.
		816065	350	2-298	948
18	HCESP56	1121751	28	452-72	626	Glu-1 to Leu-6,	AR061: 8, AR089: 5
						Asp-90 to Asp-107.	H0052: 3, S0282: 1,
							H0194: 1, H0009: 1,
							L0789: 1, L0602: 1 and
							L0439: 1.
		827671	351	147-512	949	Asp-15 to Thr-21,
						Gln-83 to Ile-91.
19	HLQDT35	1154064	29	230-502	627	Ile-1 to Ser-6,	AR089: 3, AR061: 3
						Leu-81 to Glu-91.	S0358: 8, L0766: 7,
							L0777: 7, L0731: 7,
							L0659: 4, L0748: 4,
							L0751: 4, L0783: 3,
							L0663: 3, S0418: 2,
							S0360: 2, H0486: 2,
							S0010: 2, S0250: 2,
							S0422: 2, L0763: 2,
							L0803: 2, L0775: 2,
							L0789: 2, H0520: 2,
							L0756: 2, L0752: 2,
							H0656: 1, S0376: 1,
							H0208: 1, H0574: 1,
							H0632: 1, S0414: 1,
							H0581: 1, H0052: 1,
							H0024: 1, H0014: 1,
							H0355: 1, H0688: 1,
							H0090: 1, H0623: 1,
							H0509: 1, H0529: 1,
							L0520: 1, L0761: 1,
							L0650: 1, L0809: 1,
							L0666: 1, L0665: 1,
							S0126: 1, H0684: 1,
							H0648: 1, S0390: 1,
							L0740: 1, L0745: 1,
							L0749: 1, L0750: 1,
							L0755: 1, L0591: 1,
							L0362: 1 and S0242: 1.
		839777	352	222-494	950
20	HDPBS64	846624	30	2-685	628	Phe-7 to Pro-15,	AR089: 1, AR061: 0
						Trp-34 to Gly-40.	S0222: 1, S0002: 1,
							L0804: 1, L0663: 1 and
							H0521: 1.
21	HTBAB41	1052388	31	619-798	629	Met-1 to Ser-8.	AR089: 30, AR061: 8
							S0044: 2, L0748: 2,
							H0392: 1, H0075: 1,
							L0770: 1 and H0519: 1.
		867287	353	11-178	951	Lys-1 to Asp-7,
						Gln-47 to Arg-53.
22	HTLGE31	870247	32	2-307	630	Val-47 to Gly-65.	AR089: 163, AR061:
							32
							H0618: 1, L0368: 1
							and S0053: 1.
23	HWLHK29	1152279	33	3-608	631	Gln-24 to Thr-32,	AR089: 15, AR061: 5
						Ser-154 to Phe-163.	L0754: 5, L0755: 5,
							S0354: 3, L0483: 3,
							H0648: 3, L0777: 3,
							S0374: 2, L0751: 2,
							L0758: 2, L0605: 2,
							L0362: 2, H0543: 2,
							S0114: 1, S0358: 1,
							H0411: 1, H0575: 1,
							L0105: 1, H0263: 1,
							H0596: 1, H0510: 1,
							S0003: 1, H0166: 1,
							H0169: 1, H0090: 1,
							H0059: 1, S0440: 1,
							L0373: 1, L0372: 1,
							L0800: 1, L0662: 1,
							L0794: 1, L0649: 1,
							L0803: 1, L0804: 1,
							L0659: 1, L0783: 1,
							L0809: 1, L0789: 1,
							L0790: 1, L0666: 1,
							L0665: 1, S0378: 1,
							L0602: 1, H0436: 1,
							L0779: 1, L0780: 1,
							S0434: 1, S0196: 1 and
							S0446: 1.
		876064	354	3-491	952	Gln-18 to Thr-26.
24	HHEGG20	1106816	34	3-971	632	Arg-4 to Glu-12,	AR089: 2, AR061: 1
						Glu-121 to Gly-126,	S0360: 1, H0013: 1,
						Ala-141 to Pro-146,	L0664: 1 and H0542: 1.
						Gln-161 to Phe-176,
						Lys-186 to Ser-194.
		894409	355	26-820	953
25	HDPRU43	1217035	35	1-2460	633	Pro-1 to Gly-7,	AR089: 1, AR061: 1
						Val-127 to Val-133,	H0046: 34, L0731: 5,
						Leu-162 to Ser-171,	L0534: 4, L0769: 4,
						Arg-178 to Glu-185,	H0521: 4, S0356: 3,
						Pro-195 to Thr-200,	L0800: 3, L0794: 3,
						Gln-243 to Trp-248,	L0439: 3, L0749: 3,
						Gln-252 to Asn-265,	L0752: 3, L0759: 3,
						Glu-313 to Cys-319,	L0562: 2, H0486: 2,
						His-417 to Glu-422,	L0803: 2, L0805: 2,
						Arg-464 to Ala-473,	L0809: 2, L0789: 2,
						Met-530 to Lys-538,	L0744: 2, L0485: 2,
						Arg-594 to Gly-599,	H0556: 1, H0657: 1,
						Glu-641 to Gly-649,	H0637: 1, H0580: 1,
						Asp-660 to Ala-668,	H0208: 1, H0261: 1,
						Arg-705 to Ser-727,	H0609: 1, H0455: 1,
						Ser-777 to Glu-783,	H0600: 1, H0586: 1,
						Leu-796 to Gly-806.	H0331: 1, H0635: 1,
							H0618: 1, H0544: 1,
							H0009: 1, H0050: 1,
							H0620: 1, H0288: 1,
							S0312: 1, S0314: 1,
							H0252: 1, H0688: 1,
							H0644: 1, S0366: 1,
							H0135: 1, H0063: 1,
							H0087: 1, H0551: 1,
							H0264: 1, S0002: 1,
							L0639: 1, L0771: 1,
							L0648: 1, L0766: 1,
							L0650: 1, L0378: 1,
							L0655: 1, H0699: 1,
							H0660: 1, L0743: 1,
							L0750: 1, L0777: 1,
							L0758: 1, L0097: 1,
							S0194: 1 and H0543: 1.
		909841	356	1-342	954	Pro-8 to Gln-16.
26	HE8PK12	1227647	36	2-367	634	Val-30 to Ser-37.	AR089: 6, AR061: 4
							L0754: 6, L0777: 6,
							L0740: 5, L0731: 4,
							L0758: 4, L0759: 4,
							S0001: 3, S0280: 3,
							L0770: 3, L0764: 3,
							L0747: 3, L0749: 3,
							L0366: 3, S0412: 3,
							S0007: 2, H0411: 2,
							H0013: 2, L0471: 2,
							T0004: 2, L0598: 2,
							L0638: 2, L0662: 2,
							L0783: 2, L0438: 2,
							H0696: 2, L0744: 2,
							L0748: 2, L0751: 2,
							L0745: 2, L0779: 2,
							L0752: 2, H0170: 1,
							S0282: 1, H0662: 1,
							H0574: 1, T0060: 1,
							H0427: 1, H0590: 1,
							S0010: 1, L0105: 1,
							S0049: 1, H0194: 1,
							H0373: 1, L0163: 1,
							H0201: 1, H0031: 1,
							H0553: 1, S0306: 1,
							L0776: 1, L0659: 1,
							L0526: 1, L0809: 1,
							L0663: 1, H0144: 1,
							H0547: 1, H0648: 1,
							H0672: 1, L0743: 1,
							L0780: 1, S0031: 1,
							H0343: 1, L0604: 1 and
							H0653: 1.
		909884	357	2-367	955	Val-30 to Ser-37,
						Gln-43 to Asp-62,
						Pro-74 to Glu-79,
						Thr-102 to Phe-109.
27	HE9HV92	1227519	37	1-1050	635	Asn-2 to Gly-10,	AR061: 1, AR089: 0
						Asp-86 to Ile-110,	L0439: 3, H0616: 2,
						Gly-116 to Gln-121,	L0749: 2, S0420: 1,
						Ala-135 to Arg-140,	H0415: 1, H0013: 1,
						Ala-167 to Ser-172,	H0590: 1, S0010: 1,
						Leu-176 to Lys-183.	H0046: 1, H0050: 1,
							H0375: 1, H0615: 1,
							S0366: 1, H0529: 1,
							H0144: 1, S0126: 1,
							S0152: 1, S3014: 1 and
							L0779: 1.
		911510	358	2-1048	956	Thr-1 to Gly-9.
28	HOHCE47	1217059	38	578-2143	636	Tyr-83 to Ser-92,	AR061: 1, AR089: 0
						Leu-118 to Tyr-123,	S0040: 1, H0580: 1,
						Leu-137 to Ser-143,	S0222: 1, H0355: 1,
						Gln-148 to Ser-158,	S0250: 1, L0565: 1 and
						Thr-258 to Pro-266,	S0152: 1.
						Gln-274 to His-283,
						Asp-325 to Ser-334,
						Gln-343 to Thr-349,
						Ser-366 to Val-378,
						Arg-381 to Asp-388,
						Pro-426 to Asn-431,
						Cys-446 to Ser-457,
						Leu-469 to Lys-486,
						Cys-501 to Arg-510.
		911566	359	1-429	957	Gly-1 to Trp-6.
29	HSDII69	1154067	39	74-412	637	His-13 to Gly-21,	AR061: 6, AR089: 5
						Tyr-61 to Asp-66,	H0328: 4, H0031: 3,
						Ala-105 to Thr-110.	L0519: 3, L0748: 2,
							L0777: 2, L0731: 2,
							S0260: 2, H0624: 1,
							S6024: 1, H0650: 1,
							S0116: 1, H0254: 1,
							S0007: 1, H0393: 1,
							H0441: 1, H0438: 1,
							H0574: 1, H0156: 1,
							H0599: 1, S0051: 1,
							H0615: 1, H0039: 1,
							L0564: 1, L0763: 1,
							L0766: 1, L0774: 1,
							L0776: 1, L0659: 1,
							L0518: 1, L0792: 1,
							L0666: 1, L0663: 1,
							S0242: 1 and H0423: 1.
		917180	360	202-540	958	His-13 to Gly-21,
						Tyr-61 to Asp-66,
						Ala-105 to Thr-110.
30	HKAKM10	1227639	40	3-2840	638	Leu-15 to Ser-21,	AR089: 1, AR061: 1
						Leu-89 to Tyr-94,	L0794: 4, L0438: 4,
						Gly-130 to Gln-136,	L0761: 3, L0766: 3,
						Asn-163 to Leu-168,	L0748: 3, L0439: 3,
						Lys-176 to His-181,	H0556: 2, L0602: 2,
						Ile-187 to Arg-193,	L0754: 2, L0779: 2,
						Ala-239 to Thr-244,	H0580: 1, H0208: 1,
						Pro-263 to Val-268,	H0013: 1, T0082: 1,
						Ala-401 to Ser-406.	S0010: 1, H0428: 1,
							H0553: 1, H0038: 1,
							H0616: 1, H0494: 1,
							L0796: 1, L0800: 1,
							L0773: 1, L0533: 1,
							L0803: 1, L0776: 1,
							L0657: 1, L0791: 1,
							H0520: 1, H0519: 1,
							H0521: 1, H0187: 1,
							L0731: 1, S0031: 1 and
							L0366: 1.
		918685	361	2-547	959	Gly-25 to Gln-31,
						Asn-58 to Leu-63,
						Lys-71 to His-76,
						Ile-82 to Arg-88,
						Ala-134 to Thr-139.
31	HCEPU56	1226120	41	1037-1840	639	Lys-65 to Thr-71,	AR061: 6, AR089: 5
						Lys-104 to Gly-109,
						Lys-116 to His-122,
						Asn-140 to Asp-146,
						Lys-184 to Lys-203,
						Glu-205 to Asn-239,
						Ala-256 to Phe-267.
		920347	362	219-593	960	Lys-16 to Thr-22,
						Lys-55 to Gly-60,
						Lys-67 to His-73,
						Asn-91 to Asp-97.
32	HUSHB54	928054	42	125-355	640		AR089: 1, AR061: 0
							H0056: 3, H0437: 1,
							H0050: 1 and S0002: 1.
33	HLMDO95	928344	43	88-435	641		AR089: 27, AR061: 11
							H0271: 3, H0250: 2,
							H0635: 2, S0216: 2,
							H0254: 1, H0638: 1,
							H0069: 1, H0416: 1,
							H0090: 1, L0761: 1,
							L0800: 1, L0776: 1,
							L0789: 1 and S0052: 1.
34	HHASQ32	1198902	44	50-892	642	Gly-1 to Gly-6,	AR089: 21, AR061: 7
						Arg-12 to Arg-17,	H0510: 3, S0438: 2,
						Gln-56 to Ser-71,	L0803: 2, L0615: 1,
						Glu-82 to Glu-89,	S0418: 1, H0393: 1,
						Phe-94 to Glu-104,	H0632: 1, H0355: 1,
						Ala-126 to Asn-131,	L0774: 1, H0144: 1,
						Pro-167 to Gly-177,	L0749: 1, L0750: 1,
						Thr-224 to Ala-233,	L0605: 1 and L0581: 1.
						Leu-237 to Lys-281.
		928730	363	40-855	961	Gly-1 to Gly-6,
						Arg-12 to Arg-17.
35	HARAB87	1164340	45	3-548	643		AR051: 29, AR050:
							24, AR054: 18, AR089:
							1, AR061: 0
							T0082: 1, T0023: 1 and
							L0596: 1.
		933441	364	181-768	962
36	HTNGF69	1152268	46	501-803	644	Ser-1 to Gly-23,	AR061: 3, AR089: 2
						Gly-85 to Leu-91.	L0758: 3, L0666: 2,
							L0751: 2, L0777: 2,
							H0663: 1, L0021: 1,
							H0309: 1, H0688: 1,
							H0617: 1, H0477: 1,
							L0766: 1, L0775: 1,
							L0367: 1, L0789: 1,
							L0663: 1, L0438: 1,
							L0749: 1, L0779: 1,
							L0757: 1 and S0456: 1.
		933614	365	483-785	963	Ser-1 to Gly-23,
						Gly-85 to Leu-91.
37	HMSJL96	1154788	47	1-1461	645	Thr-15 to Arg-22,	AR054: 16, AR051:
						Ala-38 to Met-43,	15, AR050: 12, AR089:
						Gln-49 to Lys-64,	0, AR061: 0
						Thr-97 to Gln-108,	L0777: 6, L0758: 5,
						Tyr-132 to Ser-139,	L0779: 4, L0803: 3,
						His-219 to Gln-265,	S0358: 2, H0004: 2,
						Ala-354 to Gly-362,	L0662: 2, L0775: 2,
						Ser-379 to Ala-386,	H0144: 2, S0126: 2,
						Asp-402 to Ser-417,	S0328: 2, S3014: 2,
						Leu-424 to Glu-433,	S0027: 2, L0743: 2,
						Arg-443 to Gly-459,	L0748: 2, H0265: 1,
						Ser-463 to Ser-472.	H0656: 1, S0212: 1,
							H0663: 1, H0638: 1,
							H0580: 1, H0632: 1,
							H0486: 1, H0599: 1,
							H0618: 1, L0105: 1,
							H0251: 1, H0309: 1,
							H0544: 1, H0123: 1,
							H0050: 1, L0471: 1,
							H0024: 1, H0399: 1,
							S0003: 1, H0364: 1,
							H0553: 1, H0038: 1,
							H0412: 1, H0413: 1,
							T0041: 1, S0344: 1,
							S0002; 1, L0598: 1,
							H0529: 1, L0645: 1,
							L0363: 1, L0649: 1,
							L0804: 1, L0805: 1,
							L0558: 1, L0659: 1,
							L0528: 1, L0789: 1,
							L0792: 1, L0666: 1,
							S0374: 1, H0555: 1,
							S3012: 1, S0028: 1,
							S0206: 1, S0032: 1,
							L0439: 1, L0757: 1,
							S0031: 1, H0707: 1,
							S0192: 1, H0423: 1,
							S0042: 1 and H0008: 1.
		934483	366	1-426	964	Thr-15 to Arg-22,
						Ala-38 to Met-43,
						Gln-49 to Lys-64,
						Thr-97 to Gln-108,
						Thr-131 to Lys-137.
38	HDTBT06	1205261	48	3-905	646		AR089: 2, AR061: 1
							L0754: 6, H0318: 3,
							H0486: 2, H0014: 2,
							L0777: 2, H0543: 2,
							H0171: 1, S6024: 1,
							H0650: 1, S0354: 1,
							H0455: 1, H0013: 1,
							L0483: 1, H0494: 1,
							S0450: 1, L0520: 1,
							L0763: 1, L0769: 1,
							L0641: 1, L0521: 1,
							L0662: 1, L0774: 1,
							L0776: 1, L0783: 1,
							L0663: 1, S0136: 1,
							H0478: 1, L0742: 1,
							L0439: 1, L0780: 1,
							L0592: 1, S0192: 1 and
							S0424: 1.
		935404	367	1-906	965
39	HTTIE47	1165363	49	2-574	647	Thr-8 to Ser-16,	AR061: 4, AR089: 4
						Arg-34 to Leu-42,	L0615: 1, S0420: 1,
						Thr-46 to Glu-51,	H0333: 1, H0286: 1,
						Thr-57 to Arg-66,	H0634: 1 and H0144: 1.
						Gln-94 to Ala-100,
						Ser-127 to Glu-134.
		941834	368	1-567	966	Thr-6 to Ser-14,
						Arg-32 to Leu-40,
						Thr-44 to Glu-49,
						Thr-55 to Arg-64,
						Gln-92 to Ala-98,
						Ser-125 to Glu-132.
40	HHFBP47	946668	50	825-253	648	Cys-9 to Arg-14,	AR089: 5, AR061: 5
						Arg-21 to Gly-28.	L0748: 2, L0749: 2,
							H0085: 1, H0050: 1,
							H0090: 1 and L0758: 1.
41	HCCCC81	1083553	51	562-2	649		AR089: 12, AR061: 7
							H0583: 1, H0675: 1
							and H0457: 1.
		949062	369	139-921	967	Gly-8 to Ile-13,
						Glu-141 to His-146,
						Glu-186 to Glu-195,
						Asp-213 to Asn-218.
42	HPJEV71	1197841	52	976-164	650	Gln-49 to Pro-66,	AR089: 7, AR061: 6
						Ser-96 to Thr-108,	H0521: 2, H0039: 1,
						Glu-116 to Glu-135,	H0641: 1, H0529: 1,
						Arg-140 to Pro-152,	L0654: 1, H0701: 1,
						Ser-167 to Arg-172,	H0518: 1, S0152: 1 and
						Pro-175 to Leu-185,	H0522: 1.
						Ala-199 to Lys-215,
						Pro-228 to Leu-237,
						Pro-247 to Ser-253.
		949153	370	269-2029	968	Ser-5 to Gly-20.
43	HTEIL07	1136121	53	43-1143	651	Glu-13 to Asp-29,	AR061: 1, AR089: 0
						Glu-50 to Lys-58,	L0758: 4, L0617: 2,
						Thr-61 to Glu-66,	L0794: 2, H0253: 1,
						Ala-94 toTyr-100,	H0038: 1, H0616: 1,
						Gln-146 to Ser-156,	L0789: 1 and L0779: 1.
						Pro-171 to Asp-177,
						Ile-179 to Trp-191,
						Glu-197 to Val-203,
						Asp-238 to Lys-244,
						Pro-304 to Ala-315.
		953803	371	42-443	969	Glu-13 to Thr-27.
44	HTEAG49	954614	54	510-208	652		AR089: 1, AR061: 0
							L0759: 4, L0770: 2,
							S0040: 1, S0318: 1,
							S0334: 1, S0316: 1,
							S0340: 1, H0038: 1,
							L0598: 1, L0800: 1 and
							S0276: 1.
45	HSLCF96	637670	55	355-1248	653	Val-2 to Trp-7,	AR054: 38, AR050:
						Lys-9 to Trp-18,	26, AR051: 25, AR061:
						Gln-20 to Gly-25,	2, AR089: 1
						Gln-79 to His-85,	S0028: 1
						Pro-134 to Asp-139,
						Asp-164 to Thr-171,
						Pro-223 to Arg-228.
		954777	372	1332-430	970	Thr-1 to Cys-6,
						Ser-52 to Gly-57,
						Gln-111 to His-117.
46	HNHCI32	861673	56	183-593	654	Lys-17 to Thr-23,	AR051: 23, AR050:
						His-95 to Thr-101.	14, AR061: 10, AR054:
							4, AR089: 3
							S0053: 1
		956105	373	963-553	971	Lys-17 to Thr-23,
						His-95 to Thr-101.
47	HPMFL08	1050684	57	191-391	655		AR089: 1, AR061: 1
							H0031: 2
		959569	374	191-346	972	Met-43 to Trp-52.
48	HTXRA13	959622	58	3-1091	656	Ser-1 to Ser-6,	AR061: 1, AR089: 0
						Thr-14 to Gly-28.	H0556: 2, L0756: 2,
							H0423: 2, S0134: 1,
							H0580: 1, H0271: 1,
							T0006: 1, H0264: 1,
							H0560: 1, H0641: 1,
							S0142: 1, L0805: 1,
							L0809: 1, L0789: 1,
							H0555: 1, L0780: 1 and
							S0031: 1.
49	HCE3H71	1197898	59	410-988	657	His-14 to Gly-19,	AR089: 14, AR061: 10
						Pro-21 to Pro-28,	L0439: 12, L0438: 5,
						Arg-49 to Gln-54,	L0741: 4, H0052: 2,
						Pro-82 to Pro-91,	H0009: 2, L0769: 2,
						Gly-102 to Ser-108,	L0794: 2, H0229: 1,
						Arg-150 to Ser-155,	H0572: 1, L0770: 1,
						Pro-160 to Asn-168,	L0796: 1, L0789: 1 and
						Ala-175 to Glu-188.	L0786: 1.
		961681	375	275-826	973
50	HUTSF11	1134914	60	3-323	658	Pro-4 to Glu-13,	AR089: 0, AR061: 0
						Asn-23 to Arg-29,	S0464: 1 and L0356: 1.
						Gln-91 to Arg-100.
		966029	376	3-302	974	Glu-1 to Glu-6,
						Asn-16 to Arg-22.
51	HTEGI48	1021235	61	1-549	659	Arg-1 to Ser-12,	AR089: 4, AR061: 1
						Leu-33 to Leu-40,	H0038: 2, H0556: 1,
						His-42 to Phe-49,	H0341: 1 and L0596: 1.
						Glu-51 to Met-57,
						Gly-72 to Phe-78.
		530595	377	32-523	975	Val-3 to Tyr-15,
						Leu-17 to Thr-27,
						Ser-34 to Ser-61,
						Leu-82 to Leu-89,
						His-91 to Phe-98,
						Glu-100 to Met-106,
						Gly-121 to Phe-127.
52	HSFAM09	1153913	62	152-295	660	Arg-1 to Ser-8,	AR061: 5, AR089: 2
						Lys-42 to Lys-48.	H0154: 2
		573345	378	147-332	976	Arg-1 to Ser-8,
						Lys-42 to Lys-48.
53	HNFHK77	1182286	63	165-662	661	Pro-38 to Lys-43,	AR061: 1, AR089: 0
						Glu-126 to Tyr-132,	H0271: 2
						Trp-161 to Arg-166.
		576186	379	165-422	977	Pro-38 to Lys-43.
54	HFXDO83	1012602	64	12-608	662		AR089: 1, AR061: 1
							S0001: 3
		578847	380	16-207	978	Arg-1 to Cys-10.
55	HSDIW73	1104406	65	1-1068	663	Leu-4 to Pro-9,	AR051: 4, AR054: 1,
						Ile-64 to Arg-69,	AR089: 1, AR061: 0,
						Asn-142 to Pro-147,	AR050: 0
						Pro-349 to Asp-356.	S0046: 1, S0028: 1,
							S0031: 1 and S0260: 1.
		587311	381	2-1075	979	Leu-6 to Pro-11,
						Ile-66 to Arg-71,
						Asn-144 to Pro-149,
						Pro-351 to Asp-358.
		954821	382	1595-549	980	Ile-57 to Arg-62,
						Asn-135 to Pro-140,
						Pro-342 to Asp-349.
56	HFVGD23	1199645	66	2-1003	664	Ser-4 to Arg-9,	AR089: 5, AR061: 3
						Glu-41 to Ser-53,	S0250: 4, L0745: 2,
						Arg-67 to Ser-72,	H0393: 1, H0587: 1,
						Asn-111 to Arg-122,	L0744: 1, L0748: 1,
						Gly-212 to Arg-218,	L0439: 1 and L0752: 1.
						Gln-229 to Ser-235,
						Arg-239 to Lys-244.
		676214	383	2-478	981	Ser-4 to Arg-9,
						Glu-41 to Ser-53,
						Arg-67 to Ser-72,
						Asn-111 to Arg-122.
57	HMSBZ24	1082367	67	2-718	665	Lys-79 to ASp-87,	AR061: 4, AR089: 2
						Lys-100 to Asp-106.	H0331: 1, S0002: 1,
							H0519: 1 and L0741: 1.
		678707	384	2-322	982
58	HWHHB69	1217042	68	3-2186	666	Thr-1 to Ser-10,	AR089: 1, AR061: 1
						Ala-73 to Tyr-80,	L0803: 3, S0354: 2,
						Arg-133 to Ser-143,	H0052: 2, H0617: 2,
						Gly-174 to His-179,	L0770: 2, L0646: 2,
						Ser-201 to Arg-224,	S0028: 2, L0753: 2,
						Asn-236 to Gly-241,	H0445: 2, H0556: 1,
						Tyr-260 to Cys-272,	S6024: 1, H0657: 1,
						Pro-274 to Thr-284,	S0418: 1, S0420: 1,
						Gln-292 to Glu-306,	H0351: 1, H0441: 1,
						Cys-409 to Arg-414,	H0586: 1, H0013: 1,
						Arg-424 to Arg-432,	S0280: 1, H0156: 1,
						Asp-523 to His-531,	L0021: 1, H0122: 1,
						Thr-552 to Pro-557,	S0010: 1, H0571: 1,
						Asn-601 to Pro-606,	L0163: 1, H0135: 1,
						His-612 to His-618,	H0412: 1, H0100: 1,
						Pro-678 to His-684,	L0351: 1, L0769: 1,
						Asn-698 to Gln-705.	L0639: 1, L0764: 1,
							L0649: 1, L0659: 1,
							L0809: 1, L0530: 1,
							H0520: 1, H0547: 1,
							H0519: 1, H0690: 1,
							H0539: 1, S0136: 1,
							H0696: 1, L0748: 1,
							L0747: 1, L0756: 1,
							L0779: 1, L0757: 1,
							S0434: 1, S0436: 1,
							S0011: 1 and H0136: 1.
		690442	385	1-261	983	Gly-1 to Ser-7.
59	HFXLC69	1162543	69	16-939	667	Gly-49 to Gly-60,	AR061: 1, AR089: 1
						Arg-84 to Cys-97,	H0052: 2, H0135: 2,
						Pro-100 to Gln-106,	S0282: 1, H0254: 1,
						Ala-113 to Ala-137,	H0051: 1, H0634: 1,
						Ala-145 to Trp-156,	S0152: 1, H0436: 1 and
						Ala-172 to Tyr-182,	H0677: 1.
						Asn-218 to Tyr-225.
		692773	386	3-230	984
60	HBXBW40	1156765	70	124-588	668	Ser-1 to Ser-12,	AR089: 16, AR061: 8
						Arg-33 to Arg-50,	S0038: 2, H0438: 1,
						Tyr-117 to Leu-125.	S0049: 1 and H0547: 1.
		706115	387	124-456	985	Gln-3 to Ser-12,
						Arg-33 to Arg-50,
						Ser-93 to Glu-98.
61	HCE1L51	1140498	71	3-434	669		AR089: 4, AR061: 3
							S0206: 2, H0052: 1,
							T0010: 1 and H0604: 1.
		715899	388	3-434	986
62	HRADM45	1148046	72	2-472	670	Lys-1 to Leu-6,	AR089: 14, AR061: 6
						Asp-25 to Pro-30.	H0555: 1 and L0777:
							1.
		717358	389	2-472	987	Lys-1 to Leu-6,
						Asp-25 to Pro-30.
63	HTEFO45	1153918	73	61-597	671	Leu-59 to Thr-82,	AR061: 6, AR089: 3
						Lys-89 to Gly-94,	L0758: 2, S0222: 1,
						Gln-155 to Val-161,	H0038: 1 and H0539: 1.
						Lys-169 to Ala-179.
		723446	390	3-482	988	Gln-6 to Lys-14,
						Leu-68 to Glu-90.
64	HOHBN82	1152271	74	2-1465	672	Asn-41 to Pro-50,	AR089: 1, AR061: 0
						Asp-60 to Glu-71,	S0002: 2, H0521: 2,
						Leu-121 to Pro-130,	S0360: 1, H0123: 1,
						Glu-139 to Thr-144,	S0250: 1, L0654: 1,
						Asp-155 to Ser-166,	S0152: 1, L0740: 1 and
						Gly-174 to Leu-187,	L0749: 1.
						Pro-194 to Pro-199,
						Arg-211 to Asp-228,
						Gly-256 to Phe-270,
						Asp-334 to Gly-344,
						Gly-356 to Val-373,
						Glu-398 to Met-403,
						Asn-418 to Leu-424,
						Glu-444 to Trp-451,
						Cys-465 to Tyr-474.
		724322	391	3-629	989	Asn-41 to Pro-50,
						Asp-60 to Glu-71,
						Leu-121 to Pro-130,
						Glu-139 to Thr-144,
						Asp-155 to Ser-166,
						Gly-174 to Asp-188.
65	HWHGF52	1217026	75	834-1	673	Lys-1 to Ala-6,	AR089: 1, AR061: 0
						Ser-38 to Gln-43,	L0776: 5, L0764: 4,
						Pro-88 to Ala-112,	L0743: 4, L0740: 3,
						Pro-141 to Asp-148,	L0750: 3, L0777: 3,
						Gly-186 to Thr-200,	L0731: 3, S0001: 2,
						Pro-231 to Ala-238,	H0438: 2, H0052: 2,
						Leu-248 to Ser-254.	H0194: 2, H0201: 2,
							L0526: 2, H0144: 2,
							L0742: 2, H0662: 1,
							H0619: 1, H0261: 1,
							H0392: 1, H0455: 1,
							H0586: 1, H0587: 1,
							H0574: 1, H0486: 1,
							H0013: 1, H0427: 1,
							S0010: 1, S0346: 1,
							T0110: 1, H0009: 1,
							L0157: 1, H0320: 1,
							H0051: 1, T0006: 1,
							H0604: 1, H0163: 1,
							H0646: 1, L0763: 1,
							L0638: 1, L0630: 1,
							L0646: 1, L0773: 1,
							L0651: 1, L0523: 1,
							L0805: 1, L0666: 1,
							L0663: 1, L0664: 1,
							H0547: 1, H0660: 1,
							S0404: 1, L0744: 1,
							L0439: 1, L0752: 1,
							S0434: 1 and L0595: 1.
		726102	392	1-453	990	Gln-1 to Lys-8,
						Gly-10 to Trp-17,
						Val-28 to Gly-43,
						Thr-54 to Glu-63.
66	HBKDI30	1223861	76	1115-321	674		AR089: 1, AR061: 0
							S0364: 3, S0366: 3,
							L0604: 3, H0624: 1,
							L0622: 1, L0623: 1,
							H0041: 1, L0791: 1,
							S0380: 1 and L0748: 1.
		729048	393	1-381	991	Gly-15 to Thr-21,
						Glu-76 to Lys-86.
67	HSQFR54	1185143	77	1-1170	675	Ser-116 to Asp-125,	AR061: 4, AR089: 2
						Glu-183 to Ser-188,	H0650: 2, H0052: 2,
						Arg-228 to Gln-234,	H0547: 2, H0542: 2,
						Leu-280 to Lys-303.	S0212: 1, S0222: 1,
							T0114: 1, L0483: 1,
							H0628: 1, L0455: 1,
							H0413: 1, S0344: 1,
							L0766: 1, L0775: 1,
							L0805: 1, L0665: 1,
							H0520: 1, H0519: 1,
							S0126: 1, H0521: 1,
							S0044: 1, S0390: 1,
							L0592: 1 and S0026: 1.
		730964	394	2-319	992	Glu-41 to Ser-46.
68	HAGBA56	1102593	78	1-735	676	Pro-2 to Gly-10.	AR061: 2, AR089: 1
							S0010: 1, H0135: 1,
							L0766: 1, L0745: 1,
							L0779: 1 and L0758: 1.
		732597	395	115-633	993	Asp-52 to Leu-57,
						Lys-82 to Thr-87,
						Ser-90 to Trp-98,
						Ser-118 to Leu-123.
69	HHSAE29	1220851	79	563-985	677	His-13 to Asn-24.	AR061: 2, AR089: 1
							S0282: 1 and S0051: 1.
		743166	396	2-325	994
70	HMSHO64	746582	80	1-411	678	Ser-11 to Ser-21,	AR089: 2, AR061: 2
						Ser-84 to Ala-89,	S0002: 2
						Pro-98 to Arg-107.
71	HFPBW22	1154786	81	762-376	679	Lys-1 to Ala-6,	AR061: 4, AR089: 2
						Ala-17 to Leu-25,	S0222: 1, S0280: 1,
						Arg-54 to Ala-59,	L0774: 1, L0376: 1 and
						Val-61 to Arg-66,	S0378: 1.
						Ser-90 to Gly-95.
		750631	397	224-619	995
72	HTLBH67	1224371	82	2886-2005	680	Lys-31 to Ala-48,	AR061: 2, AR089: 1
						Gln-51 to Thr-62,	L0752: 3, L0747: 2,
						Gln-105 to Ser-110,	H0294: 1, H0253: 1,
						Cys-126 to Leu-134,	H0046: 1, H0040: 1,
						Gln-137 to Gly-150,	H0063: 1, H0494: 1,
						His-174 to Ala-205,	S0352: 1, L0769: 1,
						Arg-212 to Pro-220,	L0766: 1, L0804: 1,
						Pro-227 to Gly-232,	L0805: 1, L0791: 1,
						Gly-245 to Ala-251,	H0521: 1, L0779: 1,
						Ala-257 to Ser-263,	L0780: 1, L0731: 1 and
						Leu-266 to His-283.	L0758: 1.
		751985	398	1-282	996
73	HNTMH70	1143523	83	2-679	681	Pro-1 to Glu-6,	AR089: 0, AR061: 0
						His-17 to Lys-22,	H0520: 1
						Pro-52 to Gln-58,
						Gly-123 to Arg-130,
						His-205 to Ala-210.
		757184	399	2-688	997	Pro-1 to Glu-6,
						His-17 to Lys-22,
						Pro-52 to Gln-58.
74	HCETC59	1183334	84	105-326	682		AR089: 1, AR061: 1
							H0052: 1 and H0194:
							1.
		761881	400	105-326	998
75	HE8UX76	1161223	85	2-1237	683	Asp-8 to Ala-13,	AR061: 1, AR089: 1
						Ala-26 to Arg-33,	H0539: 4, L0439: 4,
						Pro-38 to Ala-50,	L0438: 2, H0013: 1,
						Pro-60 to Asn-65,	L0758: 1 and L0592: 1.
						Asp-68 to Ser-74,
						Arg-109 to Arg-132,
						Asp-140 to Leu-145,
						Ala-149 to Ser-154,
						Ile-158 to Asp-169,
						Glu-171 to Ala-177,
						Cys-213 to Pro-218,
						Pro-226 to Lys-231,
						Thr-244 to Phe-249,
						Arg-361 to Ile-370.
		767871	401	214-798	999	Arg-39 to Arg-62,
						Asp-70 to Leu-75,
						Ala-79 to Ser-84,
						Ile-88 to Asp-99,
						Glu-101 to Ala-107.
76	HTLEN77	1136124	86	3-947	684	His-1 to Thr-6,	AR089: 33, AR061: 18
						Arg-30 to Thr-35,	L0748: 2 and H0253:
						Lys-40 to Ala-71,	1.
						Pro-209 to Glu-222,
						Arg-231 to Tyr-237,
						Pro-239 to Tyr-245,
						Arg-263 to Ala-271,
						Gln-290 to Trp-306.
		772363	402	90-422	1000	Ala-1 to Ala-35.
77	HBGDI80	1124695	87	2-523	685	Asp-44 to Ile-50,	AR061: 13, AR089: 5
						Arg-121 to Leu-132,	L0805: 2, H0436: 2,
						Lys-148 to Ser-160.	L0439: 2, L0362: 2,
							S0358: 1, L0483: 1,
							H0181: 1, S0422: 1,
							L0369: 1, L0804: 1,
							L0787: 1 and L0663: 1.
		781600	403	1-429	1001	Asp-13 to Ile-19,
						Pro-37 to Arg-42.
78	HELHB88	1225632	88	138-3230	686	Gln-1 to Thr-7,	AR061: 2, AR089: 2
						Glu-28 to Gln-35,	L0777: 3, L0794: 2,
						Lys-188 to Lys-207,	S0027: 2, L0748: 2,
						Ser-238 to Gly-245,	L0747: 2, L0601: 2,
						Asp-278 to Gly-283,	S0342: 1, S0212: 1,
						Pro-317 to Ser-324,	S0282: 1, L0004: 1,
						Ser-335 to Glu-342,	S0045: 1, H0581: 1,
						Pro-344 to Lys-355,	T0110: 1, L0471: 1,
						Glu-362 to Asn-373,	S6028: 1, H0551: 1,
						Glu-385 to Arg-393,	H0494: 1, H0509: 1,
						Arg-399 to Gln-417,	L0646: 1, L0665: 1,
						Lys-422 to Gln-457,	H0520: 1, H0547: 1,
						Glu-461 to Glu-477,	S0390: 1, L0591: 1,
						Leu-514 to Glu-529,	L0366: 1 and H0653: 1.
						Leu-538 to Met-548,
						Gln-562 to Gln-567,
						Asn-569 to Asp-574,
						Arg-594 to Gln-609,
						Asn-626 to Met-636,
						Ala-638 to Lys-649,
						Glu-654 to Gln-670,
						Gln-676 to Leu-716,
						Ser-736 to Gly-741,
						Phe-762 to Asp-768,
						Glu-808 to Val-815,
						Ser-847 to Trp-856,
						Asp-858 to Trp-876,
						Gln-892 to Ala-898,
						Pro-964 to Ile-976.
		811935	404	136-567	1002	Arg-1 to His-10.
79	HTEMV66	1152261	89	1-669	687	Ile-33 to Ser-40,	AR061: 5, AR089: 1
						Val-63 to Gln-69,	H0616: 1 and L0758:
						Phe-84 to Ser-94,	1.
						Lys-205 to Lys-212.
		813038	405	1-318	1003	Ser-38 to Pro-45.
80	HMTAJ73	1063989	90	704-3	688	Gly-5 to Gln-15,	AR061: 24, AR089: 14
						Gly-104 to Gly-111,	L0806: 3, L0772: 2,
						Gly-136 to Asp-141,	L0648: 2, H0255: 1,
						His-228 to Pro-234.	L0717: 1, H0586: 1,
							H0599: 1, H0618: 1,
							H0581: 1, H0052: 1,
							H0123: 1, L0629: 1,
							L0659: 1, L0663: 1,
							S0330: 1, H0518: 1 and
							H0555: 1.
		813296	406	1-438	1004	Pro-23 to Lys-28,
						Gln-39 to Thr-51,
						Lys-93 to Ala-106,
						Gln-112 to Pro-129,
						Pro-132 to Pro-143.
81	HE9TD31	815845	91	3-674	689	Ser-119 to Thr-127,	AR089: 0, AR061: 0
						Gln-134 to Ser-152.	S0354: 1, L0657: 1,
							H0144: 1 and S0330: 1.
82	HGBDG55	1141363	92	26-535	690	Gly-1 to Ala-8,	AR089: 1, AR061: 1
						Phe-31 to Leu-36,	S0040: 1, H0014: 1,
						Glu-54 to Lys-62,	H0030: 1, H0063: 1,
						Gly-69 to Gly-75,	L0803: 1, H0521: 1 and
						Leu-100 to Gly-106,	S0028: 1.
						Ser-125 to Lys-131.
		815858	407	26-400	1005	Gly-1 to Ala-8,
						Phe-31 to Leu-36,
						Glu-54 to Lys-62,
						Gly-69 to Gly-75,
						Leu-100 to Gly-106.
83	HOUHL51	1125914	93	2-508	691	Ala-12 to Trp-19,	AR061: 6, AR089: 2
						Ala-21 to Arg-27,	L0758: 6, L0794: 3,
						Glu-38 to Phe-49,	H0038: 2, L0768: 2,
						Arg-90 to Val-102,	L0790: 2, L0731: 2,
						Glu-144 to Gly-151,	S0342: 1, H0664: 1,
						Tyr-164 to Ala-169.	H0616: 1, S0210: 1,
							L0773: 1 and L0608: 1.
		815891	408	3-527	1006
84	HEOPP67	1020119	94	1-972	692	Asp-27 to Val-32,	AR061: 1, AR089: 0
						Asp-66 to Gly-71.	H0457: 2, H0650: 1
							and H0622: 1.
		827630	409	2-448	1007	Arg-8 to Arg-17,
						Asp-47 to Val-52,
						Asp-86 to Gly-91.
85	HKAOV71	1165423	95	1-732	693		AR089: 6, AR061: 2
							H0013: 2, H0046: 2,
							H0036: 1, H0590: 1,
							H0581: 1, H0551: 1 and
							H0494: 1.
		827679	410	1-732	1008
86	HDQID90	1137752	96	2-361	694	Leu-12 to Gln-21.	AR089: 7, AR061: 3
							L0766: 14, H0521: 4,
							L0748: 4, L0804: 3,
							L0776: 3, L0749: 3,
							L0731: 3, L0485: 3,
							S0376: 2, H0580: 2,
							L0483: 2, H0316: 2,
							S0002: 2, L0803: 2,
							L0775: 2, L0805: 2,
							L0659: 2, L0438: 2,
							H0265: 1, H0686: 1,
							H0656: 1, H0341: 1,
							S0212: 1, H0638: 1,
							H0125: 1, S0360: 1,
							H0411: 1, S0222: 1,
							H0409: 1, H0587: 1,
							H0014: 1, S0003: 1,
							H0163: 1, H0591: 1,
							H0488: 1, H0494: 1,
							H0641: 1, L0598: 1,
							H0529: 1, L0772: 1,
							L0764: 1, L0768: 1,
							L0774: 1, L0655: 1,
							L0783: 1, L0809: 1,
							L0792: 1, L0663: 1,
							L0665: 1, H0702: 1,
							H0519: 1, S0126: 1,
							H0682: 1, H0435: 1,
							H0672: 1, H0704: 1,
							S3012: 1, L0751: 1,
							L0750: 1, L0777: 1,
							L0752: 1, L0757: 1,
							L0758: 1, L0759: 1,
							L0362: 1, H0423: 1 and
							H0506: 1.
		831976	411	221-724	1009
87	HFRBN81	1182552	97	2331-598	695		AR050: 10, AR051: 3,
							AR061: 1, AR089: 1,
							AR054: 0
							S0028: 4, S0001: 2,
							S0278: 2, S0050: 2,
							S0282: 1, H0632: 1,
							H0271: 1, H0416: 1,
							H0027: 1, S0038: 1,
							S0052: 1, S0053: 1,
							H0684: 1 and S0044: 1.
		833061	412	1-1116	1010	Gly-113 to Gly-119,
						Gln-173 to Thr-181,
						Ala-362 to Pro-368.
		973206	413	1-435	1011
		973208	414	138-587	1012	Leu-51 to Ser-62.
88	HFKJW01	1187134	98	487-8	696		AR089: 1, AR061: 0
							H0620: 2, H0012: 1,
							S0152: 1 and S0260: 1.
		836491	415	3-440	1013
89	HSDFL63	1219300	99	2590-1844	697	Ser-83 to Lys-88,	AR061: 402, AR089:
						Pro-95 to Asn-112,	142
						Arg-180 to Asp-185,	H0038: 7, L0758: 5,
						Met-231 to Arg-240.	H0616: 4, L0731: 4,
							S0002: 3, L0637: 3,
							H0623: 2, L0794: 2,
							L0809: 2, L0663: 2,
							H0522: 2, L0779: 2,
							L0777: 2, S0046: 1,
							H0431: 1, T0060: 1,
							H0013: 1, S0010: 1,
							H0545: 1, H0050: 1,
							S0023: 1, S0003: 1,
							H0328: 1, H0135: 1,
							H0163: 1, H0412: 1,
							H0102: 1, H0100: 1,
							T0042: 1, L0768: 1,
							L0803: 1, L0375: 1,
							L0542: 1, L0647: 1,
							L0367: 1, L0791: 1,
							L0664: 1, H0693: 1,
							S0328: 1, S0168: 1,
							S0031: 1 and H0008: 1.
		836498	416	1-249	1014	Glu-1 to Asp-7,
						Met-53 to Met-60,
						Ile-78 to Ser-83.
90	HPJET90	836503	100	39-377	698	His-8 to Gly-18,	AR061: 0, AR089: 0
						Leu-40 to Ile-45,	S0152: 2
						Asn-100 to Asp-105.
91	HEMFC61	836514	101	1-714	699	Glu-4 to Ser-9,	AR061: 4, AR089: 3
						Ser-58 to Arg-65.	H0038: 7, L0758: 5,
							H0616: 4, L0731: 4,
							S0002: 3, L0637: 3,
							H0623: 2, L0794: 2,
							L0809: 2, L0663: 2,
							H0522: 2, L0779: 2,
							L0777: 2, S0046: 1,
							H0431: 1, T0060: 1,
							H0013: 1, S0010: 1,
							H0545: 1, H0050: 1,
							S0023: 1, S0003: 1,
							H0328: 1, H0135: 1,
							H0163: 1, H0412: 1,
							H0102: 1, H0100: 1,
							T0042: 1, L0768: 1,
							L0803: 1, L0375: 1,
							L0542: 1, L0647: 1,
							L0367: 1, L0791: 1,
							L0664: 1, H0693: 1,
							S0328: 1, S0168: 1,
							S0031: 1 and H0008: 1.
92	HDTBR50	1174351	102	467-234	700	Thr-26 to Arg-31,	AR089: 41, AR061: 4
						Gly-73 to Trp-78.	H0486: 2
		846630	417	130-342	1015	Ala-2 to Glu-7,
						Arg-50 to Glu-58.
93	HACCH94	847143	103	1-897	701	Gly-1 to Ser-6,	AR061: 4, AR089: 2
						Arg-76 to Gln-88,	L0754: 6, L0766: 3,
						Lys-113 to Ser-119,	L0731: 2, H0624: 1,
						Tyr-125 to Lys-132,	H0170: 1, S0116: 1,
						Ser-167 to Tyr-179,	S0280: 1, H0545: 1,
						Arg-263 to Tyr-281,	T0006: 1, S0344: 1,
						Ser-294 to Thr-299.	S0426: 1, L0770: 1,
							L0790: 1, L0748: 1,
							L0756: 1, L0779: 1,
							L0589: 1 and L0462: 1.
94	HE8T139	1223481	104	441-1166	702	Thr-21 to Trp-26,	AR061: 2, AR089: 2
						Thr-72 to Val-88,	L0438: 4, L0746: 4,
						Arg-115 to Tyr-127.	H0581: 2, H0656: 1,
							H0013: 1, L0471: 1,
							H0266: 1, H0328: 1,
							H0553: 1, S0438: 1,
							H0529: 1, L0766: 1,
							L0805: 1, H0520: 1,
							H0521: 1, L0752: 1 and
							S0192: 1.
		849161	418	3-470	1016	Ser-8 to Thr-15,
						Arg-73 to Thr-79,
						Phe-86 to Leu-92.
95	HEGAP32	1140393	105	525-1	703		AR061: 6, AR089: 3
							H0550: 1, H0494: 1
							and L0659: 1.
		851207	419	2-397	1017	Arg-1 to Thr-14.
96	HCWFU66	853005	106	3-311	704		AR061: 1, AR089: 1
							H0305: 1 and H0589:
							1.
97	HUSY129	853149	107	3-470	705	Gln-57 to Ile-67,	AR061: 5, AR089: 2
						Asp-77 to Asp-85.	H0650: 2, H0052: 2,
							H0547: 2, H0542: 2,
							S0212: 1, S0222: 1,
							T0114: 1, L0483: 1,
							H0628: 1, L0455: 1,
							H0413: 1, S0344: 1,
							L0766: 1, L0775: 1,
							L0805: 1, L0665: 1,
							H0520: 1, H0519: 1,
							S0126: 1, H0521: 1,
							S0044: 1, S0390: 1,
							L0592: 1 and S0026: 1.
98	HMEFT66	1134131	108	82-933	706	Gly-61 to Glu-67,	AR061: 1, AR089: 1
						Ala-88 to Gly-96,	H0175: 1, H0266: 1,
						Gly-127 to Trp-137.	H0292: 1, H0628: 1 and
							L0779: 1.
		856149	420	2-349	1018
99	HKAAR71	863023	109	54-977	707	Gln-1 to Gln-6,	AR061: 1, AR089: 0
						Ser-24 to Thr-31,	H0494: 2, H0693: 2,
						Pro-57 to Gln-63,	H0521: 2, H0580: 1,
						Ala-96 to Met-104,	H0253: 1, H0628: 1,
						Asn-124 to Lys-133,	H0522: 1 and H0422: 1.
						Ser-172 to Trp-182,
						Ser-186 to Glu-194,
						Pro-286 to Pro-294.
100	H7TBC95	865922	110	3-704	708	Gln-154 to Ser-163.	AR089: 1, AR061: 1
							S0198: 57, S0274: 12,
							S0252: 4, S0270: 3,
							S0264: 1, S0268: 1 and
							S0228: 1.
		908115	421	3-704	1019	Gln-154 to Ser-163.
101	HAPPX52	637493	111	827-1222	709	Ser-59 to Ile-66,	AR050: 16, AR054:
						Arg-73 to Gly-85.	10, AR051: 5, AR061:
							2, AR089: 1
							H0305: 4, S0282: 1,
							H0575: 1, H0150: 1 and
							H0617: 1.
		872075	422	3-359	1020
		872076	423	400-2	1021	His-73 to Phe-81,
						Thr-92 to Trp-102.
102	HBGSJ13	1152326	112	1-756	710	Lys-1 to Lys-6,	AR089: 1, AR061: 0
						Gln-25 to Asp-36,	H0617: 2, H0013: 1,
						Ser-85 to Ile-96,	H0271: 1, L0455: 1 and
						Val-115 to Ser-136,	H0539: 1.
						Lys-172 to Trp-177,
						Pro-188 to Phe-201,
						Gly-217 to Ala-224,
						Asn-230 to Gly-239.
		878322	424	1-684	1022
103	HFKLX38	880220	113	3-308	711		AR089: 1, AR061: 1
							H0620: 2
104	HTLGP15	1165362	114	196-786	712	Gly-2 to Thr-10,	AR089: 4, AR061: 3
						Glu-160 to Gly-175,	T0010: 3, S0049: 2,
						Thr-189 to Glu-197.	H0052: 2, L0415: 1,
							H0618: 1 and S0010: 1.
		880297	425	189-662	1023	Gly-2 to Thr-10,
						Glu-99 to Gly-104.
105	HMEGH46	1092158	115	2-547	713	Asp-13 to Asp-19,	AR054: 29, AR051:
						Lys-76 to Asp-84.	12, AR061: 6, AR089:
							3, AR050: 2
							H0196: 1 and H0266:
							1.
		887791	426	1-315	1024	Asp-13 to Asp-19,
						Lys-76 to Asn-83.
106	HE8PY29	1129488	116	2-277	714	Asp-28 to Ser-36,	AR061: 2, AR089: 1
						Glu-47 to Gln-60,	H0013: 1 and S0126: 1.
						Phe-68 to Gly-77,
						Pro-81 to Val-86.
		887862	427	2-277	1025	Asp-28 to Ser-36,
						Glu-47 to Gln-60,
						Phe-68 to Gly-77,
						Pro-81 to Val-86.
107	HTDAB17	890384	117	3-605	715	Asp-1 to Gly-14,	AR089: 1, AR061: 0	6p24-p23	125264,
						Ala-60 to Lys-71,	L0747: 28, L0588: 22,		134570,
						Gln-101 to Glu-118.	L0757: 19, H0251: 15,		600511,
							S0358: 14, S0045: 13,		601556
							L0731: 12, H0551: 10,
							H0412: 10, L0771: 10,
							L0748: 9, L0758: 9,
							H0506: 9, H0556: 8,
							S0046: 8, H0622: 8,
							H0013: 7, H0623: 7,
							L0662: 7, S0192: 7,
							S0003: 6, L0659: 6,
							L0666: 6, S0328: 6,
							L0439: 6, L0750: 6,
							L0759: 6, L0599: 6,
							L0608: 6, S0040: 5,
							S0360: 5, H0581: 5,
							H0529: 5, L0763: 5,
							L0764: 5, L0664: 5,
							H0144: 5, S0026: 5,
							S0212: 4, H0486: 4,
							H0674: 4, L0776: 4,
							S0126: 4, H0672: 4,
							S0136: 4, L0752: 4,
							H0624: 3, S0420: 3,
							H0599: 3, H0004: 3,
							H0266: 3, H0615: 3,
							H0031: 3, H0553: 3,
							H0591: 3, H0264: 3,
							H0413: 3, H0494: 3,
							S0210: 3, L0770: 3,
							L0806: 3, H0519: 3,
							H0435: 3, L0740: 3,
							L0751: 3, L0749: 3,
							H0170: 2, H0657: 2,
							H0656: 2, S0356: 2,
							S0408: 2, H0619: 2,
							H0393: 2, H0333: 2,
							T0040: 2, H0427: 2,
							S0280: 2, H0156: 2,
							H0318: 2, H0596: 2,
							T0110: 2, H0545: 2,
							H0046: 2, H0009: 2,
							H0050: 2, L0471: 2,
							H0188: 2, H0328: 2,
							H0428: 2, L0483: 2,
							H0644: 2, H0038: 2,
							S0426: 2, L0772: 2,
							L0646: 2, L0766: 2,
							L0649: 2, L0651: 2,
							L0655: 2, L0789: 2,
							L0663: 2, L0665: 2,
							L0352: 2, H0658: 2,
							S0152: 2, H0521: 2,
							H0696: 2, S0404: 2,
							H0555: 2, S0028: 2,
							H0445: 2, L0591: 2,
							L0594: 2, H0543: 2,
							H0422: 2, H0171: 1,
							H0265: 1, S6024: 1,
							H0295: 1, T0049: 1,
							S0134: 1, H0661: 1,
							H0663: 1, H0664: 1,
							S0418: 1, L0005: 1,
							S0354: 1, S0376: 1,
							S0468: 1, H0351: 1,
							S0220: 1, H0431: 1,
							H0392: 1, H0403: 1,
							H0592: 1, H0587: 1,
							H0642: 1, H0574: 1,
							H0485: 1, L0021: 1,
							H0575: 1, H0274: 1,
							S0346: 1, T0048: 1,
							S0049: 1, H0434: 1,
							H0230: 1, H0196: 1,
							H0052: 1, H0263: 1,
							H0597: 1, H0572: 1,
							H0012: 1, H0620: 1,
							T0003: 1, H0024: 1,
							H0057: 1, H0051: 1,
							H0083: 1, H0510: 1,
							H0687: 1, H0288: 1,
							S0022: 1, H0039: 1,
							H0030: 1, H0628: 1,
							H0166: 1, H0212: 1,
							H0135: 1, H0163: 1,
							H0090: 1, H0040: 1,
							H0634: 1, H0087: 1,
							H0477: 1, H0488: 1,
							H0433: 1, H0268: 1,
							H0269: 1, H0056: 1,
							S0038: 1, H0100: 1,
							H0429: 1, S0450: 1,
							H0132: 1, H0633: 1,
							S0472: 1, H0647: 1,
							H0646: 1, H0652: 1,
							S0344: 1, L0640: 1,
							L0371: 1, L0372: 1,
							L0374: 1, L0767: 1,
							L0768: 1, L0364: 1,
							L0794: 1, L0650: 1,
							L0375: 1, L0378: 1,
							L0606: 1, L0656: 1,
							L0783: 1, L0647: 1,
							S0374: 1, T0068: 1,
							L0438: 1, H0547: 1,
							H0689: 1, H0711: 1,
							H0684: 1, H0659: 1,
							H0670: 1, H0648: 1,
							S0330: 1, S0378: 1,
							S0380: 1, H0709: 1,
							S0146: 1, S3012: 1,
							S0037: 1, S0206: 1,
							L0742: 1, L0744: 1,
							L0755: 1, H0707: 1,
							S0434: 1, S0436: 1,
							L0584: 1, L0593: 1,
							L0362: 1, S0011: 1,
							S0424: 1 and H0293: 1.
108	HCFCF47	1199931	118	1-780	716	Arg-8 to Glu-15,	AR089: 14, AR061: 7
						Gln-49 to Ala-58,	H0341: 1 and H0422:
						Gly-175 to Gly-182,	1.
						Arg-184 to Leu-191,
						Pro-198 to Phe-205.
		894415	428	2-298	1026	Arg-1 to Glu-8.
109	HDQHB19	1194798	119	2-709	717	Arg-1 to Thr-7,	AR061: 3, AR089: 3
						Pro-19 to Ala-25,	L0759: 12, L0439: 11,
						Pro-56 to Leu-64,	L0766: 7, L0775: 5,
						His-72 to Asn-81,	H0521: 5, L0755: 5,
						Phe-184 to Pro-192,	L0748: 4, L0756: 4,
						Pro-218 to Val-226,	L0777: 4, L0731: 4,
						Ser-229 to Arg-236.	L0581: 4, L0619: 3,
							L0666: 3, L0779: 3,
							L0757: 3, L0588: 3,
							S0418: 2, L0618: 2,
							H0580: 2, L0055: 2,
							L0769: 2, L0773: 2,
							L0774: 2, L0791: 2,
							L0747: 2, L0750: 2,
							H0265: 1, H0663: 1,
							S0356: 1, H0208: 1,
							H0370: 1, H0108: 1,
							H0575: 1, H0618: 1,
							H0544: 1, H0545: 1,
							S0050: 1, H0510: 1,
							H0286: 1, H0031: 1,
							H0644: 1, H0068: 1,
							H0135: 1, L0564: 1,
							H0494: 1, L0475: 1,
							H0396: 1, S0144: 1,
							S0002: 1, S0426: 1,
							L0763: 1, L0761: 1,
							L0642: 1, L0764: 1,
							L0662: 1, L0768: 1,
							L0806: 1, L0661: 1,
							L0659: 1, L0367: 1,
							L0663: 1, H0519: 1,
							H0435: 1, H0658: 1,
							S3014: 1, L0751: 1,
							L0749: 1, L0603: 1,
							H0665: 1 and H0542: 1.
		895106	429	2-538	1027	Pro-14 to Ala-20,
						Pro-51 to Leu-59,
						His-67 to Thr-77.
110	HAGDN53	1129154	120	3-329	718	Gln-22 to Lys-30,	AR050: 17, AR051:
						Phe-40 to Tyr-49,	11, AR054: 2, AR089:
						Gln-70 to Trp-75,	1, AR061: 0
						Arg-80 to Gln-87,	S0010: 1 and S0027: 1.
						Gly-95 to Arg-101.
		895963	430	129-428	1028	Pro-9 to Gln-16,
						Phe-31 to Tyr-40,
						Gln-61 to Trp-66,
						Arg-71 to Gln-78,
						Gly-86 to Arg-92.
111	HUFDB74	1162672	121	2-562	719	Gln-43 to Thr-58,	AR061: 1, AR089: 1
						Asn-74 to His-79,	H0575: 2, L0754: 2,
						Gly-109 to Trp-114,	H0599: 1, T0048: 1,
						Asp-136 to Phe-145.	L0163: 1, H0051: 1,
							H0188: 1, H0379: 1,
							L0438: 1, H0670: 1,
							H0672: 1, L0439: 1,
							L0747: 1, S0260: 1,
							L0591: 1 and H0506: 1.
		901451	431	2-412	1029	Gln-43 to Thr-58,
						Asn-74 to His-79,
						Gly-109 to Trp-114.
112	HNHFH24	1092567	122	28-516	720	His-8 to Gly-18,	AR054: 20, AR050:
						Ala-39 to Gly-45,	15, AR061: 7, AR089:
						Pro-94 to Glu-101,	4, AR051: 1
						Pro-134 to Gly-142.	S0053: 1
		903741	432	28-480	1030	His-8 to Gly-18,
						Ala-39 to Gly-45,
						Pro-94 to Glu-101.
113	HBGQT03	1188175	123	11-790	721	Glu-1 to Ala-12,	AR061: 6, AR089: 3
						Glu-19 to Val-28,	H0617: 10, L0665: 4,
						Glu-34 to Thr-45,	H0333: 3, S0366: 3,
						Leu-140 to Asp-157,	L0759: 3, H0599: 2,
						Thr-167 to Ala-198,	L0648: 2, L0653: 2,
						Ala-211 to Asp-216.	L0664: 2, H0519: 2,
							H0686: 1, H0484: 1,
							H0664: 1, H0392: 1,
							L0622: 1, S0280: 1,
							H0545: 1, T0010: 1,
							H0424: 1, H0031: 1,
							H0181: 1, H0708: 1,
							H0494: 1, H0633: 1,
							L0371: 1, L0764: 1,
							L0773: 1, L0768: 1,
							L0375: 1, L0651: 1,
							L0659: 1, L0783: 1,
							L0789: 1, L0438: 1,
							H0684: 1, H0670: 1,
							L0744: 1, L0780: 1,
							L0755: 1 and L0595: 1.
		908173	433	3-791	1031	Lys-1 to Ala-15,
						Glu-22 to Val-31,
						Glu-37 to Thr-48,
						Leu-143 to Asp-160,
						Thr-170 to Ala-201,
						Ala-214 to Asp-219.
114	HETLF29	1103959	124	3-482	722	Asp-119 to Tyr-124.	AR061: 4, AR089: 2
							H0046: 1 and L0758:
							1.
		909762	434	3-416	1032
115	HOUGD29	1204931	125	199-1821	723	Arg-9 to Gln-17,	AR061: 6, AR089: 5
						Ile-33 to Asn-39,	L0770: 4, L0789: 3,
						Gln-93 to Ser-104,	L0439: 3, L0750: 3,
						Asp-141 to Leu-155,	L0641: 2, L0747: 2,
						Ser-224 to Asn-234,	L0758: 2, S0040: 1,
						Asn-243 to Lys-248,	H0575: 1, T0010: 1,
						Ser-308 to Gln-320,	H0087: 1, S0422: 1,
						Thr-350 to Glu-357,	L0803: 1, L0375: 1,
						Ser-384 to Thr-390,	L0776: 1, L0659: 1,
						Asp-435 to Ser-447,	L0783: 1, H0144: 1,
						Ala-480 to Lys-487,	L0352: 1, H0684: 1,
						Lys-496 to Leu-508,	H0660: 1, S0027: 1,
						Ser-519 to Val-528,	L0777: 1 and H0445: 1.
						Ser-533 to Gln-541.
		909797	435	199-909	1033	Arg-9 to Leu-15.
116	HTEMV09	1128254	126	1-711	724	Asp-22 to Asp-28,	AR089: 13, AR061: 13
						Leu-98 to Trp-103,	L0666: 3, L0758: 3,
						Glu-123 to Trp-154,	H0616: 2, L0779: 2,
						Pro-158 to Gln-178,	S0036: 1, L0598: 1,
						Pro-180 to Met-189,	L0766: 1, L0651: 1,
						Glu-207 to Lys-226,	L0806: 1, L0776: 1,
						Ser-231 to Leu-237.	H0144: 1, H0547: 1,
							H0672: 1 and H0555: 1.
		909843	436	1-711	1034	Asp-22 to Asp-28,
						Leu-98 to Trp-103,
						Glu-123 to Trp-154.
117	HNTNB14	1128964	127	3-614	725	Phe-2 to Gln-9,	AR089: 1, AR061: 1
						Arg-22 to Val-29,	S0007: 1, S0222: 1,
						Glu-51 to Leu-64,	S0049: 1, L0438: 1,
						Tyr-73 to Ile-83,	H0520: 1 and L0439: 1.
						Glu-98 to Thr-104,
						Ala-119 to Asp-126,
						Arg-155 to Ser-161.
		909942	437	2-658	1035	Ala-2 to Gln-9,
						Arg-22 to Val-29,
						Glu-51 to Leu-64.
118	HE2KZ07	1149808	128	708-166	726		AR061: 9, AR089: 4
							H0624: 1
		909948	438	2-796	1036	Leu-10 to Gly-16,
						Pro-37 to Glu-45,
						Glu-78 to Cys-87.
119	HSIGN57	1105444	129	3-974	727	Val-10 to Gly-16,	AR061: 2, AR089: 1
						Met-19 to Val-34,	H0229: 1, H0590: 1,
						Ala-84 to Asp-90,	S0049: 1, H0014: 1,
						Met-107 to Trp-120,	H0560: 1, L0439: 1 and
						Gln-191 to Ala-201,	H0543: 1.
						Glu-223 to Val-229,
						Asn-309 to Gly-314.
		910078	439	2-760	1037	Val-10 to Gly-16,
						Met-19 to Val-34.
120	HLHBC30	1106654	130	39-512	728	Gln-7 to Glu-17,	AR061: 8, AR089: 5
						Thr-36 to Asn-42,	L0456: 3, H0024: 2
						Val-44 to Phe-49,	and L0747: 1.
						Tyr-76 to Ile-85,
						Cys-94 to Glu-99,
						Pro-105 to Ser-110.
		910079	440	39-512	1038	Gln-7 to Glu-17.
121	HFBDJ13	1195217	131	172-1368	729	Ser-45 to Glu-53,	S0007: 2, L0794: 2,
						Ile-78 to Asn-94,	S0434: 2, S0354: 1,
						Leu-99 to Ser-104,	N0006: 1, H0622: 1 and
						Ser-110 to Trp-128,	H0478: 1.
						Tyr-145 to Gly-153,
						Gln-168 to Trp-173,
						Leu-196 to Ala-205.
		911264	441	3-410	1039	Ser-6 to Trp-24.
122	HTPGG25	1217208	132	786-1628	730	Glu-29 to Arg-35,	AR061: 2, AR089: 2
						Arg-50 to Leu-55,	L0439: 6, L0777: 6,
						Leu-60 to Ser-69,	H0052: 4, L0748: 4,
						Lys-102 to Asp-108,	H0634: 3, L0662: 3,
						Pro-227 to Glu-233,	L0805: 3, L0659: 3,
						Leu-249 to Glu-261.	L0438: 3, H0547: 3,
							L0750: 3, L0758: 3,
							H0208: 2, H0123: 2,
							H0014: 2, H0617: 2,
							H0135: 2, L0769: 2,
							L0766: 2, L0803: 2,
							L0776: 2, L0666: 2,
							L0751: 2, L0745: 2,
							L0731: 2, H0265: 1,
							S0408: 1, H0549: 1,
							H0497: 1, L0622: 1,
							H0581: 1, H0194: 1,
							L0738: 1, H0546: 1,
							H0024: 1, S0362: 1,
							L0163: 1, T0010: 1,
							H0083: 1, H0510: 1,
							H0266: 1, H0428: 1,
							H0622: 1, H0673: 1,
							H0598: 1, S0036: 1,
							H0163: 1, H0413: 1,
							L0370: 1, T0041: 1,
							H0647: 1, L0637: 1,
							L0667: 1, L0772: 1,
							L0646: 1, L0800: 1,
							L0764: 1, L0649: 1,
							L0657: 1, L0809: 1,
							L0788: 1, L0663: 1,
							S0374: 1, H0520: 1,
							H0670: 1, H0666: 1,
							S0330: 1, H0539: 1,
							H0521: 1, H0696: 1,
							H0478: 1, S0028: 1,
							L0741: 1, L0747: 1,
							L0749: 1, L0780: 1,
							L0752: 1 and H0543: 1.
		911282	442	3-392	1040	Pro-3 to Arg-8.
123	HSSMT34	911294	133	56-553	731	Glu-29 to Arg-35,	AR061: 4, AR089: 3
						Arg-50 to Leu-55,	L0439: 6, L0777: 6,
						Leu-60 to Ser-69,	H0052: 4, L0748: 4,
						Lys-102 to Asp-108,	H0634: 3, L0662: 3,
						Pro-133 to Gln-141.	L0805: 3, L0659: 3,
							L0438: 3, H0547: 3,
							L0750: 3, L0758: 3,
							H0208: 2, H0123: 2,
							H0014: 2, H0617: 2,
							H0135: 2, L0769: 2,
							L0766: 2, L0803: 2,
							L0776: 2, L0666: 2,
							L0751: 2, L0745: 2,
							L0731: 2, H0265: 1,
							S0408: 1, H0549: 1,
							H0497: 1, L0622: 1,
							H0581: 1, H0194: 1,
							L0738: 1, H0546: 1,
							H0024: 1, S0362: 1,
							L0163: 1, T0010: 1,
							H0083: 1, H0510: 1,
							H0266: 1, H0428: 1,
							H0622: 1, H0673: 1,
							H0598: 1, S0036: 1,
							H0163: 1, H0413: 1,
							L0370: 1, T0041: 1,
							H0647: 1, L0637: 1,
							L0667: 1, L0772: 1,
							L0646: 1, L0800: 1,
							L0764: 1, L0649: 1,
							L0657: 1, L0809: 1,
							L0788: 1, L0663: 1,
							S0374: 1, H0520: 1,
							H0670: 1, H0666: 1,
							S0330: 1, H0539: 1,
							H0521: 1, H0696: 1,
							H0478: 1, S0028: 1,
							L0741: 1, L0747: 1,
							L0749: 1, L0780: 1,
							L0752: 1 and H0543: 1.
124	HWWDN34	1152430	134	2-1012	732	Ser-15 to Leu-21,	AR089: 1, AR061: 1
						Pro-24 to Val-30,	S0354: 16, H0457: 7,
						Ser-91 to Lys-99,	L0758: 3, H0555: 2,
						Thr-113 to Lys-120,	H0170: 1, H0657: 1,
						Pro-168 to Gln-174,	H0255: 1, H0662: 1,
						Glu-226 to Ser-231,	S0360: 1, H0036: 1,
						Ser-296 to Gln-307,	H0150: 1, H0051: 1,
						Asp-319 to Gly-328,	H0553: 1, L0800: 1,
						Gly-330 to Ala-337.	L0644: 1, L0771: 1,
							L0803: 1, L0787: 1,
							L0663: 1, H0144: 1,
							S0374: 1, H0670: 1,
							H0522: 1, L0749: 1,
							S0452: 1 and H0506: 1.
		911357	443	2-1000	1041	Ser-11 to Leu-17,
						Pro-20 to Val-26,
						Ser-87 to Lys-95,
						Thr-109 to Lys-116,
						Pro-164 to Gln-170,
						Glu-222 to Ser-227,
						Ser-292 to Gln-303,
						Asp-315 to Gly-324,
						Gly-326 to Ala-333.
125	HCEPW85	911374	135	3-314	733	Thr-2 to Gln-7.	H0052: 1 and L0471:
							1.
126	HMTAW83	1071602	136	1-363	734	Ile-26 to Trp-33,	AR089: 0, AR061: 0
						Glu-52 to Leu-71.	H0583: 1, H0644: 1,
							L0766: 1 and H0518: 1.
		911385	444	1-363	1042	Ile-26 to Trp-33,
						Glu-52 to Leu-71.
127	HDMAV01	1194697	137	1-657	735	Pro-1 to Glu-15,	AR089: 2, AR061: 2
						Ala-26 to Lys-32,	L0766: 5, L0776: 5,
						Glu-46 to Leu-65,	L0754: 4, H0013: 3,
						Arg-82 to Cys-94,	S0126: 3, L0742: 3,
						Leu-101 to Glu-107,	L0750: 3, H0624: 2,
						Leu-146 to Asp-151,	S0360: 2, H0560: 2,
						Gln-157 to Ser-162,	L0769: 2, L0641: 2,
						Ser-165 to Ala-187,	L0665: 2, S0330: 2,
						Phe-210 to Leu-217.	L0756: 2, L0731: 2,
							L0759: 2, L0588: 2,
							H0171: 1, H0650: 1,
							H0402: 1, H0638: 1,
							H0340: 1, H0637: 1,
							H0351: 1, S0222: 1,
							H0581: 1, H0263: 1,
							H0545: 1, H0050: 1,
							S0051: 1, S0214: 1,
							H0039: 1, L0055: 1,
							H0090: 1, H0412: 1,
							H0022: 1, H0359: 1,
							H0561: 1, H0641: 1,
							L0770: 1, L0637: 1,
							L0646: 1, L0764: 1,
							L0773: 1, L0662: 1,
							L0768: 1, L0651: 1,
							L0653: 1, L0659: 1,
							L0792: 1, H0519: 1,
							H0522: 1, H0576: 1,
							S0028: 1, L0439: 1,
							L0740: 1, L0749: 1,
							L0777: 1, H0444: 1,
							L0596: 1, L0601: 1,
							H0542: 1 and H0543: 1.
		911386	445	3-428	1043	Asp-1 to Glu-11,
						Ala-22 to Lys-28,
						Glu-42 to Leu-61,
						Arg-78 to Cys-90,
						Leu-97 to Glu-103.
128	HDPSR74	911396	138	212-583	736	Leu-31 to Ser-39,	AR050: 48, AR054:
						Val-57 to Trp-63,	42, AR051: 35, AR089:
						Pro-103 to Gln-111,	3, AR061: 1
						Leu-118 to Leu-124.	H0575: 2, H0580: 1,
							S0002: 1, S0426: 1,
							H0521: 1, H0436: 1 and
							L0748: 1.
129	HHEZT58	1160657	139	1212-937	737	Pro-4 to His-21,	AR089: 8, AR061: 3
						Glu-35 to Gln-43.	L0794: 3, L0758: 2,
							L0759: 2, H0624: 1,
							L0717: 1, T0082: 1,
							H0581: 1, H0553: 1,
							H0038: 1, T0067: 1,
							L0665: 1, H0436: 1,
							L0439: 1, L0745: 1 and
							H0543: 1.
		911416	446	1-558	1044	Glu-9 to Lys-14,
						Gln-51 to Gln-57.
130	HTLDU05	911649	140	2-469	738	Pro-89 to Ala-97.	AR061: 8, AR089: 7	9q31	109400,
							H0253: 3, H0618: 1		132800,
							and L0758: 1.		132800,
									186855,
									223900,
									253800,
									253800,
									278700,
									602088
131	HTLET56	1189721	141	144-1211	739	Ser-54 to Lys-61,	AR061: 6, AR089: 5
						Pro-118 to Lys-128,	H0253: 18, H0618: 7,
						Pro-233 to Val-244,	L0794: 3, H0038: 1,
						Leu-262 to Ser-270,	H0616: 1, L0788: 1 and
						Ser-322 to Gly-344,	L0758: 1.
						Pro-347 to Ser-353.
		911654	447	95-826	1045	Ser-54 to Lys-61,
						Pro-118 to Lys-128,
						Thr-208 to Ser-213,
						Ser-218 to Ala-227,
						Pro-230 to Ser-236,
						Pro-238 to Ser-244.
132	HTLCA95	911655	142	38-1096	740		AR061: 373, AR089:
							188
							H0253: 3, H0618: 2,
							H0038: 2, H0616: 1 and
							L0758: 1.
133	HTEJT86	1090517	143	1-1119	741	Ala-39 to Ala-45,	AR089: 1, AR061: 1
						Gln-57 to Ser-63,	L0794: 3, H0038: 2,
						Tyr-90 to Lys-95,	H0265: 1, S0358: 1,
						Leu-113 to Ile-119.	T0039: 1, H0616: 1,
							L0768: 1, L0804: 1,
							L0664: 1, L0777: 1,
							L0731: 1, L0758: 1 and
							L0465: 1.
		911656	448	1-411	1046	Ala-39 to Ala-45,
						Gln-57 to Ser-63,
						Tyr-90 to Lys-95.
134	HTEMA54	1134919	144	22-1359	742	Gly-23 to Asn-30,	AR089: 19, AR061: 13
						Thr-58 to Val-79,	H0618: 14, H0253: 12,
						Arg-101 to Ile-106,	H0038: 11, H0616: 2,
						Thr-117 to Glu-126,	L0794: 1, L0779: 1 and
						Pro-184 to Lys-193,	L0758: 1.
						Ile-298 to Val-303,
						Phe-381 to Leu-389.
		911666	449	22-1167	1047	Gly-23 to Asn-30,
						Arg-45 to Lys-50.
135	HTLGJ17	1135518	145	216-587	743	Gly-35 to Ser-44.	AR089: 18, AR061: 5
							H0618: 5, H0549: 1
							and H0543: 1.
		915136	450	93-464	1048	Val-6 to Arg-12.
136	HOUES64	918119	146	3-317	744	Pro-89 to Leu-102.	AR061: 1, AR089: 0
							S0040: 1 and S0278: 1.
137	HMSCD15	982250	147	507-1	745	Asp-16 to Gln-22,	AR089: 1, AR061: 1
						Val-44 to Ser-57.	S0002: 2 and L0766: 1.
		918133	451	237-635	1049
138	HDQDX20	1223474	148	228-1715	746	Met-7 to Ser-12,	AR089: 30, AR061: 4
						Ser-20 to Arg-30,	H0521: 3, H0051: 2,
						Asp-85 to Ala-92,	L0756: 2, H0590: 1,
						Met-119 to Asn-146,	S0250: 1, L0772: 1,
						Pro-151 to Asp-161,	H0522: 1, S0406: 1 and
						Gln-253 to Glu-260,	L0748: 1.
						Ile-333 to Val-342,
						Leu-396 to Ala-406.
		919027	452	210-1037	1050	Met-7 to Ser-12,
						Ser-20 to Arg-30,
						Asp-85 to Ala-92,
						Met-119 to Asn-146,
						Pro-151 to Asp-161.
139	HLTHP86	1110457	149	3-1352	747	His-35 to Glu-44,	AR089: 1, AR061: 1
						Lys-88 to Tyr-94,	L0439: 3, L0438: 2,
						Asp-140 to Ser-152,	S0028: 2, H0656: 1,
						Leu-166 to Lys-171,	H0645: 1, H0369: 1,
						Glu-183 to Glu-197,	S0222: 1, S0346: 1,
						Glu-210 to Leu-217,	H0328: 1, H0029: 1,
						Pro-231 to Gln-236.	H0644: 1, H0169: 1,
							H0591: 1, H0646: 1,
							H0520: 1, H0539: 1,
							L0746: 1 and L0366: 1.
		919354	453	3-1310	1051
140	HMSOL52	1182715	150	1146-832	748	Ser-1 to Gly-12,	AR061: 5, AR089: 2
						Arg-30 to Pro-36,	L0770: 4, L0803: 4,
						Thr-65 to Met-76,	H0638: 1, H0123: 1,
						Pro-86 to Asp-95.	S0426: 1, L0662: 1,
							H0648: 1, L0747: 1,
							L0756: 1, L0779: 1,
							L0752: 1 and L0759: 1.
		921126	454	90-473	1052	Glu-29 to Gly-35,
						Arg-53 to Pro-59,
						Thr-88 to Met-99,
						Pro-109 to Asp-118.
141	HAHGD33	1219819	151	3-1745	749	Gly-59 to Ser-68,	AR061: 7, AR089: 5
						Ala-87 to Glu-98,	H0039: 5, H0622: 5,
						Pro-106 to Asn-121,	L0748: 4, H0667: 4,
						Ser-148 to Lys-159,	H0255: 3, S0126: 3,
						Phe-207 to Ala-222,	H0393: 2, S0278: 2,
						Cys-279 to Asn-285,	H0599: 2, H0618: 2,
						Gly-322 to Pro-330,	H0318: 2, H0123: 2,
						Glu-357 to Ala-364,	H0050: 2, H0179: 2,
						Ile-402 to Asp-407,	H0271: 2, S0036: 2,
						Pro-456 to Val-466,	H0135: 2, H0634: 2,
						Ser-474 to Thr-487.	H0087: 2, H0100: 2,
							H0633: 2, S0210: 2,
							S0002: 2, H0144: 2,
							L0438: 2, L0602: 2,
							L0744: 2, L0731: 2,
							L0595: 2, L0601: 2,
							H0665: 2, H0542: 2,
							H0556: 1, H0222: 1,
							H0294: 1, H0583: 1,
							H0650: 1, H0657: 1,
							H0484: 1, H0306: 1,
							S0418: 1, S0420: 1,
							S0354: 1, H0580: 1,
							S0007: 1, S0046: 1,
							H0619: 1, H0550: 1,
							H0392: 1, H0586: 1,
							H0333: 1, H0486: 1,
							H0122: 1, H0196: 1,
							H0597: 1, H0544: 1,
							H0009: 1, H0172: 1,
							L0471: 1, H0023: 1,
							H0071: 1, H0266: 1,
							H0290: 1, H0553: 1,
							H0628: 1, H0551: 1,
							H0056: 1, H0623: 1,
							S0038: 1, H0494: 1,
							H0625: 1, H0561: 1,
							H0386: 1, H0509: 1,
							H0131: 1, H0130: 1,
							H0646: 1, S0144: 1,
							S0426: 1, H0529: 1,
							L0565: 1, H0547: 1,
							H0689: 1, H0435: 1,
							H0670: 1, S0330: 1,
							H0521: 1, S0027: 1,
							S0028: 1, S0032: 1,
							L0439: 1, L0747: 1,
							L0759: 1, S0260: 1,
							H0445: 1, L0597: 1,
							L0604: 1, L0593: 1,
							L0366: 1, H0668: 1,
							S0242: 1 and H0422: 1.
		921782	455	1-1020	1053	Phe-22 to Ala-37,
						Cys-94 to Asn-100,
						Gly-137 to Pro-145,
						Glu-172 to Ala-179,
						Ile-217 to Asp-222.
142	HHEHC53	921783	152	3-908	750	Gly-59 to Ser-68,	AR089: 3, AR061: 2	19p
						Ala-87 to Glu-98,	L0748: 8, H0039: 5,
						Pro-106 to Asn-121,	H0622: 5, L0664: 5,
						Ser-148 to Lys-159,	L0439: 5, L0779: 5,
						Phe-207 to Ala-222,	L0731: 5, L0758: 5,
						Ile-284 to Lys-289.	L0665: 4, L0744: 4,
							L0601: 4, H0667: 4,
							H0255: 3, H0618: 3,
							L0666: 3, L0438: 3,
							S0126: 3, L0602: 3,
							L0742: 3, L0604: 3,
							L0595: 3, H0542: 3,
							H0265: 2, S0358: 2,
							H0393: 2, S0278: 2,
							H0550: 2, H0333: 2,
							H0599: 2, H0318: 2,
							H0545: 2, H0123: 2,
							H0050: 2, H0620: 2,
							H0179: 2, H0271: 2,
							S0036: 2, H0135: 2,
							H0634: 2, H0087: 2,
							H0100: 2, H0633: 2,
							S0210: 2, S0002: 2,
							L0769: 2, L0646: 2,
							L0768: 2, L0774: 2,
							H0144: 2, L0565: 2,
							H0689: 2, S0027: 2,
							L0747: 2, L0755: 2,
							L0593: 2, H0665: 2,
							H0556: 1, T0002: 1,
							H0222: 1, H0685: 1,
							H0294: 1, S0430: 1,
							H0583: 1, H0650: 1,
							H0657: 1, S0212: 1,
							S0282: 1, H0484: 1,
							H0306: 1, S0418: 1,
							S0420: 1, S0354: 1,
							S0360: 1, H0580: 1,
							S0007: 1, S0046: 1,
							H0619: 1, H0351: 1,
							H0549: 1, H0392: 1,
							H0586: 1, H0486: 1,
							T0060: 1, L0022: 1,
							H0122: 1, H0196: 1,
							H0597: 1, H0544: 1,
							H0009: 1, H0172: 1,
							L0471: 1, H0023: 1,
							H0071: 1, H0266: 1,
							H0290: 1, S0022: 1,
							H0030: 1, H0553: 1,
							H0628: 1, H0182: 1,
							H0617: 1, H0606: 1,
							H0551: 1, H0413: 1,
							H0056: 1, H0623: 1,
							S0038: 1, H0494: 1,
							H0625: 1, H0561: 1,
							H0386: 1, H0509: 1,
							H0131: 1, H0130: 1,
							H0646: 1, S0144: 1,
							S0344: 1, S0426: 1,
							H0529: 1, L0763: 1,
							L0770: 1, L0637: 1,
							L0372: 1, L0662: 1,
							L0775: 1, L0776: 1,
							L0659: 1, L0383: 1,
							L0790: 1, H0547: 1,
							H0435: 1, H0658: 1,
							H0670: 1, S0330: 1,
							H0521: 1, H0436: 1,
							S0390: 1, S0028: 1,
							S0032: 1, L0750: 1,
							L0753: 1, L0757: 1,
							L0759: 1, S0260: 1,
							H0445: 1, H0595: 1,
							L0597: 1, L0366: 1,
							H0668: 1, S0242: 1,
							H0423: 1, H0422: 1 and
							H0352: 1.
143	HE2PB01	1206665	153	695-1228	751	Arg-1 to Asn-12,	AR061: 9, AR089: 6
						Leu-87 to Gln-92,	L0754: 6, H0318: 3,
						Phe-111 to Ser-117,	H0486: 2, H0013: 2,
						Arg-161 to Gly-168.	H0014: 2, L0439: 2,
							L0777: 2, H0543: 2,
							H0171: 1, H0556: 1,
							S6024: 1, H0583: 1,
							H0650: 1, H0638: 1,
							S0354: 1, H0580: 1,
							H0619: 1, H0455: 1,
							H0009: 1, S0003: 1,
							L0483: 1, S0036: 1,
							H0591: 1, H0494: 1,
							S0014: 1, S0450: 1,
							L0520: 1, L0763: 1,
							L0769: 1, L0641: 1,
							L0521: 1, L0662: 1,
							L0803: 1, L0774: 1,
							L0776: 1, L0783: 1,
							L0663: 1, H0144: 1,
							H0520: 1, H0547: 1,
							H0519: 1, S0136: 1,
							H0521: 1, H0522: 1,
							H0478: 1, L0742: 1,
							L0780: 1, L0592: 1,
							S0011: 1, S0192: 1,
							S0424: 1 and H0506: 1.
		921850	456	2-691	1054	Glu-1 to Gly-7,
						Gln-43 to Arg-50,
						Asp-60 to Gly-67,
						Phe-150 to Glu-156,
						Arg-176 to Lys-181.
144	HOUDP52	1219522	154	3-1361	752	Lys-54 to Arg-60.	AR061: 2, AR089: 1
							L0794: 7, L0743: 2,
							H0543: 2, S0040: 1,
							S0134: 1, S0356: 1,
							T0082: 1, H0251: 1,
							H0494: 1, H0625: 1,
							H0649: 1, L0806: 1,
							L0657: 1, L0565: 1,
							L0758: 1, L0608: 1 and
							S0026: 1.
		922102	457	196-1104	1055
145	HHGAE47	1127881	155	2-517	753	Gly-1 to Arg-19,	AR061: 3, AR089: 2
						Asp-27 to Glu-34,	L0769: 5, L0774: 5,
						Asp-40 to Lys-46,	L0756: 4, H0624: 2,
						Pro-63 to Arg-70,	S0358: 2, S0444: 2,
						Lys-97 to Lys-103,	S0408: 2, H0587: 2,
						Asp-113 to Gly-118,	L0764: 2, L0766: 2,
						Ala-148 to Tyr-158.	L0775: 2, L0601: 2,
							H0170: 1, S0442: 1,
							S0410: 1, H0497: 1,
							H0333: 1, H0632: 1,
							H0156: 1, L0022: 1,
							L0738: 1, H0271: 1,
							H0039: 1, S0344: 1,
							L0637: 1, L0772: 1,
							L0646: 1, L0773: 1,
							L0662: 1, L0518: 1,
							L0783: 1, L0791: 1,
							L0663: 1, S0374: 1,
							H0593: 1, H0660: 1,
							H0648: 1, H0672: 1,
							H0696: 1, L0749: 1,
							L0750: 1, L0779: 1,
							L0752: 1, L0755: 1,
							L0599: 1 and H0667: 1.
		922194	458	3-503	1056	Gly-25 to Arg-45,
						Asp-53 to Glu-60,
						Asp-66 to Lys-72,
						Arg-89 to Trp-106,
						Asn-121 to Gly-147,
						Val-152 to Gly-159,
						Ala-161 to Ser-166.
146	HMCGL45	1165349	156	89-922	754	Glu-8 to Pro-16,	AR061: 8, AR089: 5
						Gln-21 to Glu-26,	L0769: 5, L0774: 5,
						Gly-105 to Arg-125,	L0756: 4, H0624: 2,
						Asp-133 to Glu-140,	S0358: 2, S0444: 2,
						Asp-146 to Lys-152,	S0408: 2, H0587: 2,
						Pro-169 to Arg-176,	L0764: 2, L0766: 2,
						Lys-203 to Lys-209,	L0775: 2, L0601: 2,
						Asp-219 to Gly-224,	H0170: 1, S0442: 1,
						Ala-254 to Tyr-264.	S0410: 1, H0497: 1,
							H0333: 1, H0632: 1,
							H0156: 1, L0022: 1,
							L0738: 1, H0271: 1,
							H0039: 1, S0344: 1,
							L0637: 1, L0772: 1,
							L0646: 1, L0773: 1,
							L0662: 1, L0518: 1,
							L0783: 1, L0791: 1,
							L0663: 1, S0374: 1,
							H0593: 1, H0660: 1,
							H0648: 1, H0672: 1,
							H0696: 1, L0749: 1,
							L0750: 1, L0779: 1,
							L0752: 1, L0755: 1,
							L0599: 1 and H0667: 1.
		922195	459	442-885	1057	Gln-1 to Glu-10,
						Asp-16 to Lys-22,
						Pro-39 to Arg-46,
						Lys-73 to Lys-79,
						Asp-89 to Gly-94,
						Ala-124 to Tyr-134.
147	HELEF11	1153884	157	1310-501	755	Ser-29 to Val-36,	AR061: 1, AR089: 1
						Leu-217 to Ser-222,	S0045: 1 and H0457: 1.
						Lys-255 to Ile-262.
		926930	460	53-625	1058	Phe-21 to Lys-27.
148	HETJX04	1212235	158	3-704	756	Asp-11 to Val-21,	AR089: 4, AR061: 2
						Pro-27 to Thr-43,	H0046: 1, H0032: 1,
						Trp-92 to Lys-97,	H0040: 1 and L0565: 1.
						Pro-136 to Gly-149,
						Met-182 to Val-193,
						Thr-197 to Asn-203.
		927120	461	3-704	1059	Asp-11 to Val-21,
						Pro-27 to Thr-43,
						Trp-92 to Lys-97,
						Pro-136 to Gly-149,
						Met-182 to Val-193,
						Thr-197 to Asn-203.
149	HSOBC04	1165357	159	3-395	757	Asn-61 to Glu-70,	AR061: 5, AR089: 2
						Ser-80 to Arg-85,	L0747: 14, H0551: 9,
						Pro-88 to Ile-96,	H0617: 7, S0022: 6,
						Gln-101 to Gly-109,	H0135: 6, S3014: 6,
						Lys-117 to His-128.	L0750: 6, L0757: 6,
							L0759: 6, H0545: 5,
							S0126: 5, H0124: 4,
							H0529: 4, L0769: 4,
							L0764: 4, L0665: 4,
							H0547: 4, S3012: 4,
							L0740: 4, L0731: 4,
							H0624: 3, H0294: 3,
							L0717: 3, H0251: 3,
							H0024: 3, S0250: 3,
							H0100: 3, L0375: 3,
							L0651: 3, L0758: 3,
							H0170: 2, S0040: 2,
							H0583: 2, H0550: 2,
							H0333: 2, H0041: 2,
							H0012: 2, H0620: 2,
							H0284: 2, H0553: 2,
							H0606: 2, H0130: 2,
							L0641: 2, L0662: 2,
							L0650: 2, L0783: 2,
							L0666: 2, L0664: 2,
							L0744: 2, L0439: 2,
							L0751: 2, L0755: 2,
							H0667: 2, S0418: 1,
							S0354: 1, S0222: 1,
							H0441: 1, H0370: 1,
							T0109: 1, H0156: 1,
							H0318: 1, H0544: 1,
							H0546: 1, H0123: 1,
							L0471: 1, T0003: 1,
							H0014: 1, T0010: 1,
							H0266: 1, S0312: 1,
							H0428: 1, H0048: 1,
							H0413: 1, H0059: 1,
							H0560: 1, S0150: 1,
							H0633: 1, S0210: 1,
							L0770: 1, L0639: 1,
							L0772: 1, L0773: 1,
							L0768: 1, L0649: 1,
							L0775: 1, L0653: 1,
							L0776: 1, L0657: 1,
							L0656: 1, L0659: 1,
							L0526: 1, L0384: 1,
							L0809: 1, T0068: 1,
							H0593: 1, H0689: 1,
							H0435: 1, H0660: 1,
							S0330: 1, H0539: 1,
							S0152: 1, L0743: 1,
							L0777: 1, H0595: 1,
							L0591: 1, L0601: 1,
							S0192: 1, S0242: 1,
							S0194: 1, S0196: 1 and
							H0352: 1.
		927280	462	2-388	1060	Asn-59 to Glu-67.
150	HE8PW83	1069980	160	1-546	758	Glu-69 to Gln-76.	AR089: 0, AR061: 0
							L0748: 6, L0749: 6,
							L0803: 3, L0774: 3,
							L0775: 3, H0574: 1,
							H0632: 1, H0013: 1,
							L0789: 1, L0790: 1,
							H0144: 1 and L0581: 1.
		927532	463	1-546	1061	Glu-69 to Gln-76.
151	HWLEA48	927676	161	100-408	759	Pro-1 toThr-8.	AR089: 1, AR061: 0
							S0354: 1 and L0596: 1.
152	HNHNP81	1129143	162	143-514	760	Ile-1 to Ser-16.	AR051: 23, AR054:
							11, AR050: 9, AR061:
							8, AR089: 5
							S0216: 1
		928378	464	143-514	1062	Ile-1 to Ser-16.
153	HFIDL68	1123641	163	1161-535	761	Pro-18 to Pro-27,	AR089: 7, AR061: 4,
						Glu-67 to Lys-73,	AR050: 2, AR054: 2,
						Phe-147 to Tyr-165,	AR051: 1
						Thr-203 to Ser-209.	S0192: 1
		928475	465	2-529	1063	Glu-40 to Lys-46,
						Phe-120 to Ser-132.
154	HUJCT05	1165261	164	2-1618	762	Gly-1 to Glu-7,	AR089: 8, AR061: 4
						Lys-16 to Leu-21,	H0653: 2, H0650: 1,
						Ser-26 to Val-31,	H0050: 1, L0370: 1,
						Asp-64 to Thr-70,	L0800: 1, L0662: 1,
						Asp-131 to Asn-136,	L0653: 1, H0436: 1 and
						Lys-191 to Asp-197,	L0749: 1.
						Ala-259 to Glu-264,
						Glu-273 to Gly-279,
						Gln-296 to Ala-305,
						Asn-317 to Ser-322,
						Asn-345 to Ser-352,
						Gln-384 to Asn-392,
						Asn-407 to Gly-412,
						Gly-434 to Pro-441,
						Lys-476 to Asp-481,
						Gln-497 to Asn-507,
						His-523 to Asn-528.
		929264	466	2-520	1064	Lys-10 to Leu-15,
						Ser-20 to Val-25,
						Asp-58 to Thr-64,
						Asp-125 to Asn-130.
155	HTEGO05	932583	165	3-884	763	Pro-12 to Tyr-21.	AR089: 1, AR061: 0
							H0038: 2, L0745: 2
							and H0616: 1.
156	HRDBH58	1226719	166	183-2591	764	Asp-35 to Leu-41,	AR089: 1, AR061: 0
						Val-45 to Ser-57,	H0620: 3, L0794: 3,
						Glu-134 to Asp-139,	S0212: 2, H0254: 2,
						Pro-253 to Leu-259,	H0545: 2, H0266: 2,
						Ser-301 to Gly-306,	L0639: 2, L0759: 2,
						Leu-324 to Arg-330,	H0556: 1, H0657: 1,
						Val-374 to Tyr-381,	S0418: 1, H0580: 1,
						Gly-422 to Gly-427,	S0045: 1, H0619: 1,
						Gly-466 to Gly-481,	H0550: 1, H0600: 1,
						Lys-500 to Asp-505,	H0590: 1, H0253: 1,
						Pro-540 to Asn-554,	H0581: 1, H0052: 1,
						Arg-610 to Ala-616,	H0309: 1, H0085: 1,
						Pro-773 to Ala-780.	H0083: 1, H0628: 1,
							H0617: 1, H0124: 1,
							H0059: 1, H0494: 1,
							S0144: 1, S0142: 1,
							S0426: 1, H0529: 1,
							L0796: 1, L0659: 1,
							L0790: 1, H0519: 1,
							H0711: 1, S0328: 1,
							H0521: 1, H0522: 1,
							S3014: 1, L0758: 1,
							S0260: 1, H0343: 1,
							S0434: 1, L0601: 1,
							H0668: 1 and H0542: 1.
		933364	467	455-2239	1065
157	HSDGW22	934467	167	124-324	765	Leu-49 toTyr-54.	AR061: 0, AR089: 0
							L0794: 4, L0438: 4,
							L0761: 3, L0766: 3,
							L0748: 3, L0439: 3,
							H0556: 2, L0602: 2,
							L0754: 2, L0779: 2,
							H0580: 1, H0208: 1,
							H0013: 1, T0082: 1,
							S0010: 1, H0428: 1,
							H0553: 1, H0038: 1,
							H0616: 1, H0494: 1,
							L0796: 1, L0800: 1,
							L0773: 1, L0533: 1,
							L0803: 1, L0776: 1,
							L0657: 1, L0791: 1,
							H0520: 1, H0519: 1,
							H0521: 1, H0187: 1,
							L0731: 1, S0031: 1 and
							L0366: 1.
158	HNTMD79	1126594	168	1-663	766	Thr-1 to Gly-11,	AR089: 2, AR061: 2
						Thr-26 to Gly-34.	H0519: 2, S0420: 1,
							T0114: 1, H0013: 1,
							S0346: 1, H0038: 1,
							S0142: 1, H0520: 1,
							H0521: 1 and H0136: 1.
		934522	468	182-586	1066
159	HCE5J51	1197900	169	2-703	767	Arg-20 to Ala-25,	AR061: 4, AR089: 2
						Asp-56 to Val-62,	H0052: 7, L0809: 4,
						Gln-88 to Ala-93,	H0663: 3, L0439: 3,
						Thr-126 to Ala-132,	L0752: 3, H0587: 2,
						Gln-142 to Asn-160,	L0565: 2, H0550: 1,
						Ser-189 to Asn-196.	H0194: 1, H0562: 1,
							H0571: 1, L0435: 1,
							L0769: 1, L0787: 1 and
							L0755: 1.
		934524	469	227-781	1067	Pro-15 to Cys-22.
160	HHEFQ42	1151482	170	3-947	768	Val-57 to Tyr-65,	AR089: 8, AR061: 3
						Asp-73 to Lys-81,	L0803: 6, L0759: 6,
						Arg-118 to Arg-123,	L0740: 4, S0410: 3,
						Asp-140 to Leu-147,	L0764: 3, L0766: 3,
						Pro-151 to Thr-156,	L0804: 3, H0144: 3,
						Ala-163 to Glu-168,	S0406: 3, L0731: 3,
						Pro-177 to Thr-187,	L0362: 3, S0358: 2,
						Asp-220 to Thr-229,	S0444: 2, H0596: 2,
						Thr-283 to Thr-289.	H0644: 2, H0124: 2,
							L0770: 2, L0663: 2,
							H0539: 2, L0747: 2,
							L0750: 2, L0779: 2,
							L0757: 2, L0758: 2,
							H0624: 1, H0171: 1,
							H0639: 1, L0717: 1,
							H0411: 1, S0222: 1,
							H0441: 1, H0431: 1,
							H0574: 1, H0013: 1,
							H0156: 1, H0085: 1,
							L0471: 1, T0023: 1,
							H0163: 1, H0130: 1,
							L0762: 1, L0763: 1,
							L0662: 1, L0794: 1,
							L0775: 1, L0375: 1,
							L0805: 1, L0659: 1,
							L0783: 1, L0666: 1,
							S0374: 1, H0520: 1,
							H0658: 1, H0672: 1,
							S0330: 1, L0743: 1,
							L0751: 1, L0777: 1 and
							H0542: 1.
		934527	470	29-1072	1068
161	HLQDC55	1082368	171	2-499	769	Gly-19 to Ile-27,	AR061: 9, AR089: 3
						Thr-31 to Asp-41,	H0574: 1 and S0344: 1.
						Asp-58 to Phe-67,
						Ser-79 to Lys-85,
						Leu-119 to Glu-127.
		934528	471	1-444	1069	Gly-19 to Ile-27,
						Thr-31 to Asp-41,
						Asp-58 to Phe-67,
						Ser-79 to Lys-85,
						Leu-119 to Glu-127.
162	HFPHI62	1195825	172	1-1119	770	Ala-5 to Gly-13,	AR061: 226, AR089:
						Pro-31 to Gln-37,	79
						Ala-46 to Ala-69,	L0439: 8, H0052: 7,
						Tyr-81 to Ser-87,	L0741: 7, L0756: 4,
						Ser-120 to Ile-137,	S0010: 3, H0261: 2,
						Thr-148 to Thr-156,	H0156: 2, S0049: 2,
						Lys-181 to Phe-191,	L0770: 2, L0776: 2,
						Pro-275 to Asn-297,	L0742: 2, L0745: 2,
						Asp-322 to Gly-331,	L0366: 2, S0222: 1,
						Lys-352 to Glu-359,	H0438: 1, H0390: 1,
						Gln-365 to Ser-372.	S0346: 1, H0009: 1,
							L0455: 1, S0038: 1,
							L0789: 1 and L0758: 1.
		934529	472	3-410	1070	Met-1 to Gln-6,
						Pro-38 to Asn-60.
163	HE8QH09	1152238	173	1-597	771	Ala-46 to Ser-53,	AR089: 3, AR061: 3
						Pro-63 to Leu-78,	H0261: 1, H0013: 1,
						Asp-106 to Asp-114,	H0052: 1, H0009: 1,
						Glu-129 to Leu-136,	H0144: 1 and L0438: 1.
						Gly-144 to Asp-149.
		934532	473	2-625	1071	Gly-4 to Thr-9.
164	HFAAX29	1128791	174	1-585	772	Ala-108 to His-113,	AR089: 12, AR061: 4
						Asp-149 to Asn-154,	H0242: 2, S0040: 1,
						Cys-179 to Val-186.	S6024: 1, S6014: 1,
							H0586: 1, H0013: 1,
							H0124: 1, L0756: 1,
							L0592: 1, L0366: 1 and
							H0542: 1.
		934540	474	2-565	1072
165	HHFOC79	1182276	175	157-681	773	Ala-1 to Trp-9,	AR051: 14, AR089: 6,
						Pro-12 to Gln-17,	AR061: 4, AR050: 2,
						Arg-37 to Pro-42,	AR054: 2
						Thr-44 to Lys-51,	L0744: 9, L0747: 8,
						Pro-66 to Pro-80,	S3014: 7, L0740: 7,
						Thr-97 to Ala-106,	S0192: 6, S0027: 5,
						Pro-120 to Trp-128,	S0212: 4, H0124: 4,
						Leu-131 to Gly-137.	L0731: 4, L0662: 3,
							L0743: 3, L0752: 3,
							L0759: 3, H0662: 2,
							S0418: 2, S0046: 2,
							H0575: 2, H0545: 2,
							H0041: 2, H0413: 2,
							L0775: 2, H0696: 2,
							S0037: 2, L0748: 2,
							L0751: 2, L0754: 2,
							L0749: 2, L0758: 2,
							H0445: 2, S0276: 2,
							H0624: 1, L0778: 1,
							L0005: 1, H0645: 1,
							H0441: 1, H0391: 1,
							S0005: 1, T0040: 1,
							H0069: 1, H0427: 1,
							S0280: 1, H0042: 1,
							T0048: 1, H0505: 1,
							H0309: 1, H0544: 1,
							H0009: 1, H0266: 1,
							H0617: 1, H0412: 1,
							H0623: 1, T0004: 1,
							L0564: 1, T0041: 1,
							H0494: 1, H0633: 1,
							H0646: 1, H0652: 1,
							L0769: 1, L0646: 1,
							L0655: 1, L0659: 1,
							L0546: 1, L0783: 1,
							L0809: 1, H0144: 1,
							L0565: 1, S0126: 1,
							H0689: 1, H0435: 1,
							H0659: 1, H0672: 1,
							S0378: 1, H0555: 1,
							S0206: 1, L0777: 1,
							L0780: 1, S0434: 1,
							S0011: 1, S0194: 1 and
							H0506: 1.
		935406	475	3-443	1073	Glu-6 to Glu-15,
						Thr-21 to Asp-28,
						Ser-42 to Lys-47.
166	HOGEQ43	1223485	176	1-2970	774	Gly-1 to Trp-10,	AR089: 1, AR061: 0
						Glu-12 to Thr-48,	H0457: 8, L0766: 7,
						Phe-94 to Gly-99,	L0599: 6, H0677: 6,
						Tyr-105 to Ser-119,	L0438: 5, L0779: 5,
						Thr-136 to Ala-147,	H0012: 3, L0809: 3,
						Ser-165 to Ala-171,	H0656: 2, H0620: 2,
						Glu-222 to Trp-227,	L0771: 2, H0435: 2,
						His-233 to Trp-238,	H0436: 2, L0748: 2,
						Glu-251 to Glu-258,	L0439: 2, L0751: 2,
						Asn-265 to Ser-270,	L0749: 2, S0134: 1,
						Gln-305 to Trp-310,	H0645: 1, H0587: 1,
						Asn-325 to Phe-335,	H0635: 1, H0581: 1,
						Ser-341 to Glu-349,	H0546: 1, H0477: 1,
						Lys-378 to Trp-383,	H0560: 1, H0641: 1,
						Ala-390 to Gly-398,	S0422: 1, H0529: 1,
						Asn-451 to Trp-458,	L0521: 1, L0662: 1,
						Met-476 to Trp-486,	L0794: 1, L0774: 1,
						Gln-497 to Gly-505,	L0775: 1, L0606: 1,
						Arg-567 to Glu-573,	L0659: 1, L0647: 1,
						Gln-610 to Phe-618,	L0789: 1, L0791: 1,
						Glu-687 to Arg-697,	L0792: 1, L0666: 1,
						Gly-732 to Glu-742,	L0663: 1, L0665: 1,
						Thr-797 to Asp-802,	H0702: 1, H0547: 1,
						Arg-818 to Thr-827,	H0576: 1, S0028: 1,
						Ile-840 to Lys-849,	L0756: 1, L0777: 1,
						Ala-853 to Gly-860,	L0755: 1, L0758: 1,
						Pro-879 to Tyr-886,	H0543: 1 and H0506: 1.
						Ser-893 to Ile-901,
						Thr-904 to Phe-911,
						Asp-931 to Pro-937,
						Arg-952 to Thr-962.
		935465	476	1-150	1074	Glu-1 to Thr-13.
167	HCECQ23	938398	177	810-289	775	Pro-26 to Tyr-31.	AR089: 1, AR061: 0
							L0769: 3, H0052: 2,
							L0439: 2, H0572: 1,
							H0015: 1, L0438: 1 and
							L0741: 1.
168	HTGAU79	1178621	178	52-966	776	His-12 to Arg-20,	AR061: 7, AR089: 4
						Pro-26 to Asp-43,	H0551: 3, H0529: 3,
						Ala-62 to Glu-70,	L0769: 3, L0758: 3,
						Arg-78 to Arg-83,	S0418: 2, L0770: 2,
						Phe-100 to Gln-105,	L0773: 2, L0521: 2,
						Gly-129 to Glu-136,	H0701: 2, S0126: 2,
						Met-182 to Ile-187,	L0747: 2, L0731: 2,
						Tyr-277 to Ala-284.	L0759: 2, L0589: 2,
							L0601: 2, H0624: 1,
							H0149: 1, H0556: 1,
							H0295: 1, S0134: 1,
							H0583: 1, H0661: 1,
							H0592: 1, H0013: 1,
							H0635: 1, H0581: 1,
							S0250: 1, H0212: 1,
							H0412: 1, S0144: 1,
							L0763: 1, L0645: 1,
							L0764: 1, L0794: 1,
							L0766: 1, L0775: 1,
							L0783: 1, L0665: 1,
							H0519: 1, H0435: 1,
							H0672: 1, H0436: 1,
							S3014: 1, S0028: 1,
							L0750: 1, L0777: 1,
							L0366: 1, H0667: 1 and
							H0423: 1.
		940369	477	63-977	1075	His-12 to Arg-20,
						Pro-26 to Asp-43,
						Ala-62 to Glu-70,
						Arg-78 to Arg-83,
						Phe-100 to Gln-105,
						Gly-129 to Glu-136.
169	HE9FI33	1156432	179	2-286	777	Glu-65 to Pro-70.	AR061: 6, AR089: 2
							L0749: 2, H0144: 1
							and L0748: 1.
		941348	478	3-434	1076
170	HNHCP79	565781	180	23-301	778	Gly-16 to Asn-21.	AR051: 9, AR054: 9,
							AR050: 7, AR061: 3,
							AR089: 2
							H0271: 26, H0521: 26,
							H0046: 20, L0747: 20,
							S0278: 14, S0052: 14,
							L0754: 12, L0599: 12,
							S0142: 11, S0428: 11,
							H0179: 10, S0344: 10,
							L0776: 9, H0638: 8,
							L0771: 8, L0666: 8,
							S0360: 7, S0144: 7,
							L0775: 7, L0659: 7,
							H0422: 7, S0354: 6,
							H0580: 6, H0622: 6,
							H0641: 6, H0522: 6,
							L0740: 6, L0595: 6,
							H0581: 5, H0416: 5,
							H0673: 5, L0598: 5,
							L0774: 5, S3014: 5,
							L0777: 5, L0759: 5,
							L0362: 5, H0423: 5,
							H0069: 4, H0674: 4,
							L0770: 4, L0769: 4,
							L0750: 4, L0752: 4,
							L0731: 4, L0757: 4,
							L0603: 4, S0114: 3,
							S0134: 3, S0116: 3,
							H0341: 3, S0418: 3,
							S0358: 3, H0545: 3,
							H0050: 3, H0646: 3,
							L0768: 3, L0664: 3,
							S0053: 3, S0216: 3,
							S0374: 3, S0404: 3,
							S0206: 3, L0745: 3,
							L0756: 3, L0581: 3,
							H0170: 2, H0222: 2,
							L0785: 2, H0663: 2,
							S0376: 2, S0132: 2,
							S0222: 2, H0370: 2,
							H0486: 2, H0013: 2,
							H0635: 2, S0280: 2,
							H0575: 2, H0036: 2,
							H0618: 2, H0597: 2,
							H0014: 2, H0039: 2,
							L0142: 2, H0551: 2,
							H0056: 2, H0561: 2,
							S0426: 2, L0763: 2,
							L0761: 2, L0648: 2,
							L0662: 2, L0767: 2,
							L0655: 2, L0519: 2,
							L0665: 2, H0519: 2,
							H0435: 2, H0696: 2,
							S0027: 2, L0743: 2,
							L0751: 2, S0031: 2,
							S0260: 2, H0445: 2,
							S0434: 2, L0590: 2,
							S0276: 2, H0395: 1,
							H0556: 1, T0002: 1,
							H0685: 1, S0040: 1,
							H0294: 1, S0218: 1,
							S0001: 1, H0484: 1,
							H0483: 1, H0662: 1,
							H0176: 1, H0589: 1,
							H0459: 1, S0356: 1,
							S0408: 1, S0410: 1,
							L0717: 1, H0411: 1,
							H0549: 1, H0550: 1,
							H0431: 1, H0608: 1,
							H0409: 1, H0404: 1,
							H0587: 1, H0485: 1,
							H0250: 1, L0021: 1,
							H0590: 1, H0318: 1,
							T0071: 1, H0421: 1,
							H0263: 1, H0596: 1,
							H0150: 1, H0009: 1,
							L0471: 1, H0011: 1,
							S0051: 1, H0083: 1,
							H0510: 1, H0594: 1,
							S0318: 1, H0687: 1,
							H0286: 1, S0250: 1,
							H0328: 1, H0553: 1,
							L0055: 1, H0032: 1,
							H0169: 1, H0316: 1,
							H0135: 1, H0090: 1,
							H0591: 1, H0634: 1,
							H0413: 1, H0623: 1,
							H0059: 1, T0069: 1,
							S0038: 1, H0100: 1,
							T0041: 1, H0509: 1,
							S0150: 1, H0633: 1,
							S0002: 1, H0529: 1,
							L0762: 1, L0667: 1,
							L0772: 1, L0646: 1,
							L0643: 1, L0521: 1,
							L0766: 1, L0389: 1,
							L0653: 1, L0629: 1,
							L0527: 1, L0657: 1,
							L0517: 1, L0384: 1,
							L0809: 1, L0663: 1,
							H0144: 1, H0697: 1,
							S0126: 1, H0690: 1,
							H0670: 1, H0648: 1,
							S0378: 1, S0380: 1,
							H0518: 1, S0152: 1,
							S0013: 1, S0044: 1,
							H0214: 1, H0555: 1,
							H0436: 1, H0478: 1,
							S0432: 1, S3012: 1,
							S0032: 1, L0744: 1,
							L0439: 1, L0779: 1,
							L0758: 1, S0308: 1,
							S0436: 1, L0591: 1,
							L0593: 1, S0011: 1,
							H0543: 1 and S0458: 1.
		775293	479	138-275	1077
		941862	480	2-748	1078
171	HTLIY52	1194806	181	164-1351	779	Pro-3 to Gly-8,	AR061: 0, AR089: 0
						Val-21 to Gly-30,	H0618: 64, H0253: 52,
						Gly-68 to Ala-85,	L0758: 6, L0779: 2,
						His-94 to Gly-99,	H0392: 1, H0038: 1,
						Ala-105 to Arg-110,	L0761: 1, L0803: 1,
						Ala-114 to Gln-138,	L0806: 1 and L0697: 1.
						Arg-143 to Glu-155,
						Leu-202 to Arg-222,
						Arg-287 to Ser-292,
						Pro-325 to Arg-332,
						Arg-337 to Gly-351,
						Val-388 to Lys-396.
		942161	481	1-1368	1079
172	HRAED74	942527	182	289-651	780	His-9 to Ile-15.	AR061: 1, AR089: 1
							S0222: 3, H0052: 3,
							L0361: 3, H0179: 2,
							L0769: 2, H0521: 2,
							H0555: 2, L0779: 2,
							L0758: 2, H0663: 1,
							H0549: 1, S0220: 1,
							H0586: 1, H0156: 1,
							S0010: 1, H0596: 1,
							S0051: 1, T0010: 1,
							H0271: 1, L0143: 1,
							H0617: 1, H0652: 1,
							L0764: 1, L0794: 1,
							L0806: 1, L0809: 1,
							H0518: 1, H0478: 1,
							L0751: 1, L0747: 1,
							L0750: 1, L0780: 1,
							L0731: 1 and L0366: 1.
173	HFKKN77	943757	183	145-684	781	Thr-9 to Val-16.	AR061: 6, AR089: 2
							H0620: 2, H0024: 2,
							H0208: 1, S0222: 1,
							H0194: 1, H0123: 1,
							H0051: 1 and S0052: 1.
174	HTEMU66	1205381	184	462-962	782	His-3 to Ser-14,	AR061: 7, AR089: 5
						Thr-20 to Ser-27,	H0616: 1
						Pro-41 to Asn-50,
						Glu-101 to Asp-109,
						Leu-149 to Ser-154.
		944419	482	454-963	1080	Ala-1 to Gln-7,
						Lys-24 to Ser-30,
						Pro-44 to Asn-53,
						Glu-104 to Asp-112,
						Leu-152 to Ser-157.
175	HWAGU62	1206797	185	210-1511	783	Thr-1 to Leu-9,	AR061: 5, AR089: 5
						Pro-34 to Lys-40,	S0356: 9, L0803: 3,
						Glu-82 to Gln-87,	L0766: 2, L0743: 2,
						Ala-216 to His-233,	L0731: 2, L0785: 1,
						Met-235 to His-243,	S0116: 1, S0354: 1,
						Pro-322 to Lys-327,	S0358: 1, S0278: 1,
						Arg-346 to Trp-351.	H0642: 1, H0486: 1,
							H0581: 1, H0596: 1,
							H0355: 1, S0003: 1,
							L0455: 1, H0090: 1,
							H0591: 1, S0142: 1,
							S0344: 1, S0422: 1,
							S0426: 1, L0598: 1,
							L0794: 1, L0804: 1,
							L0659: 1, L0789: 1,
							L0664: 1, H0547: 1,
							H0660: 1, S0330: 1,
							L0754: 1, L0779: 1,
							L0758: 1, L0608: 1,
							S0026: 1 and H0543: 1.
		945368	483	1-1500	1081	Pro-100 to Lys-106,
						Glu-148 to Gln-153.
176	HFPFB39	1198036	186	93-1643	784	Glu-62 to Tyr-67,	AR061: 6, AR089: 3
						Pro-169 to Lys-179,	S0010: 4, S0222: 3,
						Pro-189 to Ala-201,	H0455: 2, L0803: 2,
						Ala-218 to Arg-223,	L0439: 2, L0745: 2,
						Tyr-324 to Asn-331,	S0282: 1, S0400: 1,
						Gly-352 to Val-357,	H0456: 1, H0441: 1,
						Leu-365 to Lys-371,	S0346: 1, H0509: 1,
						His-393 to Ala-399,	L0769: 1, L0438: 1,
						Asp-420 to Asn-425,	L0756: 1 and S0106: 1.
						Thr-460 to Lys-473,
						Ser-488 to Gly-502.
		946170	484	1613-462	1082	Pro-36 to Lys-46,
						Pro-56 to Ala-68,
						Ala-85 to Arg-90,
						Tyr-191 to Asn-198,
						Gly-219 to Val-224,
						Leu-232 to Lys-238,
						His-260 to Ala-266.
177	HPMFI38	1165993	187	3-410	785	Pro-128 to Ser-134.	AR061: 3, AR089: 2
							L0754: 3, H0644: 2,
							L0803: 2, L0748: 2,
							H0620: 1, H0031: 1,
							L0774: 1 and L0789: 1.
		946252	485	992-495	1083	Leu-143 to Thr-149,
						Gln-152 to Glu-157.
178	HBXDJ07	946830	188	125-652	786	Glu-62 to Lys-68,	AR061: 2, AR089: 2
						Asn-105 to Gly-113.	L0439: 11, L0794: 5,
							L0666: 5, S0222: 4,
							H0052: 3, L0756: 3,
							H0624: 2, S6028: 2,
							S0038: 2, L0638: 2,
							L0805: 2, L0664: 2,
							L0438: 2, L0740: 2,
							H0171: 1, S6024: 1,
							H0013: 1, H0374: 1,
							H0050: 1, S0050: 1,
							H0051: 1, S0386: 1,
							L0769: 1, L0768: 1,
							L0776: 1, L0659: 1,
							L0789: 1, H0144: 1,
							L0745: 1 and L0746: 1.
179	HOFMS43	1152417	189	1-1029	787	Pro-1 to Asp-16,	AR051: 15, AR050: 9,
						Pro-60 to Asn-65,	AR089: 7, AR061: 5,
						Tyr-83 to Tyr-89,	AR054: 1
						Ser-102 to Pro-115,	H0415: 1
						Pro-130 to Glu-141,
						Ser-151 to Glu-160,
						Trp-177 to Glu-183,
						Phe-191 to Arg-198,
						Phe-203 to Tyr-209,
						Asn-234 to Ala-240,
						Pro-266 to Pro-271,
						Ser-276 to Thr-311,
						Arg-338 to Gly-343.
		947973	486	3-359	1084	Asp-1 to Asp-17,
						Pro-61 to Asn-66,
						Tyr-84 to Tyr-90,
						Ser-103 to Trp-110.
180	HOVCO14	1091087	190	3-563	788	Arg-78 to His-85,	AR089: 3, AR061: 2
						Leu-99 to Lys-104,	S6016: 1 and H0428: 1.
						Lys-123 to His-132,
						Thr-164 to Pro-171.
		947999	487	3-539	1085	Arg-78 to His-85,
						Leu-99 to Lys-104,
						Lys-123 to His-132,
						Ser-157 to Pro-174.
181	HTEPE35	1105272	191	1-762	789	Tyr-1 to Lys-8,	AR061: 4, AR089: 1
						Phe-19 to Ser-24,	L0758: 7, L0768: 2,
						Thr-28 to Ser-34,	H0616: 1 and L0151: 1.
						Pro-54 to Trp-70,
						Leu-110 to Asn-118,
						Ser-145 to Asp-151,
						Pro-162 to Val-172,
						Pro-180 to Thr-185.
		948475	488	839-78	1086	Tyr-1 to Lys-8,
						Phe-19 to Ser-24,
						Thr-28 to Ser-34,
						Pro-54 to Trp-70.
182	HE8UA52	1229490	192	1-1728	790	Pro-22 to Gly-32,	AR061: 6, AR089: 1
						Arg-52 to Gly-60,	L0752: 5, H0013: 2,
						Ser-78 to Met-89,	L0780: 2, H0624: 1,
						Ile-100 to Ser-106,	H0170: 1, H0645: 1,
						Asp-130 to Leu-137,	H0318: 1, L0750: 1,
						Tyr-146 to Ala-151.	L0779: 1 and L0777: 1.
		948509	489	1-615	1087	Pro-22 to Gly-32,
						Arg-52 to Gly-60,
						Ser-78 to Met-89,
						Ile-100 to Ser-106,
						Asp-130 to Leu-137,
						Tyr-146 to Ser-152.
183	HOUBE50	1090776	193	1-1188	791	Ser-50 to Glu-62.	AR061: 1, AR089: 0
							S0040: 1, S0222: 1,
							L0471: 1 and L0517: 1.
		948519	490	1-243	1088	Ser-50 to Ser-66.
184	HAJAV28	1165229	194	3-1073	792	Pro-1 to Ala-12,	AR089: 3, AR061: 1
						Ile-264 to Val-277,	L0747: 12, L0755: 12,
						Gln-304 to Gln-309,	L0766: 9, L0438: 9,
						Ile-324 to Leu-330.	L0754: 7, H0046: 6,
							L0751: 6, L0752: 6,
							H0068: 5, L0775: 5,
							L0439: 5, S0010: 4,
							H0547: 4, S0152: 4,
							L0740: 4, L0779: 4,
							L0759: 4, H0591: 3,
							L0771: 3, L0662: 3,
							L0774: 3, L0666: 3,
							S0028: 3, L0748: 3,
							L0756: 3, L0731: 3,
							L0757: 3, H0624: 2,
							S0045: 2, H0619: 2,
							S0222: 2, S0049: 2,
							H0052: 2, H0615: 2,
							S0036: 2, T0041: 2,
							H0509: 2, S0002: 2,
							S0426: 2, L0769: 2,
							L0776: 2, L0659: 2,
							H0521: 2, H0707: 2,
							L0594: 2, L0362: 2,
							S0011: 2, H0170: 1,
							H0171: 1, H0685: 1,
							S0040: 1, T0049: 1,
							H0657: 1, S0001: 1,
							H0638: 1, S0358: 1,
							S0360: 1, S0408: 1,
							H0637: 1, S0007: 1,
							S0132: 1, S6022: 1,
							H0550: 1, H0431: 1,
							H0455: 1, H0574: 1,
							H0486: 1, T0114: 1,
							H0250: 1, H0069: 1,
							H0156: 1, L0105: 1,
							H0597: 1, H0546: 1,
							H0545: 1, H0050: 1,
							L0163: 1, H0594: 1,
							H0266: 1, H0290: 1,
							S0214: 1, H0328: 1,
							H0688: 1, H0622: 1,
							H0032: 1, H0673: 1,
							H0674: 1, S0364: 1,
							H0090: 1, H0040: 1,
							H0551: 1, T0067: 1,
							H0268: 1, H0100: 1,
							H0494: 1, H0560: 1,
							H0561: 1, H0633: 1,
							L0762: 1, L0763: 1,
							L0638: 1, L0772: 1,
							L0773: 1, L0521: 1,
							L0768: 1, L0794: 1,
							L0803: 1, L0809: 1,
							L0545: 1, L0664: 1,
							L0665: 1, H0144: 1,
							S0126: 1, H0660: 1,
							H0672: 1, S0378: 1,
							S0380: 1, S0350: 1,
							H0555: 1, H0436: 1,
							H0540: 1, S0390: 1,
							S0206: 1, S0032: 1,
							L0741: 1, L0749: 1,
							L0786: 1, L0777: 1,
							L0758: 1, S0026: 1 and
							H0506: 1.
		948630	491	3-464	1089	Pro-1 to Ala-12.
185	HAQBZ89	1083554	195	54-1034	793	Pro-43 to Asn-61,	AR061: 9, AR089: 6
						Ala-77 to Arg-82,	L0659: 4, L0758: 4,
						Glu-207 to His-212,	L0777: 3, S0360: 2,
						Glu-252 to Glu-261,	L0775: 2, L0750: 2,
						Asp-279 to Asn-284.	L0731: 2, H0295: 1,
							S0218: 1, H0255: 1,
							H0402: 1, L0717: 1,
							H0411: 1, H0015: 1,
							H0030: 1, H0644: 1,
							H0673: 1, H0087: 1,
							L0770: 1, L0769: 1,
							L0637: 1, L0761: 1,
							L0646: 1, L0387: 1,
							L0766: 1, L0776: 1,
							L0655: 1, L0789: 1,
							H0683: 1, S0027: 1,
							L0748: 1, L0779: 1 and
							L0757: 1.
		949061	492	2-325	1090	Ala-20 to Arg-25.
186	HELHF07	949067	196	65-340	794	Thr-16 to Pro-21.	AR061: 5, AR089: 4
							S0045: 2
187	HE9QQ22	1127726	197	41-436	795		AR061: 11, AR089: 3
							L0748: 3, H0144: 2,
							H0632: 1 and L0581: 1.
		949080	493	3-563	1091
188	HSDSB06	1128280	198	3-863	796	Ile-25 to Asn-36,	AR061: 4, AR089: 3
						Glu-54 to Val-63,	H0590: 7, L0754: 5,
						Gly-81 to Glu-86,	H0156: 3, L0731: 3,
						Gly-108 to Thr-114,	L0600: 3, S0360: 2,
						Val-125 to Ser-131.	H0339: 2, S0472: 2,
							L0803: 2, L0751: 2,
							L0779: 2, L0759: 2,
							S0031: 2, L0596: 2,
							S0212: 1, H0411: 1,
							S0222: 1, H0409: 1,
							H0601: 1, H0333: 1,
							H0632: 1, H0427: 1,
							L0021: 1, H0037: 1,
							H0596: 1, H0024: 1,
							H0239: 1, S6028: 1,
							H0266: 1, H0687: 1,
							H0328: 1, H0644: 1,
							H0674: 1, H0598: 1,
							T0067: 1, H0509: 1,
							L0763: 1, L0772: 1,
							L0764: 1, L0771: 1,
							L0773: 1, L0650: 1,
							L0806: 1, L0659: 1,
							L0547: 1, L0809: 1,
							L0666: 1, L0663: 1,
							L0665: 1, S0328: 1,
							S0380: 1, S0390: 1,
							S0032: 1, L0744: 1,
							L0745: 1, L0746: 1,
							L0747: 1, L0756: 1,
							L0777: 1, L0758: 1,
							L0588: 1, S0276: 1,
							S0196: 1, S0412: 1 and
							H0506: 1.
		949151	494	3-863	1092	Ile-25 to Asn-36,
						Glu-54 to Val-63,
						Gly-81 to Glu-86,
						Gly-108 to Thr-114,
						Val-125 to Ser-131.
189	HACAD35	949199	199	1473-916	797	Leu-9 to Leu-18,	AR061: 2, AR089: 1
						Ala-49 to Gly-55,	L0637: 2, L0783: 2,
						Gly-66 to Glu-74,	L0777: 2, S6022: 1,
						Ala-95 to Gln-100.	H0392: 1, H0586: 1,
							H0050: 1, L0809: 1,
							L0759: 1 and S0192: 1.
190	HEQAP17	949358	200	819-295	798		AR051: 744, AR054:
							681, AR050: 564,
							AR061: 2, AR089: 1
							S0192: 3, H0544: 1,
							L0766: 1, L0804: 1,
							H0521: 1 and L0747: 1.
191	HMTBB17	1128589	201	1-366	799	Arg-18 to Pro-23,	AR089: 3, AR061: 3
						Pro-25 to Gly-37,	L0438: 3, L0439: 3,
						Ile-48 to Ile-61,	L0749: 3, L0758: 3,
						Asp-69 to Gly-74,	L0766: 2, L0375: 2,
						Ser-105 to Asn-112.	L0731: 2, L0759: 2,
							L0803: 1, L0655: 1,
							L0517: 1, L0666: 1,
							L0664: 1, H0518: 1,
							L0748: 1, L0779: 1,
							L0599: 1 and H0008: 1.
		950884	495	513-100	1093	Arg-34 to Pro-39,
						Pro-41 to Gly-53,
						Ile-64 to Ile-77,
						Asp-85 to Gly-90,
						Ser-121 to Asn-128.
192	HKGDE58	1129137	202	2-541	800	Asp-1 to Cys-10,	AR089: 2, AR061: 2
						Glu-31 to Pro-38,	H0538: 1, L0803: 1
						Met-43 to Val-48,	and L0731: 1.
						Asp-97 to Phe-110,
						Asp-119 to Gly-137.
		945039	496	11-937	1094	Asp-17 to Cys-26,
						Glu-47 to Pro-54,
						Met-59 to Val-64,
						Asp-113 to Phe-126,
						Asp-135 to Gly-153.
		950885	497	469-119	1095	Ser-20 to Gly-32,
						Ile-43 to Ile-56,
						Asp-64 to Gly-69,
						Ser-100 to Asn-107.
193	HCHMW40	1144323	203	539-3	801	Phe-1 to Trp-6,	AR089: 9, AR061: 4
						Ser-41 to Arg-56,	H0586: 14, H0587: 8,
						Pro-162 to Leu-174.	L0763: 6, H0592: 4,
							H0484: 3, H0081: 3,
							H0063: 3, H0483: 2,
							H0664: 2, H0601: 1,
							H0600: 1, H0494: 1,
							L0648: 1, H0658: 1,
							S0328: 1 and L0747: 1.
		951518	498	84-572	1096	Ser-7 to Gly-14,
						Leu-22 to Ala-28,
						Thr-57 to Ser-62.
194	HE8QZ34	1143411	204	2-1306	802	Ser-85 to Arg-90,	AR089: 4, AR061: 1
						His-99 to Met-105,	H0046: 4, H0591: 2,
						Met-119 to Val-125,	T0067: 2, L0766: 2,
						Lys-127 to Ile-133,	H0144: 2, H0521: 2,
						Lys-215 to Tyr-221,	L0744: 2, L0439: 2,
						Phe-239 to Lys-247,	H0170: 1, H0013: 1,
						Asn-293 to Asp-298,	H0599: 1, S0182: 1,
						Gln-404 to Tyr-411.	H0051: 1, H0510: 1,
							S6028: 1, L0455: 1,
							H0616: 1, S0422: 1,
							S0374: 1, L0438: 1,
							S0390: 1, L0748: 1 and
							L0604: 1.
		952283	499	3-1025	1097	Ser-85 to Arg-90,
						His-99 to Met-105,
						Met-119 to Val-125,
						Lys-127 to Ile-133,
						Lys-215 to Tyr-221,
						Phe-239 to Lys-247,
						Asn-293 to Gly-298.
195	HWAFG04	1227627	205	2-850	803	Gln-103 to Asp-113,	AR089: 17, AR061: 8
						Ser-182 to Phe-200,	L0789: 4, L0758: 4,
						Cys-211 to Ser-221,	H0657: 3, H0052: 3,
						Gln-233 to Ala-238,	L0438: 3, L0744: 3,
						Glu-256 to Ser-264.	L0779: 3, L0005: 2,
							H0581: 2, H0194: 2,
							H0046: 2, H0038: 2,
							L0800: 2, L0659: 2,
							H0521: 2, L0743: 2,
							L0439: 2, H0556: 1,
							S0282: 1, S0358: 1,
							H0619: 1, H0586: 1,
							H0618: 1, H0231: 1,
							S0362: 1, H0622: 1,
							T0006: 1, H0616: 1,
							H0413: 1, H0623: 1,
							L0351: 1, S0150: 1,
							L0769: 1, L0372: 1,
							L0662: 1, L0794: 1,
							L0775: 1, L0651: 1,
							L0527: 1, L0657: 1,
							L0666: 1, H0547: 1,
							H0690: 1, H0658: 1,
							H0672: 1, H0539: 1,
							S0378: 1, H0555: 1,
							L0754: 1, L0747: 1,
							L0780: 1, L0596: 1,
							S0192: 1, H0542: 1 and
							H0423: 1.
		952878	500	1658-789	1098	Gln-110 to Asp-120,
						Ser-189 to Phe-207,
						Cys-218 to Ser-228,
						Gln-240 to Ala-245,
						Glu-263 to Ser-271.
196	HTEKT33	1075836	206	189-1268	804	Pro-19 to Gly-24,	AR089: 15, AR061: 9
						Val-41 to Phe-47,	L0766: 4, L0745: 3,
						Lys-75 to Asp-83,	L0752: 3, S0360: 2,
						Ser-138 to Gln-154,	L0748: 2, L0746: 2,
						Asp-230 to Ser-235,	L0755: 2, H0624: 1,
						Asp-278 to Thr-283,	S0114: 1, H0098: 1,
						Pro-315 to Ser-324,	L0471: 1, H0083: 1,
						Trp-338 to Thr-344.	H0428: 1, L0483: 1,
							H0090: 1, H0616: 1,
							H0494: 1, H0560: 1,
							H0509: 1, L0761: 1,
							L0772: 1, L0803: 1,
							L0776: 1, L0655: 1,
							L0792: 1, L0664: 1,
							S0374: 1, L0438: 1,
							H0520: 1, H0519: 1,
							H0435: 1, H0648: 1,
							S0152: 1, H0521: 1,
							H0478: 1, L0747: 1,
							L0756: 1, L0779: 1,
							L0758: 1, L0759: 1,
							H0667: 1, H0543: 1 and
							L0465: 1.
		953308	501	200-1426	1099
197	HBXDM07	1206657	207	1-1806	805	Leu-89 to Tyr-96,	AR089: 9, AR061: 1
						Leu-195 to Glu-209,	L0777: 7, L0747: 5,
						Val-253 to Ser-259,	H0556: 4, L0794: 4,
						Ile-274 to Phe-279,	L0592: 4, H0497: 3,
						Lys-317 to His-323,	H0052: 3, L0803: 3,
						Lys-338 to Phe-345,	H0087: 2, L0439: 2,
						Ile-361 to Ser-366,	L0749: 2, L0593: 2,
						Glu-370 to Gln-375,	H0459: 1, S0046: 1,
						Lys-398 to Lys-404,	L0717: 1, H0575: 1,
						Val-482 to Arg-492,	S0010: 1, H0390: 1,
						Met-539 to Glu-548,	H0194: 1, H0050: 1,
						Gly-573 toTyr-578.	H0375: 1, L0055: 1,
							S0036: 1, H0059: 1,
							S0038: 1, H0494: 1,
							S0002: 1, L0809: 1,
							L0789: 1, L0663: 1,
							L0665: 1, S0330: 1,
							H0521: 1, H0522: 1,
							H0696: 1, H0555: 1,
							S0028: 1, L0731: 1,
							L0759: 1, L0581: 1,
							H0542: 1 and H0422: 1.
		953622	502	81-716	1100
198	HFPFA83	955614	208	187-735	806	Thr-9 to Val-16.	AR054: 375, AR051:
							284, AR050: 235,
							AR061: 96, AR089: 33
							H0620: 2, H0024: 2,
							H0208: 1, S0222: 1,
							H0194: 1, H0123: 1,
							H0051: 1 and S0052: 1.
199	HKADO36	1189002	209	3-815	807	Ala-6 to Pro-12,	AR089: 2, AR061: 1
						Glu-22 to Ala-41,	H0069: 2, H0497: 1,
						Ser-230 to Ala-238,	H0494: 1, L0769: 1,
						Asp-257 to Ser-268.	S0028: 1 and H0542: 1.
		956115	503	2-280	1101
200	HFXKG51	956596	210	578-3	808	His-13 to Asn-24,	AR089: 2, AR061: 1
						Pro-147 to Asn-157,	S0028: 2, S0282: 1 and
						Gln-164 to Glu-169.	S0051: 1.
201	HFPHR82	1187749	211	3-1328	809	Ile-258 to Val-271,	AR089: 3, AR061: 1
						Gln-298 to Gln-303,	L0747: 12, L0755: 12,
						Ile-318 to Leu-324,	L0766: 9, L0438: 9,
						Glu-353 to Leu-361,	L0754: 7, H0046: 6,
						Ser-397 to Arg-408,	L0751: 6, L0752: 6,
						Gly-427 to Leu-433.	H0068: 5, L0775: 5,
							L0439: 5, S0010: 4,
							H0547: 4, S0152: 4,
							L0740: 4, L0779: 4,
							L0759: 4, H0591: 3,
							L0771: 3, L0662: 3,
							L0774: 3, L0666: 3,
							S0028: 3, L0748: 3,
							L0756: 3, L0731: 3,
							L0757: 3, H0624: 2,
							S0045: 2, H0619: 2,
							S0222: 2, S0049: 2,
							H0052: 2, H0615: 2,
							S0036: 2, T0041: 2,
							H0509: 2, S0002: 2,
							S0426: 2, L0769: 2,
							L0776: 2, L0659: 2,
							H0521: 2, H0707: 2,
							L0594: 2, L0362: 2,
							S0011: 2, H0170: 1,
							H0171: 1, H0685: 1,
							S0040: 1, T0049: 1,
							H0657: 1, S0001: 1,
							H0638: 1, S0358: 1,
							S0360: 1, S0408: 1,
							H0637: 1, S0007: 1,
							S0132: 1, S6022: 1,
							H0550: 1, H0431: 1,
							H0455: 1, H0574: 1,
							H0486: 1, T0114: 1,
							H0250: 1, H0069: 1,
							H0156: 1, L0105: 1,
							H0597: 1, H0546: 1,
							H0545: 1, H0050: 1,
							L0163: 1, H0594: 1,
							H0266: 1, H0290: 1,
							S0214: 1, H0328: 1,
							H0688: 1, H0622: 1,
							H0032: 1, H0673: 1,
							H0674: 1, S0364: 1,
							H0090: 1, H0040: 1,
							H0551: 1, T0067: 1,
							H0268: 1, H0100: 1,
							H0494: 1, H0560: 1,
							H0561: 1, H0633: 1,
							L0762: 1, L0763: 1,
							L0638: 1, L0772: 1,
							L0773: 1, L0521: 1,
							L0768: 1, L0794: 1,
							L0803: 1, L0809: 1,
							L0545: 1, L0664: 1,
							L0665: 1, H0144: 1,
							S0126: 1, H0660: 1,
							H0672: 1, S0378: 1,
							S0380: 1, S0350: 1,
							H0555: 1, H0436: 1,
							H0540: 1, S0390: 1,
							S0206: 1, S0032: 1,
							L0741: 1, L0749: 1,
							L0786: 1, L0777: 1,
							L0758: 1, S0026: 1 and
							H0506: 1.
		957528	504	1592-273	1102	Ile-256 to Val-269,
						Gln-296 to Gln-301,
						Ile-316 to Leu-322,
						Glu-351 to Leu-359,
						Ser-395 to Arg-406,
						Gly-425 to Leu-431.
202	HISAF59	959140	212	130-843	810	Gly-33 to Ser-48.	AR089: 2, AR061: 2
							L0789: 4, L0758: 4,
							H0657: 3, H0052: 3,
							H0046: 3, L0438: 3,
							L0744: 3, L0779: 3,
							L0005: 2, H0586: 2,
							H0581: 2, H0194: 2,
							H0038: 2, L0800: 2,
							L0659: 2, H0521: 2,
							L0743: 2, L0439: 2,
							H0556: 1, S0282: 1,
							S0358: 1, H0619: 1,
							H0618: 1, H0231: 1,
							H0569: 1, S0362: 1,
							H0622: 1, T0006: 1,
							H0135: 1, H0616: 1,
							H0413: 1, H0623: 1,
							L0351: 1, S0150: 1,
							L0769: 1, L0372: 1,
							L0662: 1, L0794: 1,
							L0775: 1, L0651: 1,
							L0527: 1, L0657: 1,
							L0666: 1, H0144: 1,
							H0547: 1, H0690: 1,
							H0658: 1, H0672: 1,
							H0539: 1, S0378: 1,
							H0555: 1, L0754: 1,
							L0747: 1, L0780: 1,
							L0596: 1, S0192: 1,
							H0542: 1 and H0423: 1.
203	HCEHD66	1136122	213	2-562	811	Ala-1 to Lys-6,	AR061: 7, AR089: 3
						Leu-13 to Gln-25,	L0769: 9, S0051: 4,
						Asp-70 to Gly-75,	H0441: 3, S0036: 3,
						Gly-92 to Lys-97,	L0809: 3, L0789: 3,
						Asp-106 to Tyr-112,	L0438: 3, L0439: 3,
						Leu-135 to Val-146,	L0731: 3, H0052: 2,
						Glu-165 to Asp-173.	H0687: 2, H0181: 2,
							L0800: 2, L0794: 2,
							L0665: 2, L0741: 2,
							L0742: 2, L0756: 2,
							S0031: 2, H0171: 1,
							H0556: 1, S6024: 1,
							S0029: 1, H0411: 1,
							S0278: 1, H0455: 1,
							H0486: 1, L0109: 1,
							H0251: 1, L0163: 1,
							H0617: 1, H0413: 1,
							L0762: 1, L0638: 1,
							L0639: 1, L0761: 1,
							L0764: 1, L0662: 1,
							L0774: 1, L0807: 1,
							L0657: 1, S0053: 1,
							S0126: 1, H0626: 1,
							L0747: 1, L0757: 1,
							L0759: 1, L0597: 1 and
							L0608: 1.
		959160	505	2-583	1103	Arg-1 to Lys-13,
						Leu-20 to Gln-32,
						Asp-77 to Gly-82,
						Gly-99 to Lys-104,
						Asp-113 to Tyr-119,
						Leu-142 to Val-153,
						Glu-172 to Asp-180.
204	HE8UY74	1163590	214	1-492	812		AR061: 2, AR089: 1
							H0013: 1 and S0027: 1.
		960914	506	111-455	1104
205	HAHIY08	962113	215	3-278	813		AR061: 10, AR089: 6
206	H2CBH45	1128919	216	2-841	814	Leu-2 to Lys-10,	AR061: 3, AR089: 3
						Ala-29 to Pro-43,	H0437: 1, S0280: 1,
						Ser-63 to Thr-79,	T0110: 1, H0622: 1,
						Pro-87 to Pro-104.	L0745: 1, L0746: 1,
							L0731: 1 and L0596: 1.
		963811	507	2-421	1105	Ala-1 to Met-18,
						Leu-20 to Asn-26,
						Val-38 to Leu-46,
						Pro-48 to Gly-53,
						Leu-81 to Gly-86,
						Gln-94 to Tyr-99,
						Glu-101 to Gly-109.
207	HMVAM09	1194828	217	3-659	815	Asp-1 to Thr-7,	AR089: 4, AR061: 1
						Asp-36 to Phe-51,	L0731: 7, L0517: 5,
						Lys-61 to Gly-66,	S0212: 3, L0775: 3,
						Gly-112 to Leu-120,	L0740: 3, H0266: 2,
						Glu-134 to Tyr-150,	L0809: 2, H0696: 2,
						Arg-193 to Lys-205.	L0748: 2, S0132: 1,
							H0574: 1, H0013: 1,
							H0544: 1, H0023: 1,
							H0071: 1, H0286: 1,
							H0100: 1, H0494: 1,
							S0370: 1, L0770: 1,
							L0646: 1, L0764: 1,
							L0771: 1, L0363: 1,
							L0774: 1, L0659: 1,
							L0789: 1, L0666: 1,
							S0126: 1, H0522: 1,
							L0754: 1, L0747: 1 and
							L0755: 1.
		963814	508	2-802	1106
208	HFPEN04	1199663	218	96-1646	816	Glu-62 to Tyr-67,	AR061: 5, AR089: 2
						Pro-169 to Lys-179,	S0010: 4, S0222: 3,
						Pro-189 to Ala-201,	H0455: 2, L0803: 2,
						Ala-218 to Arg-223,	L0439: 2, L0745: 2,
						Tyr-324 to Asn-331,	S0282: 1, S0400: 1,
						Gly-352 to Val-357,	H0456: 1, H0441: 1,
						Leu-365 to Lys-371,	S0346: 1, H0509: 1,
						His-393 to Ala-399,	L0769: 1, L0438: 1,
						Asp-420 to Asn-425,	L0756: 1 and S0106: 1.
						Thr-460 to Lys-473,
						Ser-488 to Gly-502.
		964824	509	88-540	1107	Glu-62 to Tyr-67,
						Ser-129 to Asp-135.
209	HSLJD02	1104452	219	67-927	817	Leu-53 to Gln-58,	AR054: 7, AR051: 1,
						Phe-162 to Gly-167,	AR089: 1, AR061: 1,
						Gln-282 to Ala-287.	AR050: 0
							S0390: 1
		965826	510	47-907	1108	Leu-53 to Gln-58,
						Phe-162 to Gly-167,
						Gln-282 to Ala-287.
210	HDPFZ30	1220164	220	1637-819	818	Leu-31 to Gly-41,	AR089: 6, AR061: 2
						Arg-137 to Ser-143,	H0250: 5, L0770: 2,
						Glu-241 to Glu-260.	L0438: 2, L0439: 2,
							L0754: 2, S0114: 1,
							H0459: 1, H0489: 1,
							S0278: 1, H0069: 1,
							H0575: 1, H0318: 1,
							H0123: 1, L0471: 1,
							H0071: 1, H0328: 1,
							H0634: 1, T0067: 1,
							L0351: 1, H0560: 1,
							S0142: 1, S0344: 1,
							S0426: 1, L0763: 1,
							L0769: 1, L0761: 1,
							L0662: 1, L0363: 1,
							L0364: 1, L0805: 1,
							L0666: 1, L0664: 1,
							S0126: 1, H0658: 1,
							H0670: 1, H0521: 1,
							H0522: 1, S0044: 1,
							H0555: 1, H0576: 1,
							L0748: 1 and L0755: 1.
		966752	511	1637-819	1109	Leu-31 to Gly-41,
						Arg-137 to Ser-143,
						Glu-241 to Glu-260.
211	HPJCR33	1217931	221	140-1681	819	Ser-1 to Leu-13,	AR089: 2, AR061: 1
						Pro-17 to Gly-31,	L0754: 8, L0777: 8,
						Thr-44 to Leu-54,	L0439: 5, H0266: 2,
						His-84 to Arg-95,	L0438: 2, H0672: 2,
						Asn-105 to Gln-116,	S0152: 2, L0745: 2,
						Pro-132 to Leu-138,	L0758: 2, H0650: 1,
						Glu-148 to Gly-157,	S0212: 1, S0045: 1,
						Arg-180 to Trp-185,	S0046: 1, H0486: 1,
						Asn-340 to Glu-346,	L0563: 1, H0051: 1,
						Asn-401 to Cys-412,	H0644: 1, H0673: 1,
						Asp-430 to Ala-435,	H0551: 1, H0269: 1,
						Thr-473 to Lys-478,	S0344: 1, L0794: 1,
						Pro-490 to Tyr-498.	L0766: 1, L0803: 1,
							L0805: 1, L0659: 1,
							H0547: 1, H0519: 1,
							S0126: 1, H0711: 1,
							H0528: 1, S0028: 1,
							L0750: 1, L0780: 1,
							L0757: 1, L0588: 1,
							L0591: 1, S0192: 1,
							H0423: 1 and H0293: 1.
		966758	512	1-375	1110
212	HTOAK34	1081321	222	784-599	820	Ser-10 to His-15.	AR089: 1, AR061: 1
							L0766: 2, H0264: 1
							and H0521: 1.
		966800	513	918-1196	1111	Ser-67 to Trp-77.
213	HE8NI24	971296	223	318-749	821		AR050: 3, AR051: 1,
							AR089: 0, AR061: 0
							H0013: 3, L0794: 2,
							L0439: 2, L0756: 2,
							L0779: 2, L0758: 2,
							S0001: 1, H0619: 1,
							L0638: 1, L0641: 1,
							L0776: 1 and H0435: 1.
214	HAMFM39	1055532	224	782-2344	822	Gly-1 to Pro-7,	AR050: 193, AR054:
						Gly-23 to Gly-50,	122, AR051: 84,
						Ser-53 to Pro-84,	AR089: 0, AR061: 0
						Ser-89 to Thr-129,	H0255: 59, H0254: 10,
						Gly-140 to Gly-145,	H0617: 9, L0747: 8,
						Pro-148 to Lys-158,	S0358: 7, H0486: 6,
						Thr-161 to Ser-167,	L0655: 6, H0208: 4,
						Leu-179 to Arg-189,	H0545: 4, H0024: 4,
						Pro-203 to Lys-211,	S0354: 3, H0250: 3,
						Glu-233 to Asp-240,	H0123: 3, H0031: 3,
						Lys-261 to Gly-288,	L0659: 3, S0328: 3,
						Arg-296 to Glu-305,	L0731: 3, H0583: 2,
						Ala-315 to Arg-353,	L0808: 2, L0785: 2,
						Glu-372 to Pro-382,	H0662: 2, H0586: 2,
						Gln-395 to Glu-408,	H0618: 2, H0253: 2,
						Asn-419 to Gly-427,	H0424: 2, H0264: 2,
						Ala-458 to Gly-463,	H0488: 2, H0100: 2,
						Pro-477 to Ala-483.	L0771: 2, L0806: 2,
							L0809: 2, H0144: 2,
							H0689: 2, L0749: 2,
							L0750: 2, L0779: 2,
							L0777: 2, H0707: 2,
							L0595: 2, H0624: 1,
							H0341: 1, S0356: 1,
							S0360: 1, H0619: 1,
							H0411: 1, H0370: 1,
							H0485: 1, H0635: 1,
							H0025: 1, H0108: 1,
							H0318: 1, H0581: 1,
							T0110: 1, H0231: 1,
							L0738: 1, H0086: 1,
							H0271: 1, T0006: 1,
							H0644: 1, H0181: 1,
							H0124: 1, H0087: 1,
							T0067: 1, H0560: 1,
							H0646: 1, L0371: 1,
							L0800: 1, L0764: 1,
							L0768: 1, L0803: 1,
							L0774: 1, L0657: 1,
							L0368: 1, L0787: 1,
							L0666: 1, L0663: 1,
							L0665: 1, H0519: 1,
							H0414: 1, S0378: 1,
							S0380: 1, H0696: 1,
							S0044: 1, S0432: 1,
							L0439: 1, L0780: 1,
							L0755: 1, H0445: 1 and
							L0596: 1.
		971347	514	1121-2929	1112	Gln-1 to Ala-7,
						Thr-36 to Trp-42,
						Gly-45 to Gly-52,
						Glu-77 to Pro-89,
						Gly-105 to Gly-132,
						Ser-135 to Glu-162.
215	HBGMG39	1126283	225	286-14	823	Arg-27 to Gly-40,	AR089: 1, AR061: 0
						Arg-67 to Asp-91.	L0659: 12, L0769: 10,
							L0666: 8, L0747: 8,
							L0759: 7, L0439: 6,
							L0757: 6, L0756: 5,
							L0770: 4, L0761: 4,
							L0663: 4, L0665: 4,
							H0521: 4, L0749: 4,
							L0750: 4, L0777: 4,
							L0758: 4, H0550: 3,
							H0486: 3, H0544: 3,
							H0623: 3, L0662: 3,
							L0794: 3, L0766: 3,
							L0774: 3, L0664: 3,
							L0740: 3, L0779: 3,
							H0423: 3, S0418: 2,
							S0360: 2, L0717: 2,
							H0549: 2, H0618: 2,
							H0581: 2, H0545: 2,
							H0510: 2, H0617: 2,
							L0763: 2, L0772: 2,
							L0642: 2, L0764: 2,
							L0775: 2, L0655: 2,
							L0789: 2, S0374: 2,
							H0658: 2, H0522: 2,
							H0631: 2, L0745: 2,
							L0731: 2, H0556: 1,
							T0049: 1, H0656: 1,
							L0785: 1, H0483: 1,
							H0661: 1, H0664: 1,
							H0662: 1, S0420: 1,
							S0354: 1, S0358: 1,
							H0580: 1, S0468: 1,
							S0132: 1, S0222: 1,
							H0441: 1, H0586: 1,
							H0587: 1, H0497: 1,
							H0069: 1, H0427: 1,
							S0280: 1, H0046: 1,
							H0457: 1, H0081: 1,
							H0024: 1, T0010: 1,
							H0594: 1, H0188: 1,
							H0687: 1, H0553: 1,
							H0124: 1, H0494: 1,
							H0641: 1, S0422: 1,
							S0002: 1, S0426: 1,
							L0372: 1, L0646: 1,
							L0374: 1, L0648: 1,
							L0649: 1, L0803: 1,
							L0651: 1, L0653: 1,
							L0656: 1, L0635: 1,
							L0542: 1, L0526: 1,
							L0783: 1, L0809: 1,
							L0647: 1, L0791: 1,
							L0792: 1, H0698: 1,
							H0699: 1, H0693: 1,
							H0547: 1, H0689: 1,
							H0690: 1, H0683: 1,
							H0670: 1, S0378: 1,
							S0152: 1, H0555: 1,
							H0436: 1, S0392: 1,
							L0742: 1, L0751: 1,
							L0780: 1, H0668: 1,
							H0653: 1, S0242: 1,
							H0542: 1, H0543: 1 and
							S0460: 1.
		971414	515	1-195	1113	Pro-1 to Asn-14,
						Lys-17 to Phe-23,
						Met-44 to Tyr-50.
216	HSXBV89	1128699	226	1-2037	824	Gln-25 to Gly-33,	AR054: 23, AR061: 4,
						Pro-49 to Gly-55,	AR089: 3, AR050: 0
						Gly-89 to Glu-97,	L0439: 31, L0741: 9,
						Ser-176 to Glu-183,	L0438: 7, L0777: 6,
						Thr-231 to Gly-240,	H0052: 5, H0617: 5,
						Pro-267 to Thr-275,	L0748: 4, L0753: 4,
						Pro-297 to Asp-308,	L0769: 3, L0775: 3,
						Asp-340 to Ser-345,	L0776: 3, S0378: 3,
						Arg-353 to Leu-361,	L0779: 3, S0040: 2,
						Pro-375 to Gly-382,	L0103: 2, H0046: 2,
						Glu-393 to Trp-410,	H0284: 2, T0006: 2,
						Gly-470 to Ser-475,	S0036: 2, S0038: 2,
						Tyr-504 to Arg-516,	L0351: 2, S0370: 2,
						Gly-531 to Thr-539,	L0764: 2, H0670: 2,
						Pro-571 to Gln-580,	L0602: 2, L0747: 2,
						Leu-591 to Glu-598,	L0592: 2, S0342: 1,
						Gln-601 to Gly-611,	S0282: 1, S0030: 1,
						Gly-649 to Ser-654,	H0484: 1, S0007: 1,
						Asp-661 to Leu-666,	S0278: 1, H0261: 1,
						Ala-669 to Glu-674.	S0222: 1, H0441: 1,
							H0156: 1, T0082: 1,
							H0194: 1, T0010: 1,
							S6028: 1, H0271: 1,
							L0483: 1, H0424: 1,
							H0213: 1, H0181: 1,
							S0112: 1, S0144: 1,
							S0002: 1, L0520: 1,
							L0762: 1, L0763: 1,
							L0638: 1, L0772: 1,
							L0768: 1, L0653: 1,
							L0659: 1, L0636: 1,
							L0367: 1, L0791: 1,
							L0665: 1, L0352: 1,
							H0672: 1, H0539: 1,
							S0032: 1, L0742: 1,
							L0740: 1, L0758: 1 and
							H0667: 1.
		971821	516	3-509	1114	Gln-20 to Gly-28,
						Pro-44 to Gly-50.
217	HBIOZ10	1143756	227	3-572	825	Leu-50 to Asp-61,	AR054: 189, AR051:
						Ser-100 to Leu-107,	68, AR050: 35, AR089:
						Pro-119 to Leu-125.	4, AR061: 3
							H0593: 1
		973131	517	3-503	1115	Leu-50 to Asp-61,
						Ser-100 to Leu-107,
						Ala-120 to Thr-130.
218	HTLEJ11	1085651	228	2-802	826	Tyr-52 to Gln-60.	AR061: 3, AR089: 1
							H0618: 3 and H0253:
							1.
		973302	518	2-802	1116	Tyr-52 to Gln-60,
						Phe-86 to Ala-94,
						Lys-111 to Arg-118,
						His-193 to Tyr-198.
219	HAWAM69	1207835	229	1-1302	827	Val-2 to Cys-17,	AR054: 334, AR050:
						Cys-41 to Gln-52,	251, AR051: 249,
						Glu-70 to Phe-82,	AR061: 6, AR089: 6
						Glu-89 to Ser-97,	L0758: 12, L0662: 11,
						Lys-126 to Gly-132,	H0251: 9, L0731: 9,
						Val-134 to Gly-145,	S0360: 5, H0013: 5,
						Glu-167 to Arg-180,	L0659: 5, L0747: 5,
						Glu-187 to Ser-200,	H0252: 4, H0328: 4,
						Cys-204 to Ser-210,	L0666: 4, L0439: 4,
						Glu-213 to Asp-221,	H0135: 3, L0764: 3,
						Thr-260 to Ala-273,	L0783: 3, L0749: 3,
						Ala-278 to Gln-290,	S0358: 2, L0776: 2,
						Ser-317 to His-333,	L0663: 2, H0651: 2,
						Leu-347 to Gly-356,	L0744: 2, L0754: 2,
						Lys-358 to Phe-363,	H0675: 1, H0329: 1,
						Leu-367 to Cys-376,	H0619: 1, L0717: 1,
						Asp-385 to Ser-391,	H0369: 1, H0550: 1,
						Glu-406 to Gly-434.	H0333: 1, H0632: 1,
							H0486: 1, T0060: 1,
							H0042: 1, H0575: 1,
							H0618: 1, H0150: 1,
							H0123: 1, H0050: 1,
							H0105: 1, T0003: 1,
							H0024: 1, H0510: 1,
							H0594: 1, H0028: 1,
							H0644: 1, S0364: 1,
							S0366: 1, H0591: 1,
							H0100: 1, L0763: 1,
							L0631: 1, L0637: 1,
							L0646: 1, L0641: 1,
							L0644: 1, L0649: 1,
							L0803: 1, L0775: 1,
							L0782: 1, L0809: 1,
							L0519: 1, L0793: 1,
							L0665: 1, H0144: 1,
							L0438: 1, H0684: 1,
							H0672: 1, S0380: 1,
							L0748: 1, L0759: 1,
							L0596: 1, L0366: 1,
							L0600: 1 and H0352: 1.
		943104	519	1010-1441	1117	Cys-38 to Gly-43,
						Gly-70 to Pro-82,
						Arg-129 to Glu-134,
						Gly-139 to Gly-144.
		973465	520	154-2	1118	Leu-23 to Gly-32,
						Lys-34 to Lys-40.
220	HSCKD11	1056288	230	1238-2074	828	Ala-20 to Val-28,	AR089: 1, AR061: 1
						Pro-60 to Cys-66,	H0667: 1
						Ser-118 to Asp-123,
						Leu-225 to Asp-236,
						Thr-267 to His-274.
		973894	521	117-326	1119	Ala-6 to Ala-11,
						Phe-19 to Asn-24,
						Val-29 to Lys-34.
221	HDPLT62	1027241	231	195-800	829	Arg-9 to Leu-17,	AR089: 1, AR061: 0
						Pro-90 to Asn-95,	H0521: 1
						Lys-115 to Glu-125.
		973945	522	405-809	1120
222	HTPFX16	974296	232	3-422	830	Asp-40 to Asn-49,	AR061: 3, AR089: 2
						Cys-65 to Gly-71.	L0750: 2, H0024: 1,
							H0039: 1, H0622: 1,
							H0040: 1 and S0434: 1.
223	HE9NO66	1079624	233	362-871	831	Phe-8 to Lys-27,	AR061: 1, AR089: 1
						Ser-79 to Ser-87,	L0774: 2 and H0144:
						Cys-102 to Val-116.	2.
		974353	523	362-871	1121	Phe-8 to Lys-27,
						Ser-79 to Ser-87,
						Cys-102 to Val-116.
224	HSDJI44	1154068	234	218-1921	832	Ala-324 to Phe-332,	AR061: 0, AR089: 0
						Arg-336 to Thr-343,	S0045: 6, H0255: 5,
						Pro-373 to Arg-384,	S0028: 4, S0031: 2,
						Lys-424 to Asp-431.	S0260: 2, H0341: 1,
							S0278: 1, H0333: 1,
							H0250: 1, S0050: 1,
							H0271: 1, H0100: 1,
							S0216: 1, S0044: 1 and
							S0390: 1.
		974784	524	210-1847	1122	Ala-324 to Phe-332,
						Arg-336 to Thr-343,
						Pro-373 to Arg-384,
						Lys-424 to Asp-431.
225	HFXDP53	1126294	235	1-435	833	Gln-16 to Gly-25,	AR061: 3, AR089: 1
						Thr-32 to Gly-42,	S0001: 1
						Asn-46 to Asp-52.
		578868	525	3-272	1123	Lys-1 to Arg-7,
						Phe-10 to Arg-19.
226	HWADY66	734565	236	1-186	834		AR061: 1, AR089: 1
							H0581: 1, H0494: 1,
							H0521: 1, H0444: 1,
							H0543: 1 and L0465: 1.
227	HLDBC63	1144557	237	3-662	835	Phe-61 to Thr-68,	AR061: 10, AR089: 4
						Arg-70 to Ser-76,	L0754: 4, H0616: 1
						Gln-88 to Arg-93,	and H0509: 1.
						Pro-145 to Gln-157,
						Glu-164 to Ser-171,
						Gly-215 to Thr-220.
		745061	526	3-416	1124	Phe-61 to Thr-68,
						Arg-70 to Ser-76,
						Gln-88 to Arg-93.
228	HFIVB68	978211	238	3-665	836	Arg-20 to Thr-27,	AR061: 1, AR089: 1
						Leu-40 to Gly-45,	H0013: 2, S0468: 1,
						His-57 to Lys-74,	S0046: 1, H0592: 1,
						Thr-97 to Ser-112,	H0266: 1, S3014: 1,
						Asp-150 to Ser-155,	S0028: 1 and S0196: 1.
						Leu-177 to Asp-182.
		752981	527	82-663	1125	Thr-33 to Lys-47,
						Thr-70 to Ser-85,
						Asp-123 to Ser-128,
						Leu-150 to Asp-155.
229	HTLAC56	1181355	239	3-698	837		AR061: 25, AR089: 15
							L0783: 3, S0007: 2,
							L0782: 2, H0539: 2,
							L0747: 2, H0333: 1,
							H0253: 1, H0052: 1,
							H0546: 1, T0006: 1,
							H0135: 1, L0770: 1,
							L0769: 1, L0776: 1,
							L0745: 1, L0777: 1 and
							L0753: 1.
		753093	528	3-422	1126
230	HSSAD41	753094	240	3-428	838		L0783: 3, S0007: 2,
							L0782: 2, H0539: 2,
							L0747: 2, H0333: 1,
							H0253: 1, H0052: 1,
							H0546: 1, T0006: 1,
							H0135: 1, L0770: 1,
							L0769: 1, L0776: 1,
							L0745: 1, L0777: 1 and
							L0753: 1.
231	HCFMT57	1218436	241	3-1115	839	Ser-4 to Arg-15,	AR061: 0, AR089: 0
						Glu-20 to Arg-62,	L0157: 2, H0620: 2,
						Pro-107 to Gly-112,	L0666: 2, S0001: 1,
						Gly-128 to Gly-134,	L0717: 1, H0549: 1,
						Gln-137 to Arg-143,	S0222: 1, H0581: 1,
						Ala-191 to Ala-212,	H0194: 1, H0015: 1,
						Tyr-239 to Asn-247,	H0399: 1, H0271: 1,
						Leu-300 to Pro-328,	H0688: 1, H0428: 1,
						Pro-337 to Lys-350,	H0124: 1, L0637: 1,
						Ser-356 to Leu-361,	H0672: 1, L0439: 1,
						Gly-366 to Glu-371.	L0750: 1 and H0423: 1.
		765375	529	380-3	1127	Glu-5 to Arg-15,
						Glu-20 to Arg-62.
232	HDAAV61	1188787	242	1-1332	840	Asp-34 to Asp-49,	AR089: 25, AR061: 11
						Gly-276 to Ala-286,	L0601: 5, H0266: 4,
						Ile-298 to Tyr-303,	S0222: 3, H0265: 2,
						Leu-390 to Arg-395.	H0556: 2, H0575: 2,
							H0052: 2, H0271: 2,
							S0114: 1, S0134: 1,
							S0420: 1, H0393: 1,
							H0550: 1, H0497: 1,
							H0318: 1, H0581: 1,
							H0251: 1, T0115: 1,
							H0014: 1, H0286: 1,
							H0494: 1, H0561: 1,
							L0766: 1, L0657: 1,
							H0698: 1, H0684: 1,
							S0330: 1, H0521: 1,
							S3014: 1, L0777: 1,
							S0260: 1, L0591: 1,
							L0594: 1 and H0543: 1.
		810305	530	2-343	1128	Asp-90 to Lys-105.
233	HDPKD75	1096253	243	2-637	841	Gly-2 to Asp-11,	AR089: 4, AR061: 0
						Ala-23 to Asn-30,	H0581: 1, H0494: 1,
						Phe-48 to Gly-56,	H0521: 1, H0543: 1 and
						Glu-99 to His-105,	L0465: 1.
						Glu-187 to Glu-192.
		810824	531	2-445	1129	Ala-13 to Asn-20,
						Phe-38 to Gly-46,
						Glu-89 to His-95.
234	HTEON29	1126312	244	1-516	842	Pro-27 to Ala-35,	AR061: 6, AR089: 3
						Ser-138 to Asn-144.	H0038: 4, L0758: 3,
							H0616: 2, L0794: 2,
							L0747: 2, L0803: 1,
							L0789: 1 and L0590: 1.
		815852	532	2-520	1130	Pro-27 to Ala-35.
235	HSKAC24	1121800	245	1-480	843	Ala-3 to Arg-20,	AR061: 2, AR089: 1
						Ser-33 to Asp-39,	H0370: 2, S0002: 1,
						Leu-70 to Ser-76,	S0428: 1 and S0027: 1.
						Pro-117 to Tyr-122.
		823869	533	98-481	1131	Ser-1 to Asp-7,
						Leu-38 to Ser-44,
						Pro-85 to Tyr-90.
236	HTJAA71	1216498	246	25-1029	844	Arg-32 to Asn-39,	AR089: 5, AR061: 4
						Leu-76 to Gly-82,	S0328: 5, H0264: 4,
						Cys-112 to Ser-119,	L0549: 3, S0306: 2,
						Gly-129 to Gly-135,	H0379: 1, H0487: 1,
						Ala-141 to Val-167,	S0448: 1, S0450: 1,
						Ser-181 to Ile-194,	L0648: 1, L0551: 1 and
						Ser-201 to Gly-239,	S0330: 1.
						Ser-245 to Gln-250,
						Thr-256 to Thr-293,
						Ala-306 to Asp-335.
		846682	534	23-334	1132	Arg-32 to Asn-39.
237	HTEKS20	1124378	247	2-562	845	Pro-7 to Arg-12,	AR061: 2, AR089: 1
						Phe-32 to Ile-37,	L0758: 14, H0038: 5,
						Arg-39 to Lys-45,	L0779: 4, L0794: 2 and
						Leu-47 to Gly-53,	H0616: 1.
						Lys-102 to Lys-108,
						Asp-117 to Gly-122.
		846714	535	3-569	1133	Pro-9 to Arg-14,
						Phe-34 to Ile-39,
						Arg-41 to Lys-47,
						Leu-49 to Gly-55,
						Lys-104 to Lys-110,
						Asp-119 to Gly-124.
238	HE9TK49	1125192	248	3-863	846	Glu-134 to Glu-144,	AR061: 3, AR089: 1
						Gln-151 to Arg-161,	H0144: 2 and S0053: 1.
						Arg-167 to Gly-172,
						Tyr-183 to Asn-188,
						Asn-193 to Phe-209,
						Asp-261 to Trp-272.
		856343	536	2-328	1134
239	HCHAT01	1202275	249	2-2269	847	Glu-75 to Glu-86,	AR089: 1, AR061: 0
						Leu-176 to Gln-181,	L0439: 12, L0748: 11,
						Ser-276 to Ala-282,	L0751: 11, L0769: 7,
						Leu-320 to Lys-325,	H0046: 6, L0756: 6,
						Met-366 to Ser-373,	L0775: 5, L0666: 5,
						Leu-414 to Asp-419,	L0747: 5, L0770: 4,
						Thr-471 to His-506,	L0438: 4, L0740: 4,
						Lys-513 to Ile-522,	L0777: 4, H0617: 3,
						Pro-526 to Gln-532,	L0662: 3, L0774: 3,
						Asp-547 to Asp-552,	L0776: 3, H0521: 3,
						Ala-576 to Cys-585,	S0037: 3, L0749: 3,
						Glu-588 to His-598,	L0731: 3, L0757: 3,
						Gly-637 to Pro-645,	L0758: 3, S0212: 2,
						Leu-649 to Asp-657,	S0222: 2, H0586: 2,
						Ile-733 to Phe-743,	H0587: 2, H0333: 2,
						Ala-746 to Gly-753.	H0156: 2, H0052: 2,
							S0388: 2, H0290: 2,
							L0640: 2, L0521: 2,
							L0766: 2, L0375: 2,
							L0659: 2, L0783: 2,
							H0144: 2, H0539: 2,
							L0755: 2, H0445: 2,
							L0596: 2, L0599: 2,
							H0149: 1, S0342: 1,
							H0294: 1, S0114: 1,
							H0484: 1, H0483: 1,
							H0664: 1, H0638: 1,
							S0418: 1, S0420: 1,
							L0005: 1, S0046: 1,
							S0300: 1, H0549: 1,
							H0550: 1, H0370: 1,
							H0497: 1, H0331: 1,
							H0486: 1, H0575: 1,
							S0010: 1, H0434: 1,
							H0327: 1, H0457: 1,
							H0041: 1, H0081: 1,
							H0620: 1, H0024: 1,
							H0057: 1, H0051: 1,
							H0083: 1, H0266: 1,
							H0188: 1, S0250: 1,
							H0688: 1, H0644: 1,
							H0674: 1, S0366: 1,
							H0087: 1, H0116: 1,
							H0488: 1, H0494: 1,
							H0131: 1, S0150: 1,
							H0633: 1, H0649: 1,
							H0652: 1, L0369: 1,
							L0638: 1, L0646: 1,
							L0641: 1, L0771: 1,
							L0773: 1, L0653: 1,
							L0658: 1, L0809: 1,
							L0789: 1, L0663: 1,
							L0664: 1, H0693: 1,
							H0520: 1, S0126: 1,
							H0682: 1, H0659: 1,
							S0330: 1, H0696: 1,
							S0174: 1, H0555: 1,
							S3012: 1, S0028: 1,
							L0742: 1, L0744: 1,
							L0745: 1, L0750: 1,
							L0786: 1, L0779: 1,
							L0752: 1, S0434: 1,
							L0366: 1, H0542: 1,
							H0423: 1 and H0352: 1.
		867209	537	771-1556	1135	Ser-20 to Ala-26,
						Leu-64 to Lys-69,
						Met-110 to Ser-117,
						Leu-158 to Asp-163.
240	HCEEN06	1150867	250	128-664	848	Pro-7 to Pro-14,	AR089: 6, AR061: 3
						Asp-70 to Arg-80,	L0666: 6, L0761: 4,
						Asp-145 to Gln-152.	H0486: 3, L0794: 3,
							L0659: 3, H0255: 2,
							S0358: 2, H0052: 2,
							L0809: 2, L0743: 2,
							L0759: 2, H0692: 1,
							S0116: 1, H0581: 1,
							H0597: 1, L0055: 1,
							H0087: 1, L0763: 1,
							L0800: 1, L0644: 1,
							L0764: 1, L0766: 1,
							L0375: 1, L0655: 1,
							L0788: 1, L0663: 1,
							S0310: 1, H0672: 1,
							S0328: 1, H0539: 1 and
							H0436: 1.
		878658	538	2-619	1136	Ser-1 to Ala-10,
						Cys-23 to Ala-29.
241	HDPKI83	883382	251	101-673	849	Pro-19 to Lys-29,	AR061: 3, AR089: 3
						His-38 to Phe-45,	H0521: 7, H0580: 5,
						Ile-52 to Gln-66,	L0665: 4, H0457: 3,
						Glu-123 to Glu-138.	L0766: 3, L0745: 3,
							L0761: 2, L0806: 2,
							L0789: 2, L0750: 2,
							H0542: 2, H0650: 1,
							H0656: 1, H0581: 1,
							H0271: 1, H0553: 1,
							H0413: 1, H0641: 1,
							S0002: 1, L0774: 1,
							H0660: 1, H0555: 1,
							L0753: 1 and H0423: 1.
242	HSPBQ12	1152258	252	1-588	850	His-4 to Gly-21,	AR089: 2, AR061: 1
						Thr-55 to Ser-66,	L0766: 19, L0439: 9,
						Pro-118 to Gly-130,	L0803: 7, L0740: 7,
						Thr-168 to Ser-174.	L0752: 7, L0770: 5,
							L0659: 5, L0731: 5,
							L0805: 4, L0777: 4,
							H0657: 3, H0373: 3,
							L0804: 3, S0152: 3,
							L0748: 3, L0749: 3,
							L0779: 3, H0650: 2,
							L0471: 2, S6028: 2,
							H0032: 2, L0783: 2,
							L0438: 2, H0521: 2,
							H0478: 2, L0744: 2,
							L0747: 2, L0750: 2,
							L0485: 2, S0424: 2,
							S0134: 1, S0354: 1,
							S0358: 1, H0580: 1,
							S0222: 1, H0013: 1,
							L0021: 1, H0575: 1,
							H0050: 1, H0014: 1,
							H0051: 1, H0031: 1,
							H0553: 1, H0165: 1,
							H0551: 1, H0509: 1,
							H0132: 1, H0652: 1,
							S0002: 1, H0529: 1,
							L0763: 1, L0772: 1,
							L0372: 1, L0771: 1,
							L0521: 1, L0662: 1,
							L0768: 1, L0386: 1,
							L0388: 1, L0774: 1,
							L0775: 1, L0655: 1,
							L0782: 1, L0809: 1,
							L0787: 1, L0789: 1,
							L0663: 1, L0664: 1,
							H0144: 1, L0352: 1,
							H0520: 1, H0435: 1,
							H0659: 1, H0658: 1,
							H0648: 1, H0672: 1,
							S0378: 1, S0380: 1,
							S0044: 1, L0780: 1,
							L0757: 1, L0758: 1 and
							H0543: 1.
		884004	539	91-1287	1137
243	HPCID78	886915	253	1-429	851	Gly-1 to Cys-7.	AR054: 2, AR051: 1,
							AR089: 1, AR061: 0
							H0642: 1
244	HDTKQ14	886936	254	1-555	852	Ser-60 to Thr-71,	AR054: 60, AR051:
						Thr-82 to Leu-94,	40, AR050: 36, AR089:
						Gln-113 to Asp-123,	5, AR061: 2
						Val-125 to Tyr-133,	H0521: 4, H0486: 2,
						Leu-144 to Gly-149.	S0002: 2, L0770: 2,
							L0769: 2, L0766: 2,
							L0518: 2, L0783: 2,
							L0777: 2, L0731: 2,
							H0422: 2, H0556: 1,
							H0583: 1, H0650: 1,
							H0657: 1, H0179: 1,
							L0055: 1, H0488: 1,
							S0426: 1, L0662: 1,
							L0775: 1, L0655: 1,
							L0665: 1, S0053: 1,
							H0659: 1, L0754: 1,
							L0779: 1, L0759: 1 and
							H0543: 1.
245	HRACK83	888037	255	1-471	853	Gln-15 to Gln-21.	AR089: 3, AR061: 2
							L0803: 4, L0758: 3,
							S0212: 2, S0358: 2,
							H0038: 2, L0770: 2,
							L0767: 2, L0766: 2,
							L0748: 2, L0751: 2,
							L0747: 2, L0759: 2,
							L0588: 2, L0599: 2,
							H0411: 1, H0392: 1,
							H0333: 1, L0021: 1,
							H0118: 1, T0115: 1,
							L0471: 1, L0163: 1,
							H0633: 1, L0769: 1,
							L0764: 1, L0775: 1,
							L0376: 1, L0806: 1,
							L0805: 1, L0807: 1,
							L0787: 1, H0547: 1,
							S0122: 1, H0555: 1,
							H0478: 1, L0744: 1,
							L0740: 1, L0749: 1,
							L0750: 1, L0755: 1 and
							L0595: 1.
246	HSIAO78	1156438	256	2-631	854	Met-15 to Ser-20,	AR089: 1, AR061: 0
						Asp-27 to Phe-37,	S0354: 3, S0358: 3,
						Asp-53 to Tyr-59,	H0587: 3, L0764: 3,
						Pro-86 to Asp-93,	L0803: 3, L0758: 3,
						Pro-106 to Lys-129,	H0036: 2, L0794: 2,
						Leu-139 to Ser-146,	L0809: 2, S0374: 2,
						Thr-174 to Asp-183.	S0376: 1, S0444: 1,
							S0408: 1, H0231: 1,
							L0783: 1, L0777: 1 and
							L0759: 1.
		889498	540	2-622	1138	Asp-24 to Phe-34,
						Asp-50 to Tyr-56,
						Pro-83 to Asp-90,
						Pro-103 to Lys-126,
						Leu-136 to Ser-143,
						Thr-171 to Asp-180.
247	HWAGS73	894404	257	1-339	855	Val-14 to Lys-21,	AR089: 2, AR061: 2
						Gln-41 to Trp-46,	H0581: 3, H0622: 3,
						Ala-98 to Pro-103.	H0575: 2, H0090: 2,
							L0777: 2, L0757: 2,
							S0114: 1, H0650: 1,
							H0255: 1, S0360: 1,
							S0278: 1, H0486: 1,
							H0318: 1, H0046: 1,
							H0457: 1, H0039: 1,
							H0553: 1, L0763: 1,
							L0761: 1, L0764: 1,
							L0789: 1, H0144: 1,
							S0374: 1, S0310: 1,
							H0555: 1, L0758: 1,
							H0445: 1 and S0276: 1.
248	HCMSL08	898203	258	1-1221	856	Gly-1 to Thr-10,	AR051: 86, AR054:		104770,
						Ala-14 to Gly-19,	73, AR050: 67, AR089:		107670,
						Pro-52 to Val-57,	10, AR061: 5		110700,
						Pro-85 to Gln-95,	H0706: 8, S0366: 5,		135940,
						Lys-198 to His-204,	S0364: 4, L0485: 4,		145001,
						Pro-254 to Glu-260,	L0604; 4, L0777: 3,		146790,
						Glu-269 to Ser-282,	L0623: 2, S0362: 2,		152445,
						Glu-302 to Gly-307,	H0373: 2, L0520: 2,		152445,
						Asp-320 to Asp-326,	L0747: 2, H0624: 1,		159001,
						Asp-373 to Ser-380,	H0619: 1, H0550: 1,		174000,
						Ile-396 to Asp-407.	H0196: 1, L0646: 1,		179755,
							L0809: 1, H0693: 1,		182860,
							S0328: 1 and H0214: 1.		182860,
									182860,
									191315,
									230800,
									230800,
									266200,
									600897,
									601105,
									601412,
									601652,
									602491
		959176	541	1372-569	1139	Lys-59 to His-65,
						Pro-115 to Glu-121,
						Glu-130 to Ser-143,
						Glu-163 to Gly-168,
						Asp-181 to Asp-187,
						Asp-234 to Ser-241,
						Ile-257 to Asp-268.
249	HLWFN63	1101533	259	404-2566	857	Thr-7 to Phe-29,	AR051: 11, AR050: 9,
						Thr-37 to Lys-52,	AR054: 5, AR089: 0,
						Glu-89 to Val-112.	AR061: 0
							H0031: 5, S0222: 4,
							S0028: 4, H0662: 3,
							L0748: 3, S0260: 3,
							S0276: 3, S0282: 2,
							S0360: 2, S0046: 2,
							H0575: 2, H0196: 2,
							S0036: 2, H0268: 2,
							L0662: 2, S0027: 2,
							L0754: 2, L0747: 2,
							L0749: 2, L0756: 2,
							L0777: 2, L0604: 2,
							L0595: 2, H0171: 1,
							S0030: 1, S0029: 1,
							S0358: 1, H0619: 1,
							S0300: 1, L0717: 1,
							H0550: 1, H0441: 1,
							H0431: 1, H0392: 1,
							T0060: 1, S0010: 1,
							H0052: 1, H0309: 1,
							S6028: 1, S0250: 1,
							H0252: 1, H0553: 1,
							S0364: 1, S0366: 1,
							H0433: 1, H0269: 1,
							H0412: 1, L0372: 1,
							L0804: 1, L0789: 1,
							L0666: 1, L0663: 1,
							S0126: 1, S0044: 1,
							H0345: 1, S0390: 1,
							S0037: 1, S3014: 1,
							L0743: 1, L0439: 1,
							L0750: 1, L0779: 1,
							L0599: 1, L0593: 1,
							L0366: 1 and H0653: 1.
		908437	542	404-2566	1140	Thr-7 to Phe-29,
						Thr-37 to Lys-52,
						Glu-89 to Val-112.
250	HPWAY10	1128033	260	397-1167	858	Gly-1 to Trp-7,	AR089: 1, AR061: 0
						Leu-11 to Phe-21,	H0341: 1, H0013: 1
						Glu-46 to His-52,	and S0044: 1.
						Val-59 to Leu-73,
						Tyr-79 to Cys-91,
						His-111 toTyr-117,
						Ser-133 to Lys-149,
						His-167 to Tyr-173,
						His-195 to Tyr-201,
						His-251 to Lys-257.
		908549	543	149-466	1141	Cys-36 to Asn-43,
						Gln-74 to Trp-79.
251	HOUDH19	1153909	261	3-404	859	Ser-2 to Gln-12,	AR089: 1, AR061: 0
						Cys-14 to Met-19,	S0040: 1, H0250: 1,
						Ser-34 to Leu-41,	T0048: 1, L0761: 1,
						Pro-43 to Leu-48,	L0764: 1, L0783: 1,
						Glu-89 to Asp-111,	L0809: 1, L0789: 1 and
						Ile-125 to Lys-134.	L0757: 1.
		908588	544	52-573	1142	Thr-8 to Gln-19,
						Lys-26 to Glu-33,
						Lys-41 to Ile-50.
252	HDPFF24	1194719	262	124-1317	860	Ser-38 to Tyr-44,	AR089: 4, AR061: 1
						Glu-72 to Pro-77,	H0171: 5, S0026: 3,
						Asp-91 to Pro-113,	S0400: 2, L0471: 2,
						Gln-124 to Asn-134,	H0031: 2, H0553: 2,
						Ser-182 to Ile-190,	H0547: 2, H0521: 2,
						Glu-215 to Gly-220,	L0759: 2, H0423: 2,
						Leu-223 to Ser-229,	H0170: 1, H0583: 1,
						Gln-243 to Ile-250,	H0656: 1, S0001: 1,
						His-273 to His-290,	S0358: 1, S0360: 1,
						His-301 to Lys-308,	H0244: 1, H0349: 1,
						Thr-323 to Glu-336,	H0590: 1, H0310: 1,
						Met-338 to Ser-343,	H0014: 1, H0039: 1,
						Thr-358 to Tyr-363,	S0366: 1, H0551: 1,
						His-385 to Asn-398.	L0351: 1, H0509: 1,
							S0150: 1, L0369: 1,
							L0796: 1, L0773: 1,
							L0662: 1, L0766: 1,
							L0803: 1, L0635: 1,
							L0540: 1, H0519: 1,
							H0684: 1, H0660: 1,
							H0666: 1, S0044: 1,
							H0478: 1, H0479: 1,
							H0626: 1, L0748: 1,
							L0740: 1, L0777: 1,
							L0752: 1, L0755: 1 and
							H0543: 1.
		909232	545	104-460	1143
253	HWLFH94	1152278	263	589-951	861	Glu-20 to Gly-25,	AR089: 5, AR061: 2
						Gln-36 to Ser-48,	S0358: 5, L0596: 3,
						Ser-56 to Val-62.	L0771: 2, L0758: 2,
							S0354: 1, S0376: 1,
							T0109: 1, H0036: 1,
							H0590: 1, L0040: 1,
							H0038: 1, H0616: 1,
							L0646: 1, L0764: 1,
							L0768: 1, L0775: 1,
							L0659: 1 and S0404: 1.
		909682	546	134-535	1144	Ser-25 to Ala-52,
						Phe-64 to Glu-71.
254	HWMBM13	1152283	264	3-557	862	Pro-17 to Ala-41,	AR089: 2, AR061: 2
						Phe-53 to Glu-60,	S0358: 6, L0794: 4,
						Glu-84 to Gly-89,	L0758: 4, S0354: 3,
						Gln-100 to Ser-112,	L0779: 3, L0596: 3,
						Ser-120 to Val-126.	S0376: 2, H0036: 2,
							H0620: 2, H0063: 2,
							L0771: 2, L0803: 2,
							L0654: 2, L0659: 2,
							T0109: 1, H0013: 1,
							H0590: 1, H0052: 1,
							H0596: 1, T0110: 1,
							L0040: 1, H0090: 1,
							H0038: 1, H0040: 1,
							H0616: 1, H0429: 1,
							H0561: 1, L0646: 1,
							L0764: 1, L0768: 1,
							L0766: 1, L0775: 1,
							L0790: 1, L0792: 1,
							S0404: 1, S0390: 1,
							L0777: 1, L0755: 1,
							L0592: 1 and S0458: 1.
		909683	547	3-539	1145	Pro-11 to Ala-35,
						Phe-47 to Glu-54,
						Glu-78 to Gly-83,
						Gln-94 to Ser-106,
						Ser-114 to Val-120.
255	HFIUE75	1172525	265	79-1290	863	His-22 to Ile-35,	AR089: 1, AR061: 1
						Phe-39 to Glu-47,	L0748: 5, S0242: 3,
						Asp-65 to Ser-76,	H0615: 2, S0376: 1,
						Ser-82 to Lys-89,	S0360: 1, L0717: 1,
						Met-93 to Ser-98.	L0641: 1, L0766: 1,
							L0664: 1, H0478: 1,
							L0593: 1 and S0196: 1.
		909758	548	2-775	1146	Cys-1 to Val-10,
						Ala-14 to Met-22.
256	HNTCP13	1182313	266	1-957	864	Leu-6 to Tyr-15,	AR061: 3, AR089: 2
						Ser-48 to Phe-53,	L0750: 4, H0519: 3,
						Asn-66 to Ser-71,	L0666: 2, L0565: 2,
						Asp-101 to Pro-111,	H0539: 2, L0742: 2,
						Gln-116 to Glu-124,	L0744: 2, L0754: 2,
						Arg-203 to Asp-212.	L0777: 2, L0759: 2,
							H0662: 1, S0045: 1,
							S0346: 1, H0251: 1,
							H0030: 1, H0628: 1,
							H0674: 1, H0529: 1,
							L0770: 1, L0764: 1,
							L0526: 1, L0783: 1,
							L0787: 1, H0547: 1,
							H0521: 1, H0696: 1,
							H0555: 1, L0747: 1,
							L0749: 1, L0786: 1,
							L0779: 1, L0780: 1,
							L0752: 1 and L0592: 1.
		909770	549	1-960	1147
257	HBIBQ89	1175111	267	3-824	865	Gly-35 to Asp-41,	AR089: 1, AR061: 0
						Phe-113 to Met-119,	L0438: 6, L0751: 6,
						Pro-164 to Glu-170,	L0439: 5, L0770: 4,
						Val-173 to Gly-178,	H0052: 2, H0620: 2,
						Met-180 to Glu-190,	H0521: 2, L0756: 2,
						Thr-192 to Gln-199,	L0731: 2, L0758: 2,
						His-206 to Glu-211,	L0588: 2, H0556: 1,
						Arg-244 to Ile-257.	S0282: 1, H0662: 1,
							H0402: 1, S0418: 1,
							T0008: 1, S0222: 1,
							H0392: 1, H0333: 1,
							L0021: 1, H0581: 1,
							S0049: 1, L0471: 1,
							H0266: 1, L0351: 1,
							L0772: 1, L0766: 1,
							L0776: 1, L0659: 1,
							L0792: 1, H0522: 1,
							S0027: 1, L0779: 1 and
							S0011: 1.
		909782	550	2-577	1148
258	HWBEG18	1169125	268	439-161	866	Leu-42 to Ile-47.	AR089: 82, AR061: 18
							H0580: 1
		909798	551	55-696	1149	Trp-46 to Lys-51,
						Pro-109 to Asn-123,
						Phe-156 to Gly-165.
259	HTAHB43	1221956	269	3-2174	867		AR089: 1, AR061: 0
							H0046: 34, L0731: 5,
							L0534: 4, L0769: 4,
							H0521: 4, S0356: 3,
							L0800: 3, L0794: 3,
							L0439: 3, L0749: 3,
							L0752: 3, L0759: 3,
							L0562: 2, H0486: 2,
							L0803: 2, L0805: 2,
							L0809: 2, L0789: 2,
							L0744: 2, L0485: 2,
							H0556: 1, H0657: 1,
							H0637: 1, H0580: 1,
							H0208: 1, H0261: 1,
							H0609: 1, H0455: 1,
							H0600: 1, H0586: 1,
							H0331: 1, H0635: 1,
							H0618: 1, H0544: 1,
							H0009: 1, H0050: 1,
							H0620: 1, H0288: 1,
							S0312: 1, S0314: 1,
							H0252: 1, H0688: 1,
							H0644: 1, S0366: 1,
							H0135: 1, H0063: 1,
							H0087: 1, H0551: 1,
							H0264: 1, S0002: 1,
							L0639: 1, L0771: 1,
							L0648: 1, L0766: 1,
							L0650: 1, L0378: 1,
							L0655: 1, H0699: 1,
							H0660: 1, L0743: 1,
							L0750: 1, L0777: 1,
							L0758: 1, L0097: 1,
							S0194: 1 and H0543: 1.
		909845	552	18-914	1150	Gln-8 to Glu-13.
260	HSYBX32	909846	270	46-228	868		AR061: 0, AR089: 0	7q22-	126650,
							H0046: 34, L0731: 5,	q31.1	126650,
							L0534: 4, L0769: 4,		150240,
							H0521: 4, S0356: 3,		154276,
							L0800: 3, L0794: 3,		173360,
							L0439: 3, L0749: 3,		173360,
							L0752: 3, L0759: 3,		180105,
							L0562: 2, H0486: 2,		222800,
							L0803: 2, L0805: 2,		246900,
							L0809: 2, L0789: 2,		602136,
							L0744: 2, L0485: 2,		602136,
							H0556: 1, H0657: 1,		602136,
							H0637: 1, H0580: 1,		602447
							H0208: 1, H0261: 1,
							H0609: 1, H0455: 1,
							H0600: 1, H0586: 1,
							H0331: 1, H0635: 1,
							H0618: 1, H0544: 1,
							H0009: 1, H0050: 1,
							H0620: 1, H0288: 1,
							S0312: 1, S0314: 1,
							H0252: 1, H0688: 1,
							H0644: 1, S0366: 1,
							H0135: 1, H0063: 1,
							H0087: 1, H0551: 1,
							H0264: 1, S0002: 1,
							L0639: 1, L0771: 1,
							L0648: 1, L0766: 1,
							L0650: 1, L0378: 1,
							L0655: 1, H0699: 1,
							H0660: 1, L0743: 1,
							L0750: 1, L0777: 1,
							L0758: 1, L0097: 1,
							S0194: 1 and H0543: 1.
261	HCEHE35	1124531	271	2-550	869	Arg-1 to Pro-15,	AR061: 8, AR089: 3
						Asn-17 to Leu-25,	S0222: 1, H0052: 1,
						Glu-27 to Pro-36,	H0194: 1, H0290: 1 and
						Pro-41 to Pro-55,	H0264: 1.
						Glu-58 to Gln-79.
		909937	553	3-392	1151	Asn-6 to Pro-13.
262	HFCBB56	1204971	272	112-753	870	Thr-37 to Ser-42,	AR061: 1, AR089: 1
						Gln-48 to Pro-55,	H0009: 1
						Ser-75 to Ala-80,
						Ser-95 to Val-111,
						Gln-113 to Gly-124,
						Glu-153 to Gly-161,
						Tyr-188 to Asp-193.
		910073	554	209-565	1152
263	HAMFL82	910074	273	3-317	871	Glu-20 to Val-26.	AR089: 9, AR061: 4
							H0229: 1, H0590: 1,
							S0049: 1, H0014: 1,
							H0560: 1, L0439: 1 and
							H0543: 1.
264	HBXCM38	1174533	274	402-1349	872		AR061: 2, AR089: 1
							L0439: 6, S0038: 3,
							L0803: 3, H0455: 2,
							L0769: 2, L0809: 2,
							L0741: 2, L0756: 2,
							S6024: 1, S0001: 1,
							H0663: 1, S0222: 1,
							H0441: 1, H0438: 1,
							H0036: 1, S0049: 1,
							H0309: 1, H0566: 1,
							H0024: 1, S0388: 1,
							S0051: 1, T0010: 1,
							H0059: 1, L0645: 1,
							L0774: 1, L0790: 1,
							L0663: 1, L0665: 1,
							H0345: 1, L0742: 1,
							L0748: 1, L0749: 1,
							H0707: 1, L0595: 1 and
							L0366: 1.
		910086	555	402-1535	1153	Val-36 to Glu-43,
						Lys-66 to Glu-71.
265	HLHCR16	910123	275	2-3418	873	Pro-9 to Pro-15,	AR050: 9, AR061: 2,
						Gly-49 to Trp-54,	AR054: 2, AR089: 2,
						Ser-91 to Phe-96,	AR051: 2
						Thr-109 to Asp-115,	L0754: 14, L0777: 13,
						Cys-124 to Ile-130,	H0553: 10, L0600: 7,
						Cys-164 to Trp-169,	L0748: 6, L0803: 4,
						Thr-193 to Asp-207,	L0749: 4, UNKWN: 4,
						Thr-215 to Tyr-220,	H0624: 3, S0280: 3,
						Thr-228 to Ser-240,	S0126: 3, L0747: 3,
						Glu-269 to Ser-276,	S0282: 2, H0024: 2,
						Glu-327 to Ala-334,	H0030: 2, H0031: 2,
						Asn-376 to Asp-392,	H0040: 2, L0438: 2,
						Gln-420 to Asn-428,	S0028: 2, L0743: 2,
						Tyr-547 to Ser-566,	L0596: 2, L0603: 2,
						Ala-616 to Gly-623,	S0212: 1, H0270: 1,
						Pro-625 to Ser-631,	H0244: 1, H0427: 1,
						Ser-647 to Val-653,	H0251: 1, H0309: 1,
						Gly-676 to Pro-681,	S0338: 1, S0340: 1,
						Tyr-720 to Glu-740,	S0250: 1, H0252: 1,
						Ile-742 to Lys-748,	H0039: 1, L0143: 1,
						Asp-792 to Cys-804,	H0038: 1, L0659: 1,
						Leu-841 to Val-848,	L0565: 1, H0593: 1,
						Gln-850 to Gly-857,	H0684: 1, H0518: 1,
						Asp-879 to Gly-886,	S0390: 1, S0260: 1 and
						His-906 to Trp-913,	H0506: 1.
						Pro-968 to Thr-975,
						Gln-1051 to Ser-1057,
						Pro-1092 to Cys-1099,
						Lys-1113 to Cys-1120,
						Trp-1126 to Phe-1139.
		965511	556	2-1492	1154	Pro-9 to Pro-15,
						Gly-49 to Trp-54,
						Ser-91 to Phe-96,
						Thr-109 to Asp-115,
						Cys-124 to Ile-130,
						Cys-164 to Trp-169,
						Thr-193 to Asp-207,
						Thr-215 to Tyr-220,
						Thr-228 to Ser-240,
						Glu-269 to Ser-276,
						Glu-327 to Ala-334,
						Asn-376 to Asp-392,
						Gln-420 to Asn-428.
266	HE6GF02	1153883	276	1-612	874	Gln-13 to Ser-18,	AR061: 7, AR089: 4
						Glu-32 to Gly-37,	H0100: 1 and H0521: 1
						Ala-44 to Trp-49,
						Glu-56 to Val-61,
						Gln-68 to Lys-74,
						Ala-83 to Glu-88,
						Arg-111 to Gly-117,
						Tyr-123 to His-143,
						Ser-167 to Met-201.
		911263	557	1-264	1155	Gln-13 to Ser-18,
						Glu-32 to Gly-37,
						Ala-44 to Trp-49.
267	HOUFT36	1162680	277	853-1563	875	Thr-70 to Ala-83,	AR089: 2, AR061: 1
						Gly-105 to Asn-110,	L0794: 6, L0598: 2,
						Ser-181 to Val-187.	L0803: 2, L0748: 2,
							S0040: 1, S0046: 1,
							H0431: 1, H0318: 1,
							L0766: 1, L0606: 1,
							L0749: 1, L0758: 1 and
							S0192: 1.
		911293	558	160-846	1156	Lys-27 to Ile-43.
268	HAGGF84	1197460	278	415-1530	876	Arg-24 to Arg-30,	AR061: 3, AR089: 2
						Arg-39 to Tyr-44,	L0766: 18, L0748: 11,
						Lys-78 to Glu-91,	L0439: 9, L0749: 8,
						Val-215 to Lys-223.	L0438: 5, L0750: 5,
							L0777: 4, L0759: 4,
							H0441: 3, H0052: 3,
							L0637: 3, L0761: 3,
							L0740: 3, L0747: 3,
							L0103: 2, H0574: 2,
							H0156: 2, H0597: 2,
							S0250: 2, L0649: 2,
							L0803: 2, L0806: 2,
							L0792: 2, S3014: 2,
							L0757: 2, L0485: 2,
							L0599: 2, H0171: 1,
							S6024: 1, L0002: 1,
							H0657: 1, H0341: 1,
							S0358: 1, S0360: 1,
							S0132: 1, L0717: 1,
							H0632: 1, H0013: 1,
							H0599: 1, S0010: 1,
							S0346: 1, H0318: 1,
							H0251: 1, T0115: 1,
							H0544: 1, L0471: 1,
							H0014: 1, S0362: 1,
							H0083: 1, H0188: 1,
							H0428: 1, H0646: 1,
							H0538: 1, L0598: 1,
							L0762: 1, L0763: 1,
							L0769: 1, L0662: 1,
							L0768: 1, L0776: 1,
							L0655: 1, L0659: 1,
							L0526: 1, L0783: 1,
							L0789: 1, L0665: 1,
							S0148: 1, H0520: 1,
							H0519: 1, S0330: 1,
							L0602: 1, S0152: 1,
							S0136: 1, S0350: 1,
							L0752: 1, H0343: 1,
							L0366: 1, S0011: 1,
							H0665: 1, S0196: 1,
							H0423: 1, L0697: 1 and
							S0462: 1.
		911312	559	1-333	1157	Lys-14 to Glu-27.
269	HTTKP07	1119031	279	2-571	877	Thr-15 to Asp-25,	AR089: 1, AR061: 1
						Glu-69 to Leu-89,	H0634: 2
						Glu-130 to Arg-137.
		911390	560	2-337	1158	Thr-15 to Asp-25,
						Glu-69 to Leu-89.
270	HE9SE62	1171014	280	718-212	878		AR061: 16, AR089: 6
							L0804: 1, S0052: 1,
							H0144: 1 and H0659: 1.
		911476	561	1-564	1159
271	HUJAD24	1162674	281	788-1255	879	Gln-49 to Thr-69,	AR089: 1, AR061: 0
						His-129 to Cys-143.	L0750: 3, H0650: 2,
							H0637: 2, H0265: 1,
							H0556: 1, S0222: 1,
							H0040: 1, H0280: 1,
							L0655: 1, L0789: 1 and
							L0666: 1.
		911498	562	3-293	1160
272	HWLFG75	1228123	282	1-819	880	Val-15 to Gly-26,	AR089: 1, AR061: 0
						Pro-43 to Ala-64,	L0439: 7, L0770: 4,
						Arg-75 to Gly-82,	L0771: 4, L0779: 4,
						Thr-115 to Thr-120,	H0688: 3, H0617: 2,
						Leu-215 to Gly-222,	L0533: 2, L0803: 2,
						Ser-230 to Trp-235,	L0807: 2, L0791: 2,
						Pro-237 to Ala-248.	L0666: 2, H0539: 2,
							H0624: 1, S0400: 1,
							H0125: 1, H0192: 1,
							S0356: 1, S0354: 1,
							S0376: 1, S0360: 1,
							S0278: 1, H0550: 1,
							H0333: 1, S0049: 1,
							H0205: 1, S0051: 1,
							L0142: 1, L0455: 1,
							L0769: 1, L0794: 1,
							L0658: 1, L0540: 1,
							L0518: 1, L0809: 1,
							L0663: 1, H0689: 1,
							S0332: 1, H0214: 1,
							S3014: 1, L0747: 1,
							L0749: 1, L0758: 1,
							S0260: 1 and S0458: 1.
		916563	563	1-750	1161	Val-10 to Gly-21,
						Pro-38 to Ala-59,
						Arg-70 to Gly-77,
						Thr-110 to Thr-115,
						Leu-210 to Gly-217,
						Ser-225 to Trp-230,
						Pro-232 to Arg-239.
273	HT3BG12	1092417	283	9-785	881		AR061: 8, AR089: 3
							L0758: 3, H0159: 2,
							S0001: 1, H0618: 1,
							H0660: 1 and L0779: 1.
		921593	564	1-381	1162	Glu-1 to Ala-15,
						Lys-25 to Ser-32,
						Asp-45 to Thr-51,
						Pro-59 to Pro-65,
						Pro-78 to Ser-85.
274	HTLJC71	922923	284	3-1355	882	His-1 to Phe-9,	AR061: 7, AR089: 5
						Cys-13 to Thr-18,	H0618: 12, H0253: 8,
						Pro-35 to Gly-48,	H0038: 6, L0758: 6,
						Glu-61 to Pro-68,	L0779: 5, H0616: 3,
						Lys-105 to Ala-136,	T0041: 1, L0776: 1,
						Thr-144 to Gln-154,	S0274: 1 and H0543: 1.
						Leu-163 to Gly-171,
						Thr-205 to Gln-222,
						Pro-251 to Gln-257.
275	HCOMM05	1194701	285	2-850	883	Gln-22 to Asp-41,	AR089: 1, AR061: 1
						Pro-49 to Thr-58,	H0670: 1
						Leu-99 to Gly-107,
						Ala-117 to Ala-122,
						Gln-128 to Trp-134,
						Pro-136 to Pro-144,
						Phe-147 to Glu-153,
						Glu-183 to Val-188,
						Glu-195 to Glu-200,
						Glu-257 to Leu-265,
						Met-275 to Ser-283.
		925952	565	1-840	1163	Gln-19 to Asp-38,
						Pro-46 to Thr-55,
						Leu-96 to Gly-104,
						Ala-114 to Ala-119,
						Gln-125 to Trp-131,
						Pro-133 to Pro-141,
						Phe-144 to Glu-150,
						Glu-180 to Val-185,
						Glu-192 to Glu-197,
						Glu-254 to Leu-262,
						Met-272 to Ser-280.
276	HSLJE54	1229928	286	650-1654	884	Ala-17 to Val-30,	AR061: 0, AR089: 0
						Thr-32 to Arg-39,	S0036: 1, H0521: 1,
						Arg-55 to Ser-60,	H0436: 1 and S0390: 1.
						Ala-213 to Leu-219,
						Glu-236 to Glu-241,
						Ser-262 to Tyr-272,
						Pro-299 to Asn-305.
		926924	566	3-731	1164	Arg-1 to Gly-7,
						Pro-25 to His-34,
						Leu-36 to Lys-49.
277	HTGED07	927411	287	16-483	885	Lys-35 to Asn-46.	AR089: 33, AR061: 7
278	HOFNH30	928365	288	3-320	886		AR089: 4, AR061: 2
							H0415: 13, H0414: 2,
							H0355: 1, H0517: 1 and
							H0539: 1.
279	HWNCY05	1179767	289	1-981	887	Lys-15 to Gly-23,	AR061: 2, AR089: 1
						Glu-36 to His-47.	H0656: 2, S0360: 2,
							H0657: 1, H0662: 1,
							S0420: 1, S0356: 1,
							S0358: 1, S0132: 1,
							H0392: 1, S0022: 1,
							H0144: 1, H0520: 1,
							H0659: 1, H0658: 1,
							H0660: 1, H0672: 1,
							S0380: 1, L0602: 1,
							H0653: 1 and H0677: 1.
		928789	567	3-1319	1165	Lys-11 to Gly-19,
						Glu-32 to His-43,
						Lys-60 to Glu-66,
						Pro-86 to Lys-98,
						Lys-118 to Leu-128,
						Thr-142 to Trp-148.
280	HDPDA47	929193	290	103-906	888	Arg-17 to Leu-34,	AR089: 11, AR061: 3
						Asp-44 to Ser-51,	H0521: 7, H0581: 3,
						Asp-63 to Gly-72,	H0422: 3, H0650: 2,
						Pro-74 to Gly-83,	H0486: 2, S0002: 2,
						Thr-97 to Met-102.	L0770: 2, L0769: 2,
							L0766: 2, L0518: 2,
							L0783: 2, L0777: 2,
							L0731: 2, H0445: 2,
							H0556: 1, H0583: 1,
							H0657: 1, H0656: 1,
							H0341: 1, H0575: 1,
							H0457: 1, H0179: 1,
							H0271: 1, L0055: 1,
							H0264: 1, H0488: 1,
							S0426: 1, L0662: 1,
							L0775: 1, L0655: 1,
							L0665: 1, S0053: 1,
							H0702: 1, H0701: 1,
							H0659: 1, L0754: 1,
							L0779: 1, L0759: 1 and
							H0543: 1.
281	HWMEV63	931154	291	2-454	889	His-9 to Asn-26,	AR089: 1, AR061: 1	3q21-q25	106165,
						Pro-47 to Ser-61,	S0358: 1 and H0580: 1.		117700,
						Arg-116 to Thr-122.			117700,
									150210,
									169600,
									180380,
									180380,
									180380,
									190000,
									203500,
									222900,
									232050,
									276902,
									600882,
									601199,
									601199,
									601199,
									601471,
									601682
282	HCFAT25	1052857	292	2-640	890	Pro-19 to Lys-34,	AR061: 2, AR089: 2
						Arg-63 to Arg-72,	S0358: 1, H0413: 1,
						Lys-76 to Pro-113,	L0502: 1, L0657: 1,
						Gln-133 to Gln-150,	H0522: 1 and H0422: 1.
						Gln-152 to Gln-163,
						Glu-167 to Arg-187.
		932068	568	82-588	1166	Lys-15 to Ser-20,
						Arg-51 to Arg-60,
						Lys-64 to Pro-101.
283	HHEQV39	1165420	293	1-711	891	Leu-7 to Phe-27,	AR089: 3, AR061: 1
						Gln-50 to Gln-57.	T0042: 1, H0543: 1
							and H0422: 1.
		932851	569	1-711	1167	Leu-7 to Phe-27,
						Gln-50 to Gln-57.
284	HHFJH79	1228195	294	608-2260	892	Ser-39 to Pro-44,	AR061: 2, AR089: 2
						Pro-51 to Thr-56,	H0424: 9, L0747: 7,
						Gly-78 to Cys-92,	H0618: 5, H0620: 5,
						Pro-133 to Ser-146,	L0809: 5, H0549: 4,
						Glu-211 to Ala-219,	H0087: 4, L0655: 4,
						His-239 to Gln-250,	L0750: 4, S0222: 3,
						Thr-280 to Glu-285,	H0253: 3, S0346: 3,
						Asn-347 to Gly-371,	H0150: 3, H0081: 3,
						Asp-378 to Asn-385,	H0083: 3, H0188: 3,
						Arg-390 to Gly-398,	H0428: 3, H0213: 3,
						Thr-406 to Gly-420,	L0774: 3, L0805: 3,
						Pro-422 to Gly-427,	L0749: 3, L0759: 3,
						Arg-440 to Leu-450,	L0005: 2, H0619: 2,
						Pro-458 to Gly-463,	S0278: 2, H0635: 2,
						Pro-485 to Leu-490,	S0049: 2, H0251: 2,
						Gly-526 to Pro-533.	H0546: 2, H0009: 2,
							H0012: 2, H0024: 2,
							H0617: 2, H0494: 2,
							L0769: 2, L0637: 2,
							L0772: 2, L0803: 2,
							L0518: 2, L0384: 2,
							L0665: 2, L0438: 2,
							H0547: 2, H0658: 2,
							S0152: 2, H0521: 2,
							L0439: 2, L0779: 2,
							L0758: 2, L0592: 2,
							L0599: 2, L0595: 2,
							H0543: 2, S0424: 2,
							H0352: 2, H0624: 1,
							H0686: 1, H0295: 1,
							S0114: 1, S0134: 1,
							H0341: 1, S0212: 1,
							H0254: 1, S0420: 1,
							S0354: 1, H0351: 1,
							H0550: 1, H0586: 1,
							H0333: 1, H0643: 1,
							L0623: 1, H0486: 1,
							T0039: 1, H0013: 1,
							T0082: 1, H0052: 1,
							H0597: 1, H0545: 1,
							H0178: 1, L0157: 1,
							H0594: 1, H0028: 1,
							H0604: 1, H0032: 1,
							H0674: 1, S0364: 1,
							H0361: 1, H0135: 1,
							H0551: 1, H0264: 1,
							H0100: 1, T0042: 1,
							H0561: 1, L0369: 1,
							L0770: 1, L0639: 1,
							L0800: 1, L0662: 1,
							L0768: 1, L0364: 1,
							L0794: 1, L0804: 1,
							L0375: 1, L0378: 1,
							L0653: 1, L0776: 1,
							L0659: 1, L0365: 1,
							L0542: 1, L0783: 1,
							L0789: 1, L0790: 1,
							L0791: 1, L0666: 1,
							S0052: 1, T0068: 1,
							H0689: 1, H0690: 1,
							H0684: 1, H0670: 1,
							H0660: 1, H0648: 1,
							H0672: 1, S0044: 1,
							L0741: 1, L0743: 1,
							L0748: 1, L0751: 1,
							L0756: 1, L0752: 1,
							L0731: 1, L0757: 1,
							H0665: 1, L0096: 1 and
							S0194: 1.
		933308	570	2-832	1168
285	HUCOW17	1155190	295	1-993	893	Ser-30 to Ser-35.	AR089: 4, AR061: 2
							L0439: 5, S0002: 3,
							L0604: 3, H0619: 2,
							H0024: 2, H0625: 2,
							L0768: 2, L0757: 2,
							H0638: 1, S0420: 1,
							S0360: 1, H0586: 1,
							L0163: 1, S0214: 1,
							L0143: 1, H0264: 1,
							L0769: 1, L0764: 1,
							L0774: 1, L0651: 1,
							L0659: 1, L0542: 1,
							L0789: 1, H0539: 1,
							H0521: 1, S0044: 1,
							L0777: 1, L0758: 1,
							L0599: 1 and H0422: 1.
		933357	571	155-856	1169	Gln-27 to Trp-45.
286	HFKIT06	1078092	296	1-1119	894	Lys-6 to Trp-11,	AR089: 0, AR061: 0
						Pro-26 to Pro-40,	H0620: 2, L0761: 2,
						Pro-48 to Gln-53.	L0766: 2, L0744: 2,
							L0754: 2, L0596: 2,
							H0686: 1, H0295: 1,
							H0657: 1, H0597: 1,
							H0009: 1, H0264: 1,
							S0002: 1, L0769: 1,
							L0774: 1, L0805: 1,
							L0657: 1, L0790: 1,
							H0690: 1 and H0521: 1.
		934019	572	1-300	1170	Asp-2 to Pro-7,
						Pro-15 to Gln-20.
287	HDTBY88	1104159	297	3-536	895	His-130 to Lys-140.	AR089: 8, AR061: 2
							S0218: 1 and H0486: 1.
		934472	573	3-464	1171	His-130 to Lys-140.
288	HWLHS82	1082268	298	3-1349	896	Pro-22 to Thr-29,	AR089: 2, AR061: 1
						Gly-65 to Lys-75.	L0769: 3, S0354: 1,
							H0393: 1, H0355: 1 and
							H0124: 1.
		934505	574	2-427	1172	Gly-34 to Lys-44,
						Glu-113 to Glu-118.
289	HDPNC96	1081629	299	3-734	897	Val-2 to Gly-8,	AR089: 1, AR061: 1
						Asp-20 to Gln-26.	H0522: 2 and L0766:
							1.
		934520	575	3-734	1173	Val-2 to Gly-8,
						Asp-20 to Gln-26.
290	HCE5I78	1197899	300	2-1126	898	Ala-7 to Gly-15,	AR061: 5, AR089: 2
						Pro-33 to Gln-39,	L0439: 8, H0052: 7,
						Ala-48 to Ala-71,	L0741: 7, L0756: 4,
						Tyr-83 to Ser-89,	S0010: 3, H0261: 2,
						Ser-122 to Ile-139,	H0156: 2, S0049: 2,
						Thr-150 to Thr-158,	L0770: 2, L0776: 2,
						Lys-183 to Phe-193,	L0742: 2, L0745: 2,
						Pro-277 to Asn-299,	L0366: 2, S0222: 1,
						Asp-324 to Gly-333,	H0438: 1, H0390: 1,
						Lys-354 to Glu-361,	S0346: 1, H0009: 1,
						Gln-367 to Ser-374.	L0455: 1, S0038: 1,
							L0789: 1 and L0758: 1.
		934531	576	3-422	1174	Pro-14 to Gln-20,
						Ala-29 to Ala-52,
						Tyr-64 to Ser-70,
						Ser-103 to His-120.
291	HISDS62	1159625	301	182-862	899	Ser-39 to Trp-44,	AR089: 2, AR061: 1
						Ile-48 to Trp-54,	T0049: 1, S0278: 1,
						Asn-65 to Asp-87,	H0031: 1 and H0539: 1.
						Pro-94 to Gln-100,
						Lys-129 to Asp-136,
						Asp-163 to His-174,
						Ser-193 to His-199.
		935932	577	1-519	1175	Ser-11 to Trp-16,
						Ile-20 to Trp-26,
						Asn-37 to Ser-58,
						Leu-67 to Gln-72,
						Lys-101 to Asp-108,
						Asp-135 to Tyr-140.
292	HDQDV69	1212566	302	210-1697	900	Met-7 to Ser-12,	AR089: 46, AR061: 33
						Ser-20 to Arg-30,	H0521: 4, H0051: 2,
						Asp-85 to Ala-92,	L0803: 2, L0748: 2,
						Met-119 to Asn-146,	L0740: 2, L0756: 2,
						Pro-151 to Asp-161,	L0752: 2, L0755: 2,
						Gln-253 to Glu-260,	H0590: 1, H0014: 1,
						Ile-333 to Val-342,	S0250: 1, L0772: 1,
						Leu-396 to Ala-406.	L0764: 1, L0804: 1,
							H0522: 1, S0406: 1,
							L0754: 1, L0779: 1,
							L0731: 1 and L0758: 1.
		937850	578	2-829	1176
		949702	579	551-339	1177	Lys-1 to Thr-7,
						Arg-34 to Pro-41.
293	HEMBT61	939957	303	1-351	901		AR061: 8, AR089: 4
							L0547: 2, S0046: 1,
							L0471: 1, L0772: 1,
							L0529: 1 and L0780: 1.
294	HRODZ70	1088554	304	2-661	902	Lys-123 to Lys-128,	AR089: 12, AR061: 4
						Trp-180 to Lys-186,	H0598: 1 and H0135:
						Leu-204 to Thr-220.	1.
		942673	580	3-440	1178	Lys-49 to Lys-54,
						Trp-106 to Lys-112,
						Leu-130 to Gly-141.
295	HHERQ79	1184003	305	284-703	903	Ser-3 to Thr-11,	AR089: 3, AR061: 2
						Lys-32 to Gly-39,	H0597: 1, H0435: 1
						Thr-50 to Glu-57,	and H0543: 1.
						Thr-83 to Gln-88.
		944057	581	88-474	1179	Ser-3 to Thr-11,
						Lys-32 to Gly-39,
						Thr-50 to Glu-57,
						Thr-83 to Gln-88.
296	HCECM90	1031741	306	2-577	904	Gly-12 to Gly-31,	AR061: 2, AR089: 1
						Asn-38 to Gly-62,	H0013: 3, L0439: 2,
						Asp-70 to Phe-84,	H0624: 1, H0171: 1,
						Val-94 to Ser-101,	S0040: 1, S0420: 1,
						Ala-112 to Ser-125,	H0619: 1, H0156: 1,
						Lys-140 to Asn-145,	H0575: 1, H0590: 1,
						Asn-175 to Tyr-180,	H0052; 1, H0011: 1,
						Arg-187 to Thr-192.	H0266: 1, H0494: 1,
							L0519: 1, H0519: 1,
							H0555: 1, L0777: 1,
							L0758: 1, S0436: 1 and
							H0506: 1.
		945088	582	2-577	1180	Gly-12 to Gly-31,
						Asn-38 to Gly-62,
						Asp-70 to Phe-84,
						Val-94 to Ser-101,
						Ala-112 to Ser-125,
						Lys-140 to Asn-145,
						Asn-175 to Tyr-180,
						Arg-187 to Thr-192.
297	HWHGW72	1199614	307	3-1208	905	Lys-63 to Pro-72,	AR054: 23, AR050:
						Val-97 to Gly-102,	16, AR051: 3, AR089:
						His-116 to Cys-123,	1, AR061: 1
						Tyr-161 to Thr-167,	H0586: 1 and L0375:
						Pro-204 to Lys-210,	1.
						Ala-214 to Lys-222,
						Glu-276 to Lys-289,
						Tyr-305 to Thr-312,
						Pro-383 to Gly-398.
		945692	583	100-939	1181
		947361	584	327-1	1182	Gly-1 to Gly-7,
						Ala-13 to Gln-21,
						Ala-43 to Ser-48,
						Asn-67 to Gly-75,
						Pro-82 to Pro-90.
298	HPCRV84	1219890	308	123-875	906	Thr-1 to Leu-12,	AR089: 0, AR061: 0
						Asp-107 to Thr-114,
						Pro-162 to Leu-170.
		945856	585	112-417	1183	Thr-1 to Leu-12.
299	HNSAA28	946988	309	85-1557	907	Glu-9 to Ser-20,	AR050: 8, AR054: 6,
						Ile-23 to Gly-29,	AR051: 3, AR089: 1,
						Pro-50 to Cys-66,	AR061: 1
						Pro-74 to Glu-79,	H0036: 2, L0766: 2,
						Glu-93 to Trp-98,	H0686: 1, H0622: 1,
						Thr-121 to Ser-133,	H0625: 1, L0791: 1,
						Leu-180 to Lys-196,	L0779: 1 and S0434: 1.
						Thr-213 to Glu-225,
						Glu-234 to Glu-240,
						Arg-263 to Glu-270,
						Glu-283 to Ala-298,
						Lys-318 to Ala-336,
						Val-340 to Ala-351,
						Val-361 to Pro-372,
						Asn-445 to Pro-468,
						Pro-475 to Lys-491.
		972348	586	3-452	1184	Thr-1 to Ala-10,
						Val-20 to Pro-31,
						Asn-104 to Thr-124.
300	HLWAR77	947484	310	1287-292	908	Gln-97 to Pro-114,	AR050: 21, AR054: 9,
						Trp-117 to Lys-129,	AR051: 3, AR089: 1,
						Thr-166 to Gln-173,	AR061: 1
						Ser-178 to Lys-183,	H0553: 4 and L0759:
						Glu-250 to Phe-256,	2.
						Ser-295 to His-301,
						Tyr-307 to Gln-316,
						Glu-322 to Ser-330.
301	HTTJW49	1127477	311	423-1319	909	Phe-8 to Gln-13,	AR061: 3, AR089: 2
						Arg-63 to Gly-69,	L0769: 3, L0803: 3,
						Gly-135 to Lys-144,	L0748: 3, L0749: 3,
						Ala-201 to Ala-211,	H0574: 2, H0046: 2,
						Arg-248 to Thr-255,	L0794: 2, L0776: 2,
						Leu-294 to Pro-299.	L0439: 2, L0754: 2,
							L0747: 2, L0755: 2,
							L0605: 2, L0593: 2,
							H0686: 1, S0360: 1,
							L0717: 1, H0069: 1,
							H0575: 1, H0620: 1,
							H0024: 1, S0388: 1,
							H0510: 1, H0266: 1,
							H0644: 1, H0163: 1,
							H0090: 1, H0634: 1,
							H0561: 1, H0695: 1,
							L0763: 1, L0804: 1,
							L0774: 1, L0775: 1,
							L0659: 1, L0783: 1,
							L0809: 1, L0666: 1,
							L0665: 1, L0438: 1,
							H0519: 1, H0658: 1,
							H0539: 1, S0152: 1,
							H0522: 1, L0740: 1,
							L0777: 1, L0603: 1,
							S0276: 1 and H0542: 1.
		948107	587	25-660	1185	Val-11 to Gly-21,
						Gly-72 to Thr-80.
302	HWAFS18	1155193	312	54-1718	910	Pro-1 to Pro-7,	AR089: 4, AR061: 3
						Leu-10 to Lys-18,	H0581: 3, H0622: 3,
						Val-119 to Lys-126,	H0575: 2, H0090: 2,
						Gln-146 to Trp-151.	L0777: 2, L0757: 2,
							S0114: 1, H0650: 1,
							H0255: 1, S0360: 1,
							S0278: 1, H0486: 1,
							H0318: 1, H0457: 1,
							H0039: 1, H0553: 1,
							L0763: 1, L0761: 1,
							L0764: 1, L0789: 1,
							H0144: 1, S0374: 1,
							S0310: 1, H0555: 1,
							L0758: 1, H0445: 1 and
							S0276: 1.
		948434	588	54-791	1186	Pro-1 to Pro-7,
						Leu-10 to Lys-18,
						Val-119 to Lys-126,
						Gln-146 to Trp-151,
						Asp-210 to Arg-216.
303	HFCBA44	1082762	313	1-669	911		AR089: 14, AR061: 9
							H0457: 1, H0009: 1,
							L0666: 1, S0053: 1 and
							L0741: 1.
		948533	589	192-494	1187
304	HVADT77	1180374	314	1-249	912	Thr-28 to Lys-34,	AR089: 4, AR061: 2
						Pro-36 to Asn-44,	L0744: 9, L0747: 8,
						Lys-72 to Lys-83.	S3014: 7, L0740: 7,
							S0192: 6, S0027: 5,
							S0212: 4, H0124: 4,
							L0731: 4, L0662: 3,
							L0743: 3, L0752: 3,
							L0759: 3, H0662: 2,
							S0418: 2, S0046: 2,
							H0575: 2, H0545: 2,
							H0041: 2, H0413: 2,
							L0775: 2, H0696: 2,
							L0748: 2, L0751: 2,
							L0754: 2, L0749: 2,
							L0758: 2, H0445: 2,
							S0276: 2, H0624: 1,
							L0778: 1, L0005: 1,
							H0645: 1, H0441: 1,
							H0391: 1, S0005: 1,
							T0040: 1, H0069: 1,
							H0427: 1, S0280: 1,
							H0042: 1, T0048: 1,
							H0505: 1, H0309: 1,
							H0544: 1, H0009: 1,
							H0266: 1, H0617: 1,
							H0412: 1, H0623: 1,
							T0004: 1, L0564: 1,
							T0041: 1, H0494: 1,
							H0633: 1, H0646: 1,
							H0652: 1, L0769: 1,
							L0646: 1, L0655: 1,
							L0659: 1, L0546: 1,
							L0783: 1, L0809: 1,
							H0144: 1, L0565: 1,
							S0126: 1, H0689: 1,
							H0435: 1, H0659: 1,
							H0672: 1, S0378: 1,
							H0555: 1, S0037: 1,
							S0206: 1, L0777: 1,
							L0780: 1, S0434: 1,
							S0011: 1, S0194: 1 and
							H0506: 1.
		948886	590	1-330	1188	Thr-11 to Trp-25,
						Ser-35 to Arg-42,
						Asp-50 to Arg-56,
						Tyr-75 to Ser-81,
						Gly-89 to Gln-104.
305	HUFCN91	1189013	315	25-858	913	Cys-7 to Ala-24,	AR089: 2, AR061: 2
						Asn-30 to Asn-42,	H0441: 5, H0134: 3,
						Ser-80 to Ser-89,	H0050: 2, S0038: 2,
						Leu-130 to Arg-135,	L0777: 2, H0583: 1,
						Leu-142 to Ser-150,	H0650: 1, H0656: 1,
						Ser-206 to Leu-217,	H0255: 1, H0125: 1,
						Arg-234 to Trp-240.	H0192: 1, H0676: 1,
							H0438: 1, S0049: 1,
							H0038: 1, H0529: 1,
							H0690: 1, L0439: 1,
							H0677: 1 and H0506: 1.
		949137	591	25-924	1189	Cys-7 to Ala-24,
						Asn-30 to Asn-42,
						Ser-80 to Ser-89,
						Leu-130 to Arg-135,
						Leu-142 to Ser-150,
						Tyr-161 to Arg-166.
306	HAGBX32	951351	316	3-509	914	Gly-14 to Gly-32,	AR061: 4, AR089: 4		108730,
						Pro-60 to Ala-70,	L0439: 4, L0418: 1,		147781,
						Thr-145 to Gly-153,	S0010: 1, L0455: 1,		172471,
						Ser-164 to Leu-169.	S0028: 1 and L0741: 1.		186580,
									264800,
									266600,
									278760,
									600760,
									600760,
									600761,
									600761,
									602066
		956281	592	473-138	1190	Phe-4 to Gly-12.
307	HWMIB81	1092933	317	3-572	915	Ile-94 to Asp-99,	AR061: 1, AR089: 1
						Asp-118 to Pro-123,	L0748: 2, H0171: 1,
						Glu-131 to Ile-140,	S0134: 1, S0354: 1,
						Tyr-143 to Asp-152,	S0358: 1, H0014: 1,
						Glu-169 to Lys-179.	H0083: 1, H0510: 1,
							L0764: 1, L0803: 1,
							L0789: 1, H0593: 1,
							H0659: 1, H0539: 1,
							H0555: 1, L0751: 1,
							L0758: 1, L0759: 1 and
							L0595: 1.
		955336	593	1491-922	1191	Ile-94 to Asp-99,
						Asp-118 to Pro-123,
						Glu-131 to Ile-140,
						Tyr-143 to Asp-152,
						Glu-169 to Lys-179.
308	HCEMU86	1156430	318	1-795	916	Ser-3 to Lys-8,	AR061: 3, AR089: 2
						His-29 to Lys-38,	L0439: 21, L0438: 12,
						Pro-201 to Thr-206.	L0769: 9, T0010: 6,
							H0052: 5, L0776: 4,
							L0805: 3, S0126: 3,
							L0741: 3, L0589: 3,
							H0261: 2, T0006: 2,
							L0455: 2, L0659: 2,
							H0519: 2, L0742: 2,
							L0748: 2, L0751: 2,
							L0592: 2, S0276: 2,
							L0583: 1, L0418: 1,
							S0298: 1, S0001: 1,
							S0400: 1, L0394: 1,
							S0222: 1, H0455: 1,
							H0331: 1, H0156: 1,
							T0082: 1, N0006: 1,
							S6028: 1, H0644: 1,
							S0036: 1, H0100: 1,
							L0351: 1, S0352: 1,
							L0598: 1, L0369: 1,
							L0638: 1, L0666: 1,
							H0520: 1, L0777: 1,
							L0752: 1, L0753: 1,
							L0758: 1, L0593: 1 and
							L0366: 1.
		956864	594	2520-1735	1192	His-26 to Lys-35,
						Pro-198 to Thr-203.
309	HRDAF83	1153911	319	368-3	917		AR051: 23, AR050:
							20, AR054: 11, AR061:
							9, AR089: 5
							S0250: 8, S0126: 8,
							H0251: 3, H0545: 2,
							H0252: 2, L0794: 2,
							L0565: 2, L0744: 2,
							L0757: 2, S0040: 1,
							S0212: 1, S0418: 1,
							S0360: 1, H0549: 1,
							H0024: 1, L0053: 1,
							H0124: 1, S0208: 1,
							S0011: 1 and S0276: 1.
		957143	595	36-344	1193	Asn-66 to Val-71,
						Glu-82 to Thr-91.
		963999	596	230-3	1194	Ser-42 to Arg-50,
						Gln-66 to Val-73.
310	HUVGZ88	1204719	320	503-1288	918	Pro-14 to His-20,	AR089: 2, AR061: 2
						Gln-82 to Asp-92,	L0789: 4, L0758: 4,
						Ser-161 to Phe-179,	H0657: 3, H0052: 3,
						Cys-190 to Ser-200,	L0438: 3, L0744: 3,
						Gln-212 to Ala-217,	L0779: 3, L0005: 2,
						Glu-235 to Ser-243.	H0581: 2, H0194: 2,
							H0046: 2, H0038: 2,
							L0800: 2, L0659: 2,
							H0521: 2, L0743: 2,
							L0439: 2, H0556: 1,
							S0282: 1, S0358: 1,
							H0619: 1, H0586: 1,
							H0618: 1, H0231: 1,
							S0362: 1, H0622: 1,
							T0006: 1, H0616: 1,
							H0413: 1, H0623: 1,
							L0351: 1, S0150: 1,
							L0769: 1, L0372: 1,
							L0662: 1, L0794: 1,
							L0775: 1, L0651: 1,
							L0527: 1, L0657: 1,
							L0666: 1, H0547: 1,
							H0690: 1, H0658: 1,
							H0672: 1, H0539: 1,
							S0378: 1, H0555: 1,
							L0754: 1, L0747: 1,
							L0780: 1, L0596: 1,
							S0192: 1, H0542: 1 and
							H0423: 1.
		959020	597	83-439	1195	Asn-89 to Asn-95.
311	HSCKS55	1197921	321	3-1646	919	Asp-1 to Gly-12,	AR089: 13, AR061: 5
						Ala-24 to Gln-29,	H0617: 6, H0556: 4,
						Ala-43 to Asn-61,	H0305: 3, S0007: 3,
						Ala-68 to Gly-81,	H0618: 3, H0521: 3,
						Pro-84 to Gln-99,	L0439: 3, H0672: 2,
						Glu-105 to Gln-110,	L0754: 2, L0600: 2,
						Ala-118 to Asp-123,	S0442: 1, S0354: 1,
						Arg-170 to Leu-175,	S0358: 1, S0045: 1,
						Pro-296 to Thr-306,	S0046: 1, S0222: 1,
						Asn-311 to Gln-320,	H0438: 1, H0587: 1,
						Arg-327 to Ala-335,	H0599: 1, H0036: 1,
						Asp-382 to Gly-389,	H0597: 1, H0530: 1,
						Ala-441 to Pro-451,	L0118: 1, H0570: 1,
						Val-464 to Cys-491,	H0023: 1, S0250: 1,
						Ser-495 to Gly-504,	H0039: 1, H0181: 1,
						Asp-509 to Trp-516,	H0674: 1, S0036: 1,
						Gly-518 to Pro-527.	L0351: 1, T0041: 1,
							H0494: 1, H0509: 1,
							L0769: 1, L0761: 1,
							L0764: 1, L0768: 1,
							L0806: 1, H0519: 1,
							H0593: 1, H0670: 1,
							H0660: 1, S3014: 1,
							L0741: 1, L0779: 1 and
							H0667: 1.
		961074	598	703-1704	1196	Pro-72 to Thr-82,
						Asn-87 to Gln-96,
						Arg-103 to Ala-111,
						Asp-158 to Gly-165.
312	HOEET48	963290	322	2-1030	920	Ala-8 to Gly-14,	AR061: 9, AR089: 5
						Gly-32 to Arg-48,	S0356: 17, S0212: 6,
						Ala-58 to Asn-66,	L0747: 6, S0360: 5,
						Glu-82 to Gln-92,	H0486: 5, S0418: 3,
						Arg-101 to Gly-110,	H0551: 3, S0040: 2,
						Thr-124 to Asp-131,	S0354: 2, H0599: 2,
						Trp-137 to Gly-146,	H0544: 2, H0617: 2,
						Leu-153 to His-160,	H0413: 2, S0210: 2,
						Glu-171 to Lys-177,	L0794: 2, S0126: 2,
						Asp-191 to Ser-196,	S0037: 2, S0027: 2,
						Glu-225 to Gly-233,	L0743: 2, H0665: 2,
						Glu-248 to Glu-253,	S0192: 2, S0196: 2,
						Thr-259 to Trp-265,	S0116: 1, H0662: 1,
						Arg-268 to Asp-277,	S0420: 1, H0619: 1,
						Glu-303 to Arg-311,	H0550: 1, H0013: 1,
						Ala-329 to Leu-343.	H0618: 1, H0253: 1,
							H0251: 1, H0546: 1,
							H0545: 1, H0086: 1,
							H0123: 1, H0024: 1,
							H0286: 1, H0252: 1,
							H0628: 1, S0294: 1,
							L0372: 1, L0646: 1,
							L0773: 1, L0806: 1,
							L0654: 1, L0790: 1,
							L0565: 1, H0689: 1,
							H0670: 1, H0660: 1,
							S0028: 1, S0032: 1,
							L0751: 1, L0754: 1,
							L0749: 1, L0777: 1,
							L0780: 1, L0595: 1,
							H0668: 1, H0667: 1,
							S0276: 1, S0424: 1 and
							H0352: 1.
313	HBODE51	1193149	323	2704-1739	921	Phe-2 to Asp-13,	AR089: 4, AR061: 1
						Ser-47 to Gly-52,	L0751: 4, H0052: 3,
						Arg-161 to Asp-167,	S0024: 3, S0364: 3,
						Leu-256 to Leu-261,	L0438: 3, L0439: 3,
						Asp-288 to Asn-296.	H0657: 2, L0415: 2,
							H0438: 2, H0156: 2,
							H0373: 2, L0455: 2,
							H0529: 2, L0664: 2,
							H0144: 2, L0749: 2,
							L0592: 2, H0422: 2,
							L0002: 1, H0583: 1,
							H0656: 1, S0045: 1,
							S0046: 1, L0717: 1,
							H0261: 1, H0455: 1,
							H0013: 1, H0575: 1,
							T0082: 1, S0665: 1,
							S0346: 1, H0581: 1,
							H0251: 1, H0046: 1,
							H0009: 1, H0050: 1,
							H0014: 1, T0010: 1,
							S0003: 1, S0214: 1,
							S0366: 1, H0316: 1,
							H0598: 1, L0351: 1,
							S0150: 1, L0643: 1,
							L0764: 1, L0662: 1,
							L0794: 1, L0805: 1,
							L0653: 1, L0659: 1,
							L0666: 1, L0665: 1,
							H0539: 1, H0521: 1,
							S0146: 1, H0436: 1,
							H0478: 1, H0345: 1,
							L0745: 1, L0758: 1,
							L0588: 1, L0366: 1,
							S0026: 1, H0667: 1,
							S0194: 1, H0542: 1,
							H0677: 1 and S0446: 1.
		964235	599	2-2053	1197	Gln-12 to His-20,
						Val-34 to Tyr-39,
						Asn-54 to Asn-59,
						Asp-105 to Gly-110,
						Gly-247 to Lys-256,
						Gln-314 to Gly-320,
						Arg-359 to Ser-366,
						Arg-420 to Gly-428,
						Ala-558 to Tyr-563,
						Leu-574 to Pro-579,
						Arg-592 to Phe-597,
						Ala-621 to Arg-630,
						Pro-636 to His-641.
314	HHFCK09	965304	324	2692-389	922	Tyr-47 to Glu-58,	AR089: 3, AR061: 2
						Lys-70 to Gly-77,	L0666: 8, L0439: 6,
						Pro-121 to Leu-126,	H0253: 5, H0046: 4,
						Leu-150 to Leu-158,	L0769: 4, H0295: 3,
						Asn-166 to Glu-171,	H0255: 3, L0747: 3,
						Arg-417 to Ser-425,	L0756: 3, L0779: 3,
						Phe-465 to Cys-473,	H0657: 2, H0618: 2,
						Ser-485 to Asn-492,	H0318: 2, H0622: 2,
						Ser-497 to Ala-504,	H0068: 2, L0667: 2,
						Gln-531 to Trp-537,	L0772: 2, L0776: 2,
						Asp-557 to Glu-562.	L0663: 2, H0520: 2,
							H0593: 2, H0670: 2,
							H0521: 2, L0750: 2,
							L0759: 2, L0593: 2,
							L0601: 2, S0116: 1,
							H0341: 1, S0212: 1,
							H0306: 1, H0402: 1,
							L0617: 1, S0358: 1,
							H0609: 1, H0592: 1,
							H0333: 1, T0040: 1,
							H0013: 1, H0635: 1,
							H0575: 1, H0036: 1,
							H0581: 1, H0123: 1,
							H0050: 1, H0012: 1,
							H0071: 1, T0010: 1,
							H0687: 1, H0290: 1,
							H0617: 1, H0606: 1,
							H0038: 1, H0487: 1,
							H0494: 1, H0334: 1,
							S0150: 1, H0647: 1,
							S0142: 1, L0640: 1,
							L0639: 1, L0637: 1,
							L0641: 1, L0768: 1,
							L0649: 1, L0514: 1,
							L0659: 1, L0783: 1,
							L0788: 1, L0664: 1,
							L0665: 1, L0438: 1,
							H0547: 1, H0435: 1,
							H0522: 1, H0696: 1,
							S0404: 1, H0478: 1,
							L0742: 1, L0740: 1,
							L0749: 1, L0758: 1,
							S0434: 1, S0194: 1,
							H0422: 1 and H0506: 1.
315	HCOOZ11	1110364	325	89-943	923	Asp-43 to Glu-48.	AR089: 15, AR061: 5
							H0662: 2, H0670: 1,
							L0756: 1 and L0759: 1.
		965306	600	89-592	1198	Asp-43 to Glu-48.
316	HDPPO35	1119032	326	72-1202	924	Lys-7 to Gly-69,	AR089: 1, AR061: 0
						Lys-82 to Lys-88,	H0521: 15, H0638: 5,
						Ser-94 to Asp-112,	H0580: 5, H0271: 5,
						Ala-126 to Asp-131,	H0641: 5, H0560: 4,
						Tyr-134 to Ser-140,	H0090: 3, H0591: 3,
						Ser-147 to Phe-156,	L0766: 3, H0542: 3,
						Asp-159 to Ser-165,	H0543: 3, H0586: 2,
						Thr-176 to Asp-186,	H0497: 2, H0581: 2,
						Glu-230 to Leu-250,	L0655: 2, H0518: 2,
						Glu-291 to Arg-298,	H0522: 2, L0754: 2,
						Gln-313 to Glu-320,	L0747: 2, H0657: 1,
						Asn-331 to Gly-343,	H0393: 1, H0431: 1,
						Ser-348 to Leu-363.	H0250: 1, H0635: 1,
							L0021: 1, H0014: 1,
							H0179: 1, H0416: 1,
							H0488: 1, L0475: 1,
							H0359: 1, H0625: 1,
							S0426: 1, L0598: 1,
							L0667: 1, L0803: 1,
							L0804: 1, L0775: 1,
							L0651: 1, L0659: 1,
							L0792: 1, L0663: 1,
							S0428: 1, H0672: 1,
							H0555: 1, H0436: 1,
							L0779: 1, H0445: 1 and
							S0424: 1.
		966248	601	72-1202	1199	Lys-7 to Gly-69,
						Lys-82 to Lys-88,
						Ser-94 to Asp-112,
						Ala-126 to Asp-131,
						Tyr-134 to Ser-140,
						Ser-147 to Phe-156,
						Asp-159 to Ser-165,
						Thr-176 to Asp-186,
						Glu-230 to Leu-250,
						Glu-291 to Arg-298,
						Gln-313 to Glu-320,
						Asn-331 to Gly-343,
						Ser-348 to Leu-363.
317	HLWDZ53	1157542	327	2-1126	925		AR089: 5, AR061: 2
							L0439: 13, L0752: 4,
							L0015: 3, H0144: 2,
							L0438: 2, L0742: 2,
							L0747: 2, L0758: 2,
							H0556: 1, L0785: 1,
							S0001: 1, H0664: 1,
							H0580: 1, H0486: 1,
							T0060: 1, H0253: 1,
							S0010: 1, H0009: 1,
							H0178: 1, H0564: 1,
							L0471: 1, S0051: 1,
							T0010: 1, H0553: 1,
							H0412: 1, L0370: 1,
							L0763: 1, L0768: 1,
							L0794: 1, L0806: 1,
							L0776: 1, L0657: 1,
							L0666: 1, H0520: 1,
							S0126: 1, H0682: 1,
							H0659: 1, H0187: 1,
							L0749: 1, L0755: 1 and
							H0445: 1.
		968602	602	2-1126	1200
318	HEOPL36	1197910	328	100-501	926	Gly-11 to Thr-16,	AR089: 18, AR061: 5
						Ser-35 to Ser-56,	L0740: 11, L0439: 9,
						Thr-58 to Ser-73,	L0748: 8, H0616: 5,
						Tyr-85 to Asp-91,	L0666: 5, L0601: 5,
						Glu-100 to Glu-109.	S0444: 4, L0776: 4,
							L0659: 4, L0744: 4,
							L0747: 4, L0749: 4,
							L0755: 4, H0457: 3,
							L0774: 3, L0750: 3,
							H0624: 2, T0002: 2,
							S0116: 2, S0358: 2,
							H0550: 2, T0040: 2,
							H0013: 2, H0599: 2,
							H0050: 2, H0673: 2,
							H0038: 2, H0040: 2,
							H0494: 2, L0770: 2,
							L0662: 2, L0364: 2,
							L0375: 2, L0809: 2,
							L0438: 2, H0547: 2,
							L0754: 2, L0756: 2,
							L0752: 2, L0731: 2,
							L0758: 2, L0485: 2,
							S0040: 1, H0583: 1,
							H0650: 1, H0657: 1,
							H0341: 1, H0663: 1,
							H0580: 1, H0619: 1,
							L0717: 1, H0574: 1,
							H0052: 1, H0263: 1,
							H0009: 1, H0172: 1,
							H0024: 1, T0010: 1,
							H0510: 1, H0644: 1,
							S0036: 1, H0551: 1,
							H0264: 1, H0488: 1,
							H0056: 1, H0100: 1,
							L0564: 1, T0041: 1,
							H0652: 1, S0344: 1,
							S0002: 1, L0763: 1,
							L0638: 1, L0761: 1,
							L0372: 1, L0643: 1,
							L0764: 1, L0768: 1,
							L0381: 1, L0775: 1,
							L0526: 1, L0782: 1,
							L0663: 1, L0665: 1,
							H0703: 1, H0520: 1,
							H0435: 1, H0521: 1,
							S0044: 1, L0751: 1,
							L0757: 1, L0759: 1,
							H0445: 1, L0584: 1,
							L0608: 1 and H0506: 1.
		968826	603	85-486	1201	Gly-11 to Thr-16,
						Ser-35 to Ser-56,
						Thr-58 to Ser-73,
						Tyr-85 to Asp-91,
						Glu-100 to Glu-109.
319	HMCFS02	1152252	329	3-734	927	Leu-42 to Gln-49,	AR061: 2, AR089: 0
						Gln-59 to Thr-65,	L0766: 10, L0794: 7,
						Pro-119 to Lys-128,	L0758: 7, L0805: 6,
						Asn-134 to Phe-140,	L0751: 4, L0754: 4,
						Arg-150 to Phe-155,	L0803: 3, L0483: 2,
						Asp-205 to Gly-212.	L0764: 2, L0659: 2,
							L0809: 2, L0790: 2,
							L0666: 2, L0755: 2,
							L0599: 2, H0170: 1,
							H0294: 1, H0583: 1,
							H0656: 1, S0282: 1,
							H0255: 1, S0420: 1,
							H0618: 1, H0688: 1,
							L0055: 1, S0344: 1,
							H0529: 1, L0761: 1,
							L0643: 1, L0645: 1,
							L0804: 1, L0806: 1,
							L0653: 1, L0776: 1,
							L0629: 1, L0636: 1,
							L0788: 1, L0789: 1,
							L0791: 1, L0665: 1,
							S0428: 1, H0702: 1,
							L0438: 1, S0330: 1,
							H0539: 1, H0478: 1,
							L0749: 1, L0750: 1,
							L0779: 1, L0731: 1,
							L0757: 1, H0665: 1 and
							H0423: 1.
		969326	604	2-496	1202	Arg-3 to Lys-20,
						Phe-22 to Ser-28,
						Leu-50 to Gln-57.
320	HDPSR15	1194752	330	178-1167	928	Pro-26 to Leu-34,	AR061: 2, AR089: 2
						His-42 to Asn-51,	L0759: 12, L0439: 11,
						Phe-154 to Pro-162,	L0766: 7, L0775: 5,
						His-237 to Asp-246,	H0521: 5, L0755: 5,
						Pro-263 to Lys-268,	L0748: 4, L0756: 4,
						Lys-277 to Asp-282,	L0777: 4, L0731: 4,
						Pro-285 to Leu-295,	L0581: 4, L0619: 3,
						Pro-305 to Asp-312.	L0666: 3, L0779: 3,
							L0757: 3, L0588: 3,
							S0418: 2, L0618: 2,
							H0580: 2, L0055: 2,
							L0769: 2, L0773: 2,
							L0774: 2, L0791: 2,
							L0747: 2, L0750: 2,
							H0265: 1, H0663: 1,
							S0356: 1, H0208: 1,
							H0370: 1, H0108: 1,
							H0575: 1, H0618: 1,
							H0544: 1, H0545: 1,
							S0050: 1, H0510: 1,
							H0286: 1, H0031: 1,
							H0644: 1, H0068: 1,
							H0135: 1, L0564: 1,
							H0494: 1, L0475: 1,
							H0396: 1, S0144: 1,
							S0002: 1, S0426: 1,
							L0763: 1, L0761: 1,
							L0642: 1, L0764: 1,
							L0662: 1, L0768: 1,
							L0806: 1, L0661: 1,
							L0659: 1, L0367: 1,
							L0663: 1, H0519: 1,
							H0435: 1, H0658: 1,
							S3014: 1, L0751: 1,
							L0749: 1, L0603: 1,
							H0665: 1 and H0542: 1.
		969666	605	168-785	1203	Pro-26 to Leu-34,
						His-42 to Asn-51.
321	HNTAV78	1217231	331	1104-697	929	Pro-1 to Lys-6.	AR054: 10, AR089: 2,
							AR061: 1, AR051: 1,
							AR050: 1
							H0305: 1, H0580: 1,
							H0428: 1, L0803: 1,
							L0809: 1 and H0519: 1.
		971315	606	3-266	1204	Glu-52 to Leu-58,
						Arg-63 to Lys-71,
						Arg-83 to Val-88.
322	HFKDR14	1145842	332	3-1319	930	Ala-2 to Pro-9,	AR061: 3, AR089: 2
						Val-22 to Gly-28.	L0792: 2, H0012: 1,
							H0100: 1, L0663: 1,
							L0756: 1 and L0780: 1.
		974255	607	15-1733	1205	Ala-5 to Gly-18.
323	HDPBI30	974711	333	182-1312	931	Asp-1 to Asn-10.	AR051: 3, AR050: 1,
							AR089: 1, AR061: 0
							H0521: 3, H0656: 2,
							H0635: 2, H0549: 1,
							H0050: 1, H0413: 1,
							H0641: 1, L0387: 1,
							H0436: 1 and H0423: 1.
324	HODFF88	1094875	334	14-544	932	His-8 to Gly-18,	AR054: 34, AR051:
						Glu-150 to Leu-167.	29, AR050: 23, AR089:
							4, AR061: 4
							H0615: 1
		974911	608	14-544	1206	His-8 to Gly-18,
						Glu-150 to Leu-167.

[0040] The first column in Table 1A provides the gene number in the application corresponding to the clone identifier. The second column in Table 1A provides a unique “Clone ID NO:Z” for a cDNA clone related to each contig sequence disclosed in Table 1A. This clone ID references the cDNA clone which contains at least the 5′ most sequence of the assembled contig and at least a portion of SEQ ID NO:X was determined by directly sequencing the referenced clone. The reference clone may have more sequence than described in the sequence listing or the clone may have less. In the vast majority of cases, however, the clone is believed to encode a full-length polypeptide. In the case where a clone is not full-length, a full-length cDNA can be obtained by methods described elsewhere herein.

[0041] The third column in Table 1A provides a unique “Contig ID” identification for each contig sequence. The fourth column provides the “SEQ ID NO:” identifier for each of the contig polynucleotide sequences disclosed in Table 1A. The fifth column, “ORF (From-To)”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence “SEQ ID NO:X” that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A, column 6, as SEQ ID NO:Y. Where the nucleotide position number “To” is lower than the nucleotide position number “From”, the preferred ORF is the reverse complement of the referenced polynucleotide sequence.

[0042] The sixth column in Table 1A provides the corresponding SEQ ID NO:Y for the polypeptide sequence encoded by the preferred ORF delineated in column 5. In one embodiment, the invention provides an amino acid sequence comprising, or alternatively consisting of, a polypeptide encoded by the portion of SEQ ID NO:X delineated by “ORF (From-To)”. Also provided are polynucleotides encoding such amino acid sequences and the complementary strand thereto.

[0043] Column 7 in Table 1A lists residues comprising epitopes contained in the polypeptides encoded by the preferred ORF (SEQ ID NO:Y), as predicted using the algorithm of Jameson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performed using the computer program PROTEAN (Version 3.11 for the Power MacIntosh, DNASTAR, Inc., 1228 South Park Street Madison, Wis.). In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, five or more of the predicted epitopes as described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.

[0044] Column 8 in Table 1A provides an expression profile and library code: count for each of the contig sequences (SEQ ID NO:X) disclosed in Table 1A, which can routinely be combined with the information provided in Table 4 and used to determine the tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention. The first number in column 8 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. For those identifier codes in which the first two letters are not “AR”, the second number in column 8 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are “AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of 33P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after “[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression.

[0045] Column 9 in Table 1A provides a chromosomal map location for certain polynucleotides of the invention. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a “cluster”; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequence(s) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.

[0046] A modified version of the computer program BLASTN (Altshul et al., J. Mol. Biol. 215:403-410 (1990); and Gish and States, Nat. Genet. 3:266-272 (1993)) was used to search the UniGene database for EST or cDNA sequences that contain exact or near-exact matches to a polynucleotide sequence of the invention (the ‘Query’). A sequence from the UniGene database (the ‘Subject’) was said to be an exact match if it contained a segment of 50 nucleotides in length such that 48 of those nucleotides were in the same order as found in the Query sequence. If all of the matches that met this criteria were in the same UniGene cluster, and mapping data was available for this cluster, it is indicated in Table 1A under the heading “Cytologic Band”. Where a cluster had been further localized to a distinct cytologic band, that band is disclosed; where no banding information was available, but the gene had been localized to a single chromosome, the chromosome is disclosed.

[0047] Once a presumptive chromosomal location was determined for a polynucleotide of the invention, an associated disease locus was identified by comparison with a database of diseases which have been experimentally associated with genetic loci. The database used was the Morbid Map, derived from OMIM™ (supra). If the putative chromosomal location of a polynucleotide of the invention (Query sequence) was associated with a disease in the Morbid Map database, an OMIM reference identification number was noted in column 10, Table 1A, labelled “OMIM Disease Reference(s)”. Table 5 is a key to the OMIM reference identification numbers (column 1), and provides a description of the associated disease in Column 2.

TABLE 1B
Clone ID	SEQ ID	CONTIG	BAC ID:	SEQ ID	EXON
NO:Z	NO:X	ID:	A	NO:B	From-To
HCEPH71	14	522739	AL365319	1207	1-494
HCEPH71	14	522739	AL390715	1208	1-494
HLMDO95	43	928344	AC020641	1209	1-591
					627-2046
HTEAG49	54	954614	AL390796	1210	1-1310
HTEAG49	54	954614	AL357045	1211	1-1310
HTEAG49	54	954614	AL390796	1212	1-627
HTEAG49	54	954614	AL357045	1213	1-627
HACCH94	103	847143	AL161458	1214	1-1140
HACCH94	103	847143	AL161458	1215	1-90
					5811-6312
HFKLX38	113	880220	AL136383	1216	1-32
					1288-1454
					1561-1646
					3840-4700
					5482-6798
HTDAB17	117	890384	AC011078	1217	1-297
					359-416
					3247-3653
					6083-6236
					9753-10036
					11128-11233
					12148-12514
					12635-13141
					15604-16463
					19071-19190
					19476-20232
					20321-20638
					21200-21594
					21959-22219
					23120-23362
					23467-24143
					24766-24853
					25725-26143
					26310-26455
					27545-30619
					30708-31169
HTLCA95	142	911655	AC012616	1218	1-1151
HTLCA95	142	911655	AC012616	1219	1-284
HHEHC53	152	921783	AC009427	1220	1-100
					1854-1942
					3236-3463
					4629-4868
					5054-5181
					5371-5476
					5851-5953
					6104-6149
					6509-6612
					7131-8415
					8429-8492
					8638-8748
					8975-9440
					9835-10490
					10606-10899
					11149-11282
					11382-11881
					12023-12075
					12172-12315
					12496-12551
					12638-12706
					12827-12994
					13077-13630
HHEHC53	152	921783	AC009427	1221	1-428
HHEHC53	152	921783	AC009427	1222	1-388
					466-526
					698-906
					1023-1922
HELHF07	196	949067	AC073669	1223	1-597
HELHF07	196	949067	AC023605	1224	1-583
HELHF07	196	949067	AC074220	1225	1-362
HELHF07	196	949067	AC074220	1226	1-105
HACAD35	199	949199	AC007363	1227	1-98
					3271-3413
					4132-4357
					7030-7682
					11881-12001
					12874-13485
HDTKQ14	254	886936	AL359542	1228	1-140
					1249-4264
HDTKQ14	254	886936	AL359542	1229	1-499
HDTKQ14	254	886936	AL359542	1230	1-145
HWAGS73	257	894404	AL096870	1231	1-185
					393-1743
					1951-2118
					2229-2295
					2410-2906
					3043-3107
					3238-3519
					3594-3970
HWAGS73	257	894404	AL096870	1232	1-1080
					2072-2811
HSYBX32	270	909846	AC004084	1233	1-105
					839-1021
					2069-2302
					2470-2855
					3818-4265
					4371-4610
					4761-4810
					5364-5802
					5930-6517
					7073-7807
					8063-8618
					8636-8875
					9438-9537
					10568-10774
					10897-11025
					11718-12323
					13749-13849
					13978-14188
					14474-14554
					16489-16624
					16924-17019
					17239-17458
					17908-18185
					19014-19266
					19356-19451
					19620-19873
					19893-20920
					21092-21247
					21512-21579
					21621-21754
					22001-22831
					22992-23518
					23710-24370
					24426-24596
					25213-25493
					25661-26192
					26588-27433
					27598-27742
					28073-28199
					28359-28651
					28777-29249
					29379-29502
					29646-29794
					29833-30033
					30085-30630
					30702-32661
					33104-33374
					33383-33661
					33808-33871
					33978-37449
					37587-37754
					38296-38433
					38597-39343
					40047-40395
					40462-40743
					40938-41039
					41187-41634
					42504-42687
					42703-42850
					42929-43475
HSYBX32	270	909846	AC004951	1234	1-735
					991-1547
HSYBX32	270	909846	AC004084	1235	1-239
HSYBX32	270	909846	AC004084	1236	1-283
HSYBX32	270	909846	AC004951	1237	1-255
HSYBX32	270	909846	AC004951	1238	1-318
HTLJC71	284	922923	AC009516	1239	1-2009
HTLJC71	284	922923	AC007957	1240	1-1747
HTLJC71	284	922923	AC018751	1241	1-2009
HTLJC71	284	922923	AC023490	1242	1-2009
HTLJC71	284	922923	AC009516	1243	1-375
HTLJC71	284	922923	AC009516	1244	1-494
HTLJC71	284	922923	AC007957	1245	1-205
HTLJC71	284	922923	AC018751	1246	1-494
HTLJC71	284	922923	AC023490	1247	1-375
HTLJC71	284	922923	AC018751	1248	1-375
HWMEV63	291	931154	AC078816	1249	1-1574

[0048] Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, “Clone ID NO:Z”, for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, “SEQ ID NO:X”, for each contig sequence. The third column provides a unique contig identifier, “Contig ID:” for each contig sequence. The fourth column, provides a BAC identifier “BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, “SEQ ID NO:B” for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, “Exon From-To”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).

TABLE 2
		SEQ				Score/
Clone ID	Contig	ID	Analysis		PFam/NR Accession	Percent	NT	NT
NO: Z	ID:	NO: X	Method	PFam/NR Description	Number	Identity	From	To
HTPAD46	503313	335	HMMER	PFAM: Src homology	PF00018	4.14	160	186
			1.8	domain 3
HCWFF88	506577	336	HMMER	PFAM: Src homology	PF00018	4.92	140	181
			1.8	domain 3
HSSAX53	507509	337	HMMER	PFAM: Src homology	PF00018	4.36	266	331
			1.8	domain 3
HCEPH71	522739	14	HMMER	PFAM: Src homology	PF00018	4.22	33	62
			1.8	domain 3
HTEDF74	522982	338	HMMER	PFAM: C2 domain	PF00168	6.98	189	233
			1.8
HTTEK47	573649	339	HMMER	PFAM: EF hand	PF00036	10.82	224	289
			1.8
			blastx.2	DJ534K7.2 (novel	sp|CAB92087|CAB92087	100%	11	301
				protein).		65%	283	378
						52%	342	410
HTOBE75	591896	340	HMMER	PFAM: Sushi domain	PF00084	61.2	100	273
			2.1.1	(SCR repeat)
HCFAT05	592118	341	HMMER	PFAM: Ion transport	PF00520	106.1	137	361
			2.1.1	protein
			blastx.2	potassium channel protein	gb|AAA59457.1|	67%	134	427
				[Homo sapiens]		100%	18	137
						52%	360	491
HFIAH37	615597	342	HMMER	PFAM: C2 domain	PF00168	4.22	241	291
			1.8
HFTDF15	657020	343	HMMER	PFAM: Src homology	PF00018	4.85	168	203
			1.8	domain 3
HPFCU80	685294	344	HMMER	PFAM: C2 domain	PF00168	4	261	296
			1.8
HSVAW49	689674	345	HMMER	PFAM: Src homology	PF00018	36.33	77	169
			1.8	domain 3
			blastx.2	(AF146277) adapter	gb|AAD34595.1|AF146277_1	97%	65	166
				protein CMS [Homo
				sapiens]
HWHQC94	1116463	23	blastx.14	(AC004472) P1.11659_3	gi|2984587|gb|AAC07985.1|	76%	581	874
				[Homo sapiens]		41%	476	547
HWHQC94	715096	346	HMMER	PFAM: C2 domain	PF00168	4.17	214	300
			1.8
			blastx.2	Pig-o.	sp|BAA96254|BAA96254	64%	1	627
HRSMD49	723025	347	HMMER	PFAM: Src homology	PF00018	4.76	199	270
			1.8	domain 3
HFTDY67	1151220	25	blastx.14	(AF182316) myoferlin	gi|6731235|gb|AAF27176.1|	94%	1368	52
				[Homo sapiens]	AF182316_1	92%	42	1
						33%	201	94
						42%	63	1
						26%	201	145
HFTDY67	745221	348	HMMER	PFAM: C2 domain	PF00168	20.07	4	144
			1.8
			blastx.2	Myoferlin.	sp|AAF27177|AAF27177	98%	4	225
						100%	224	298
						35%	213	263
HYABL89	786157	349	HMMER	PFAM: C2 domain	PF00168	6.05	270	317
			1.8
HCUEV29	1137791	27	blastx.14	(AL110490) predicted	gi|5824799|emb|CAB54442.1|	53%	96	344
				using Genefinder		53%	387	470
				[Caenorhabditis elegans]		64%	6	47
HCUEV29	816065	350	HMMER	PFAM: EF hand	PF00036	31.87	143	229
			1.8
			blastx.2	CG10641 PROTEIN.	sp|Q9VJ26|Q9VJ26	59%	89	286
						49%	312	500
HCESP56	827671	351	HMMER	PFAM: EF hand	PF00036	11.86	240	317
			1.8
			blastx.2	HYPOTHETICAL 27.4 KDA	sp|Q9UJF6|Q9UJF6	100%	186	452
				PROTEIN
				(FRAGMENT).
HLQDT35	839777	352	HMMER	PFAM: Src homology	PF00018	3.85	342	419
			1.8	domain 3
			blastx.2	(AK000579) unnamed	dbj|BAA91269.1|	98%	252	458
				protein product [Homo
				sapiens]
HDPBS64	846624	30	HMMER	PFAM: Thioredoxins	PF00085	116.87	173	493
			1.8
			blastx.2	ZK973.11 protein.	sp|AAF40013|AAF40013	32%	182	652
HTBAB41	867287	353	HMMER	PFAM: C2 domain	PF00168	5.32	89	157
			1.8
HTLGE31	870247	32	HMMER	PFAM: Sugar (and other)	PF00083	21.4	5	115
			1.8	transporters
HWLHK29	1152279	33	blastx.14	(AF181098)	gi|5823558|gb|AAD53186.1|	27%	474	602
				synaptotagmin IV	AF181098_1	29%	198	371
				[Drosophila melanogaster]		30%	77	166
HWLHK29	876064	354	HMMER	PFAM: C2 domain	PF00168	16.97	222	488
			1.8
HHEGG20	1106816	34	blastx.14	(AF084205)	gi|3452473|gb|AAC71014.1|	84%	3	971
				serine/threonine protein
				kinase TAO1 [Rattus
				norvegicus]
HHEGG20	894409	355	HMMER	PFAM: Eukaryotic protein	PF00069	200.01	26	598
			1.8	kinase domain
HDPRU43	1217035	35	blastx.14	PUTATIVE RASGAP-	sp|O43374|O43374	97%	163	2460
				ACTIVATING-LIKE		100%	52	174
				PROTEIN.
HDPRU43	909841	356	HMMER	PFAM: C2 domain	PF00168	82.11	58	303
			1.8
HE8PK12	909884	357	HMMER	PFAM: Src homology	PF00018	58.12	197	361
			1.8	domain 3
			blastx.2	(AF136380) SH3P12	gb|AAD27647.1|AF136380_1	82%	59	367
				protein [Homo sapiens]
HE9HV92	1227519	37	blastx.14	DIFFERENTIATION	sp|O97902|O97902	53%	1	336
				ENHANCING FACTOR 1.		64%	820	1050
						37%	477	563
						47%	290	340
						36%	766	873
HE9HV92	911510	358	HMMER	PFAM: Src homology	PF00018	55.67	869	1042
			1.8	domain 3
			blastx.2	DIFFERENTIATION	sp|O97902|O97902	52%	707	1048
				ENHANCING FACTOR 1.		44%	8	418
						37%	475	561
						35%	713	871
HOHCE47	911566	359	HMMER	PFAM: Eukaryotic protein	PF00069	79.42	211	423
			1.8	kinase domain
HSDII69	917180	360	HMMER	PFAM: Src homology	PF00018	4.09	382	429
			1.8	domain 3
HKAKM10	1227639	40	blastx.14	NUCLEAR BODY	sp|Q9QUQ8|Q9QUQ8	88%	9	2840
				ASSOCIATED KINASE
				2B.
HKAKM10	918685	361	HMMER	PFAM: Eukaryotic protein	PF00069	31.4	8	127
			2.1.1	kinase domain
HCEPU56	920347	362	HMMER	PFAM: C2 domain	PF00168	3.93	243	293
			1.8
			blastx.2	HYPOTHETICAL 27.3 KDA	sp|O60362|O60362	82%	219	659
				PROTEIN.
HUSHB54	928054	42	HMMER	PFAM: C2 domain	PF00168	20.52	275	355
			1.8
HLMDO95	928344	43	HMMER	PFAM: 7 transmembrane	PF00001	43.25	220	369
			1.8	receptor (rhodopsin
				family)
			blastx.2	Inflammation-related G	sp|AAF91467|AAF91467	51%	112	375
				protein-coupled receptor		95%	375	446
				EX33.
HHASQ32	928730	363	HMMER	PFAM: Carnitate	PF00755	317	250	855
			2.1.1	acyltransferase
HARAB87	1164340	45	blastx.14	neurotransmitter	gi|914028|gb|AAB32806.1|	89%	51	350
				transporter rB21a [rats,		83%	349	549
				brain, Peptide, 616 aa]		90%	16	45
				[Rattus sp.]
HARAB87	933441	364	HMMER	PFAM:	PF00209	79.6	268	570
			2.1.1	Sodium: neurotransmitter
				symporter family
HTNGF69	933614	365	HMMER	PFAM: C2 domain	PF00168	3.94	588	659
			1.8
HMSJL96	1154788	47	blastx.14	(AF104413) large tumor	gi|4324434|gb|AAD16882.1|	80%	1	1245
				suppressor 1 [Homo		86%	1282	1371
				sapiens]		41%	1085	1171
HMSJL96	934483	366	HMMER	PFAM: Eukaryotic protein	PF00069	26.49	199	363
			1.8	kinase domain
HDTBT06	935404	367	HMMER	PFAM: Actin	PF00022	110.8	514	903
			2.1.1
			blastx.2	actin-related protein - fruit	pir|S44028|S44028	47%	52	876
				fly (Drosophila
				melanogaster)
HTTIE47	1165363	49	blastx.14	ZK550.2 [Caenorhabditis	gi|3881745|emb|CAB05312.1|	43%	188	382
				elegans]		30%	398	544
						34%	559	627
HTTIE47	941834	368	HMMER	PFAM: Sugar (and other)	PF00083	32.12	295	522
			1.8	transporters
			blastx.2	predicted using	emb|CAB01157.1|	38%	151	537
				Genefinder; Similarity to
				worm multidrug resistance
				proteins [Caenorhabditis
				elegans]
HHFBP47	946668	50	HMMER	PFAM: Sugar (and other)	PF00083	25.74	696	370
			1.8	transporters
			blastx.2	(AL050350) dJ261K5.1	emb|CAB56524.1|	98%	482	955
				(novel organic cation		95%	135	461
				transporter (BAC ORF		100%	38	139
				RG331P03)) [Homo		77%	451	516
				sapiens]
HCCCC81	1083553	51	blastx.14	(AL022605) putative	gi|3080435|emb|CAA18752.1|	50%	125	304
				protein [Arabidopsis		68%	428	514
				thaliana]		56%	302	397
						29%	588	689
						38%	514	591
						50%	334	369
HCCCC81	949062	369	HMMER	PFAM:	PF00202	178.37	187	816
			1.8	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.2	hypothetical protein	pir|T25848|T25848	46%	190	879
				T01B11.2 -
				Caenorhabditis elegans
HPJEV71	949153	370	HMMER	PFAM: von Willebrand	PF00092	47.98	866	1375
			1.8	factor type A domain
			blastx.2	CDNA FLJ10601 FIS,	sp|BAA91707|BAA91707	53%	974	1534
				CLONE NT2RP2005000.
HTEIL07	1136121	53	blastx.14	caltractin [Giardia	gi|1399341|gb|AAB05594.1|	28%	961	1128
				intestinalis]		28%	646	792
HTEIL07	953803	371	HMMER	PFAM: EF hand	PF00036	11.27	192	263
			1.8
			blastx.2	Hypothetical 41.3 kDa	sp|CAB91065|CAB91065	79%	57	392
				protein.
HTEAG49	954614	54	HMMER	PFAM: Src homology	PF00018	4.51	312	238
			1.8	domain 3
HSLCF96	637670	55	HMMER	PFAM: Sugar (and other)	PF00083	10.78	415	576
			1.8	transporters
			blastx.2	(AE000352) putative	gb|AAC75728.1|	94%	415	1179
				transport protein		100%	297	413
				[Escherichia coli]		70%	1101	1211
						20%	409	600
						26%	1021	1179
HSLCF96	954777	372	HMMER	PFAM: Sugar (and other)	PF00083	30.03	1296	1015
			1.8	transporters
			blastx.2	(AE000352) putative	gb|AAC75728.1|	96%	303	1127
				transport protein		91%	1147	1215
				[Escherichia coli]
HNHCI32	861673	56	HMMER	PFAM: 7 transmembrane	PF00001	133.17	195	545
			1.8	receptor (rhodopsin
				family)
			blastx.2	G protein-coupled	sp|AAF27279|AAF27279	100%	189	551
				receptor 57.		100%	112	186
						100%	56	112
HNHCI32	956105	373	HMMER	PFAM: 7 transmembrane	PF00001	133.17	951	601
			1.8	receptor (rhodopsin
				family)
			blastx.2	(AF112461) G protein-	gb|AAF27279.1|AF112461_1	100%	555	917
				coupled receptor 57		100%	478	552
				[Homo sapiens]		100%	422	478
HPMFL08	959569	374	HMMER	PFAM: Src homology	PF00018	4.97	209	238
			1.8	domain 3
HTXRA13	959622	58	HMMER	PFAM: C2 domain	PF00168	51.3	540	809
			2.1.1
			blastx.2	GRANUPHILIN-A.	sp|Q9R0Q1|Q9R0Q1	42%	429	1091
HCE3H71	1197898	59	blastx.14	SEIZURE-RELATED	sp|Q62223|Q62223	89%	413	961
				PROTEIN 6 TYPE 2		95%	12	413
				PRECURSOR.		27%	126	266
						34%	150	263
						56%	363	410
						39%	365	448
						41%	216	266
						43%	273	320
						36%	383	448
						46%	410	448
						57%	410	451
HCE3H71	961681	375	HMMER	PFAM: Sushi domain	PE00084	79.2	317	496
			2.1.1	(SCR repeat)
			blastx.2	seizure-related protein	pir|I52657|I52657	83%	5	685
				SEZ-6 precursor - mouse		64%	565	957
						30%	98	496
						48%	929	1000
HUTSF11	966029	376	HMMER	PFAM: Eukaryotic protein	PF00069	27.74	3	104
			1.8	kinase domain
HTEGI48	1021235	61	blastx.14	(AF074606) histone	gi|4091980|gb|AAC99368.1|	87%	1	525
				acetyltransferase [Homo
				sapiens]
HTEGI48	530595	377	HMMER	PFAM: Zinc finger,	PF01530	43.8	344	436
			2.1.1	C2HC type
HSFAM09	573345	378	HMMER	PFAM: Src homology	PF00018	5.33	195	218
			1.8	domain 3
HNFHK77	1182286	63	blastx.14	succinic semialdehyde	gi|147901|gb|AAC36831.1|	100%	180	647
				dehydrogenase		97%	653	898
				[Escherichia coli]
HNFHK77	576186	379	HMMER	PFAM: Aldehyde	PF00171	30.2	231	326
			2.1.1	dehydrogenase family
HFXDO83	1012602	64	blastx.14	No definition line found	gi|912476|gb|AAB18565.1|	85%	93	596
				[Escherichia coli]
HFXDO83	578847	380	HMMER	PFAM: Aldehyde	PF00171	46.2	58	207
			2.1.1	dehydrogenase family
HSDIW73	1104406	65	blastx.14	(AE000506) putative	gi|2367379|gb|AAC77312.1|	100%	1	1068
				transport protein, cryptic,
				orf, joins former yjiZ and
				yjjL [Escherichia coli]
HSDIW73	587311	381	HMMER	PFAM: Sugar (and other)	PF00083	19.71	5	538
			1.8	transporters
			blastx.2	(AE000506) putative	gb|AAC77312.1|	100%	8	1075
				transport protein, cryptic,
				orf, joins former yjiZ and
				yjjL [Escherichia coli]
HSDIW73	954821	382	HMMER	PFAM: Sugar (and other)	PF00083	11.23	1595	1086
			1.8	transporters
			blastx.2	(AE000506) putative	gb|AAC77312.1|	100%	3	1049
				transport protein, cryptic,
				orf, joins former yjiZ and
				yjjL [Escherichia coli]
HFVGD23	676214	383	HMMER	PFAM: Carnitate	PF00755	168.4	2	445
			2.1.1	acyltransferase
HMSBZ24	1082367	67	blastx.14	contains similarity to C2	gi|1825586|gb|AAB42222.1|	39%	8	241
				domains [Caenorhabditis		30%	548	646
				elegans]		43%	551	598
						26%	617	685
HMSBZ24	678707	384	HMMER	PFAM: C2 domain	PF00168	35.46	8	181
			1.8
			blastx.2	CG15078 PROTEIN.	sp|Q9V8M4|Q9V8M4	50%	8	289
HWHHB69	690442	385	HMMER	PFAM: Src homology	PF00018	31.65	91	255
			1.8	domain 3
			blastx.2	(AF178432) SH3 protein	gb|AAF35985.1|AF178432_1	70%	91	315
				[Homo sapiens]		100%	303	329
HFXLC69	692773	386	HMMER	PFAM: C2 domain	PF00168	17.77	84	200
			1.8
HBXBW40	1156765	70	blastx.14	Protein Kinase [Rattus	gi|2077934|dbj|BAA19880.1|	93%	214	546
				norvegicus]		78%	546	587
HBXBW40	706115	387	HMMER	PFAM: Eukaryotic protein	PF00069	34.01	280	423
			1.8	kinase domain
HCE1L51	1140498	71	blastx.14	carnitine	gi|294521|gb|AAA40876.1|	51%	3	233
				palmitoyltransferase I		59%	288	434
				[Rattus norvegicus]
HCE1L51	715899	388	HMMER	PFAM: Carnitate	PF00755	102.9	33	434
			2.1.1	acyltransferase
HRADM45	717358	389	HMMER	PFAM: Eukaryotic protein	PF00069	23.7	14	124
			1.8	kinase domain
			blastx.2	(AJ271722) putative	emb|CAB71146.1|	98%	2	469
				serine/threonine protein
				kinase MAK-V [Homo
				sapiens]
HTEFO45	1153918	73	blastx.14	Munc13-3 [Rattus	gi|1763306|gb|AAB39720.1|	94%	64	597
				norvegicus]
HTEFO45	723446	390	HMMER	PFAM: C2 domain	PF00168	30.64	111	383
			1.8
HOHBN82	1152271	74	blastx.14	(AF182316) myoferlin	gi|6731235|gb|AAF27176.1|	94%	92	1408
				[Homo sapiens]	AF182316_1	87%	1418	1465
						33%	1259	1366
						47%	1397	1459
						26%	1259	1315
HOHBN82	724322	391	HMMER	PFAM: C2 domain	PF00168	49.95	96	347
			1.8
			blastx.2	Myoferlin.	sp|AAF27176|AAF27176	80%	93	623
						58%	571	606
HWHGF52	1217026	75	blastx.14	GUANINE	sp|Q64096|DBS_MOUSE	73%	14	271
				NUCLEOTIDE		79%	338	439
				EXCHANGE FACTOR		27%	8	73
				DBS (DBLS BIG
				SISTER) (MCF2
				TRANSFORMING
				SEQUENCE-LIKE
				PROTEIN).
HWHGF52	726102	392	HMMER	PFAM: Src homology	PF00018	5.01	325	387
			1.8	domain 3
			blastx.2	Dbs = Dbl guanine	gb|AAB33461.1|	74%	3	203
				nucleotide exchange		72%	319	417
				factor homolog [mice,		73%	203	259
				32D 1
HBKDI30	1223861	76	blastx.14	BA243J16.3 (similar to	sp|CAC10006|CAC10006	100%	343	672
				MYLK (myosin, light		91%	23	307
				polypeptide 1
HBKDI30	729048	393	HMMER	PFAM: Eukaryotic protein	PF00069	42.23	1	213
			1.8	kinase domain
HSQFR54	1185143	77	blastx.14	vacuolar protein sorting	gi|1477468|gb|AAC52985.1|	86%	52	882
				homolog r-vps33a [Rattus		94%	1134	1640
				norvegicus]		96%	862	1137
						92%	1640	1837
						31%	1332	1466
HSQFR54	730964	394	HMMER	PFAM: Sec1 family	PF00995	66.1	2	259
			2.1.1
			blastx.2	VACUOLAR PROTEIN	sp|Q63615|Q63615	86%	2	310
				SORTING HOMOLOG
				R-VPS33A.
HAGBA56	1102593	78	blastx.14	(AF033655) Pftaire-1	gi|2645810|gb|AAB87504.1|	95%	187	735
				[Mus musculus]		58%	1	153
						79%	132	203
HAGBA56	732597	395	HMMER	PFAM: Eukaryotic protein	PF00069	64.9	139	516
			2.1.1	kinase domain
HHSAE29	1220851	79	blastx.14	probable sugar transport	pir|S47743|S47743	100%	572	946
				protein - Escherichia coli		95%	1021	1083
HHSAE29	743166	396	HMMER	PFAM: Sugar (and other)	PF00083	44.67	29	250
			1.8	transporters
HMSHO64	746582	80	HMMER	PFAM: Src homology	PF00018	11.08	316	405
			1.8	domain 3
			blastx.2	(AF030131) Plenty of	gb|AAC40070.1|	47%	1	411
				SH3s; POSH [Mus
				musculus]
HFPBW22	750631	397	HMMER	PFAM: C2 domain	PF00168	19	323	430
			1.8
HTLBH67	751985	398	HMMER	PFAM: Src homology	PF00018	37.78	16	162
			1.8	domain 3
HNTMH70	1143523	83	blastx.14	similar to protein kinases	gi|1072163|gb|AAA81690.1|	50%	425	667
				[Caenorhabditis elegans]		40%	101	220
						29%	344	445
						47%	62	124
HNTMH70	757184	399	HMMER	PFAM: Eukaryotic protein	PF00069	94.55	176	577
			1.8	kinase domain
HCETC59	761881	400	HMMER	PFAM: Sec1 family	PF00995	60.4	117	305
			2.1.1
			blastx.2	Vacuolar protein sorting	sp|AAF91174|AAF91174	78%	123	368
				33B.		100%	67	123
						64%	311	412
HE8UX76	1161223	85	blastx.14	(AB026803)	gi|6136784|dbj|BAA85775.1|	98%	437	1087
				synaptotagmin VI [Mus		91%	98	454
				musculus]		97%	1129	1383
						36%	692	841
						34%	1129	1242
HE8UX76	767871	401	HMMER	PFAM: C2 domain	PF00168	7.23	592	636
			1.8
HTLEN77	1136124	86	blastx.14	(AF081671) VU91D	gi|3800851|gb|AAC68892.1|	43%	240	392
				calmodulin [synthetic
				construct]
HTLEN77	772363	402	HMMER	PFAM: EF hand	PF00036	26.93	294	380
			1.8
			blastx.2	CALTRACTIN	sp|P53441|CATR_NAEGR	30%	111	374
				(CENTRIN).
HBGDI80	1124695	87	blastx.14	(AL078627) actin-like	gi|5051483|emb|CAB44762.1|	46%	5	328
				protein; (2 actin domains)
				[Schizosaccharomyces
				pombe]
HBGDI80	781600	403	HMMER	PFAM: Actin	PF00022	33.6	52	318
			2.1.1
			blastx.2	CG7940 PROTEIN.	sp|Q9VEC3|Q9VEC3	37%	13	336
HELHB88	811935	404	HMMER	PFAM: EF hand	PF00036	12.8	247	330
			1.8
			blastx.2	INTERSECTIN LONG	sp|Q9UNK2|Q9UNK2	84%	139	567
				ISOFORM.		46%	145	375
						100%	78	146
						30%	361	495
HTEMV66	1152261	89	blastx.14	contains EGF-like repeats;	gi|495684|gb|AAA50735.1|	56%	265	621
				highly similar to ZC84.1; 1		44%	61	195
HTEMV66	813038	405	HMMER	PFAM: Eukaryotic protein	PF00069	27.8	154	315
			2.1.1	kinase domain
HMTAJ73	813296	406	HMMER	PFAM: Eukaryotic protein	PF00069	21.34	4	114
			1.8	kinase domain
HE9TD31	815845	91	HMMER	PFAM: EF hand	PF00036	17.53	519	605
			1.8
			blastx.2	Intersectin 2 short	sp|AAF59904|AAF59904	81%	3	626
				isoform.		40%	378	626
HGBDG55	1141363	92	blastx.14	(AF004161) peroxisomal	gi|2352427|gb|	62%	209	529
				Ca-dependent solute	AAB69156.1|
				carrier [Oryctolagus
				cuniculus]
HGBDG55	815858	407	HMMER	PFAM: EF hand	PF00036	17.24	302	385
			1.8
			blastx.2	Calcium-binding	sp|AAF28888|AAF28888	61%	209	388
				transporter (Fragment).		64%	381	530
						37%	284	388
HOUHL51	1125914	93	blastx.14	(AJ249457) centrin,	gi|5869981|emb|CAB55607.1|	29%	230	487
				putative [Trichomonas		25%	173	244
				vaginalis]
HOUHL51	815891	408	HMMER	PFAM: EF hand	PF00036	29.3	429	506
			2.1.1
			blastx.2	CENTRIN, PUTATIVE.	sp|Q9U5I9|Q9U5I9	26%	48	506
HEOPP67	1020119	94	blastx.14	guanylate cyclase	gi|623417|gb|AAA60716.1|	31%	169	474
				activating protein [Mus
				musculus]
HEOPP67	827630	409	HMMER	PFAM: EF hand	PF00036	35	233	316
			2.1.1
			blastx.2	NADPH thyroid oxidase	sp|AAF73922|AAF73922	98%	56	433
				2.
HKAOV71	1165423	95	blastx.14	(AF123303) calcium-	gi|6841066|gb|AAF28888.1|	88%	61	753
				binding transporter [Homo	AF123303_1	93%	711	755
				sapiens]
HKAOV71	827679	410	HMMER	PFAM: EF hand	PF00036	50.7	220	300
			2.1.1
			blastx.2	Calcium-binding	sp|AAF28888|AAF28888	88%	61	753
				transporter (Fragment).		93%	711	755
HDQID90	1137752	96	blastx.14	(AF132480) Ese2 protein	gi|4378889|gb|AAD19748.1|	75%	11	268
				[Mus musculus]		47%	472	522
HDQID90	831976	411	HMMER	PFAM: EF hand	PF00036	10.08	413	496
			1.8
			blastx.2	Intersectin 2.	sp|AAF63600|AAF63600	87%	206	694
						36%	272	565
HFRBN81	1182552	97	blastx.14	(AE000192) putative	gi|1787127|gb|AAC73985.1|	99%	2163	598
				transport [Escherichia
				coli]
HFRBN81	833061	412	HMMER	PFAM: Sugar (and other)	PF00083	35.69	52	420
			1.8	transporters
			blastx.2	Hypothetical protein Y	dbj|BAA35630.1|	100%	1	1116
				[Escherichia coli]
HFRBN81	973206	413	HMMER	PFAM: Sugar (and other)	PF00083	30.84	52	393
			1.8	transporters
			blastx.2	Hypothetical protein Y	dbj|BAA35630.1|	80%	4	546
				[Escherichia coli]
HFRBN81	973208	414	blastx.2	Hypothetical protein Y	dbj|BAA35630.1|	97%	2	352
				[Escherichia coli]		75%	351	587
						18%	56	229
HFKJW01	1187134	98	blastx.14	lactaldehyde	gi|145222|gb|AAA23427.1|	100%	394	8
				dehydrogenase
				[Escherichia coli]
HFKJW01	836491	415	HMMER	PFAM: Aldehyde	PF00171	174	96	440
			2.1.1	dehydrogenase family
			blastx.2	lactaldehyde	pir|A38165|A38165	100%	96	440
				dehydrogenase (EC
				1.2.1.22) aldA -
				Escherichia coli
HSDFL63	836498	416	HMMER	PFAM: Aldehyde	PF00171	127.4	1	234
			2.1.1	dehydrogenase family
			blastx.2	RETINALDEHYDE-	sp|O94788|DHAS_HUMAN	100%	1	249
				SPECIFIC
				DEHYDROGENASE
				TYPE 2 (EC 1.2.1.—)
				(RALDH(II)) (RALDH-
				2).
HDJET90	836503	100	HMMER	PFAM: Aldehyde	PF00171	150.4	66	371
			2.1.1	dehydrogenase family
HEMFC61	836514	101	HMMER	PFAM: Aldehyde	PF00171	397.1	10	642
			2.1.1	dehydrogenase family
			blastx.2	RETINALDEHYDE-	sp|O94788|DHAS_HUMAN	98%	4	642
				SPECIFIC
				DEHYDROGENASE
				TYPE 2 (EC 1.2.1.—)
				(RALDH(II)) (RALDH-
				2).
HDTBR50	1174351	102	blastx.14	intermediate chain 1	gi|14817526|dbj|BAA09934.1|	57%	130	306
				[Anthocidaris crassispina]		44%	327	455
HDTBR50	846630	417	HMMER	PFAM: Thioredoxins	PF00085	29.85	163	297
			1.8
			blastx.2	NM23-H8.	sp|AAF20909|AAF20909	100%	130	327
						97%	327	467
HACCH94	847143	103	HMMER	PFAM: 7 transmembrane	PF00001	167.94	10	735
			1.8	receptor (rhodopsin
				family)
			blastx.2	ORPHAN G PROTEIN-	sp|O95853|O95853	99%	7	879
				COUPLED RECEPTOR.
HE8TI39	849161	418	HMMER	PFAM: EF hand	PF00036	12.66	9	86
			1.8
			blastx.2	CDNA FLJ11040 FIS,	sp|BAA91969|BAA91969	98%	3	371
				CLONE PLACE1004388.		64%	299	685
						63%	627	719
HEGAP32	851207	419	HMMER	PFAM: C2 domain	PF00168	33.03	11	172
			1.8
			blastx.2	SYNAPTOTAGMIN	sp|Q9R0N6|Q9R0N6	85%	50	238
				VIII.		90%	270	299
						70%	241	270
HCWFU66	853005	106	HMMER	PFAM: Aldehyde	PF00171	71.4	105	269
			2.1.1	dehydrogenase family
HUSYI29	853149	107	HMMER	PFAM: Sec1 family	PF00995	108.8	3	332
			2.1.1
			blastx.2	VACUOLAR PROTEIN	sp|Q63615|Q63615	95%	3	314
				SORTING HOMOLOG		93%	403	591
				R-VPS33A.		90%	335	394
						31%	87	221
HMEFT66	1134131	108	blastx.14	(AF121859) sorting nexin	gi|4689258|gb|AAD27832.1|	46%	754	909
				9 [Homo sapiens]	AF121859_1	40%	193	324
						57%	142	183
						41%	688	738
HMEFT66	856149	420	HMMER	PFAM: Src homology	PF00018	28.51	5	136
			1.8	domain 3
HKAAR71	863023	109	HMMER	PFAM: C2 domain	PF00168	16.26	309	551
			1.8
			blastx.2	TOLLIP PROTEIN.	sp|Q9UJ69|Q9UJ69	78%	147	959
H7TBC95	865922	110	HMMER	PFAM: 7 transmembrane	PF00001	189.5	3	695
			2.1.1	receptor (rhodopsin
				family)
			blastx.2	G-protein coupled	sp|BAA93001|	56%	516	701
				receptor SALPR.	BAA93001	61%	51	206
						41%	303	440
H7TBC95	908115	421	HMMER	PFAM: 7 transmembrane	PF00001	189.5	3	695
			2.1.1	receptor (rhodopsin
				family)
			blastx.2	angiotensin II receptor	gb|AAC59635.1|	34%	6	695
				[Xenopus laevis]
HAPPX52	872075	422	HMMER	PFAM: Sugar (and other)	PF00083	37.84	72	359
			1.8	transporters
HBGSJ13	1152326	112	blastx.14	ferrienterobactin receptor	gi|1778500|gb|AAB40783.1|	94%	1	753
				precursor [Escherichia
				coli]
HBGSJ13	878322	424	HMMER	PFAM: Src homology	PF00018	4.07	445	510
			1.8	domain 3
			blastx.2	ferrienterobactin receptor	gb|AAB40783.1|	92%	64	684
				precursor [Escherichia
				coli]
HFKLX38	880220	113	HMMER	PFAM: PMP-	PF00822	103.9	9	299
			2.1.1	22/EMP/MP20/Claudin
				family
			blastx.2	(AF087825) claudin-7	gb|AAD09760.1|	44%	3	299
				[Mus musculus]
HTLGP15	1165362	114	blastx.14	(AF060173) SV2 related	gi|3901268|gb|AAC78627.1|	88%	301	786
				protein [Rattus
				norvegicus]
HTLGP15	880297	425	HMMER	PFAM: Sugar (and other)	PF00083	34.17	291	590
			1.8	transporters
HMEGH46	887791	426	HMMER	PFAM: C2 domain	PF00168	12.81	10	78
			1.8
			blastx.2	GLUT4 VESICLE	sp|Q9Z1X5|Q9Z1X5	60%	7	216
				PROTEIN		50%	40	216
				(FRAGMENT).
HE8PY29	1129488	116	blastx.14	(AF100751) FK506-	gi|5410288|gb|AAD43015.1|	100%	2	277
				binding protein FKB23
				isoform [Homo sapiens]
HE8PY29	887862	427	HMMER	PFAM: EF hand	PF00036	13.65	191	250
			1.8
			blastx.2	FK506-BINDING	sp|Q9Y6B0|Q9Y6B0	100%	2	277
				PROTEIN.
HTDAB17	890384	117	HMMER	PFAM: Thioredoxin	PF00085	107.9	276	533
			2.1.1
			blastx.2	CG1837 PROTEIN.	sp|Q9VYV3|Q9VYV3	42%	225	518
						43%	231	539
						41%	348	533
HCFCF47	894415	428	HMMER	PFAM: Eukaryotic protein	PF00069	89.54	20	295
			1.8	kinase domain
HDQHB19	895106	429	HMMER	PFAM: Eukaryotic protein	PF00069	92.5	260	520
			2.1.1	kinase domain
HAGDN53	1129154	120	blastx.2	PALS1.	sp|AAF63789|AAF63789	97%	3	293
HAGDN53	895963	430	HMMER	PFAM: Src homology	PF00018	22.95	270	335
			1.8	domain 3
			blastx.2	coded for by C. elegans	gb|AAA96115.1|	43%	165	455
				cDNA yk34a9.5; coded		38%	103	156
				for by C. elegans 1
				elegans]
HUFDB74	1162672	121	blastx.14	phosphoinositide-specific	gi|1195552|gb|AAA87954.1|	58%	170	547
				phospholipase C [catfish,		69%	2	160
				olfactory rosettes, Peptide
				Partial, 502 aa]
HUFDB74	901451	431	HMMER	PFAM:	PF00387	89.4	2	127
			2.1.1	Phosphatidylinositol-
				specific phospholipase C,
				Y domain
HNHFH24	1092567	122	blastx.2	PRO1722.	sp|AAF69605|AAF69605	58%	908	756
						68%	763	632
HNHFH24	903741	432	HMMER	PFAM:	PF00209	37.2	208	306
			2.1.1	Sodium: neurotransmitter
				symporter family
			blastx.14	(AF075266) orphan	gi|3347930|gb|AAC27761.1|	76%	187	327
				transporter isoform B9		27%	414	467
				[Mus musculus]
HBGQT03	908173	433	HMMER	PFAM: SH3 domain	PF00018	68.5	615	785
			2.1.1
			blastx.2	(AF130979) SH3 domain-	gb|AAF04472.1|AF130979_1	93%	3	791
				containing protein 6511
				[Homo sapiens]
HETLF29	1103959	124	blastx.14	(AJ250839)	gi|7160989|emb|CAB76471.1|	97%	3	482
				serine/threonine protein
				kinase [Homo 1
HETLF29	909762	434	HMMER	PFAM: Eukaryotic protein	PF00069	143.18	6	416
			1.8	kinase domain
			blastx.14	similar to cAMP-	gi|3878636|emb|CAA88953.1|	56%	6	416
				dependant protein kinase;
				cDNA EST 111
HOUGD29	909797	435	HMMER	PFAM:	PF00387	118.2	202	453
			2.1.1	Phosphatidylinositol-
				specific phospholipase C,
				Y domain
			blastx.14	(AF044576)	gi|2957270|gb|AAC38963.1|	42%	202	753
				phospholipase C PLC210		35%	757	873
				[Caenorhabditis elegans]		58%	168	203
HTEMV09	1128254	126	blastx.14	protein kinase I [Rattus	gi|406113|gb|AAA19670.1|	44%	1	321
				norvegicus]
HTEMV09	909843	436	HMMER	PFAM: Eukaryotic protein	PF00069	99.16	19	312
			1.8	kinase domain
			blastx.14	protein kinase I [Rattus	gi|406113|gb|AAA19670.1|	44%	1	321
				norvegicus]
HNTNB14	1128964	127	blastx.14	calmodulin-binding	gi|349075|gb|AAA16633.1|	98%	42	476
				protein [Rattus		47%	626	676
				norvegicus]		33%	587	676
HNTNB14	909942	437	HMMER	PFAM: Eukaryotic protein	PF00069	96.28	38	343
			1.8	kinase domain
			blastx.14	calmodulin-binding	gi|349075|gb|AAA16633.1	97%	41	475
				protein [Rattus		85%	553	657
				norvegicus]		74%	553	657
						77%	553	657
						69%	559	657
						65%	553	657
						60%	553	657
						52%	553	654
						37%	553	657
						39%	553	636
						35%	553	645
						33%	559	657
						77%	512	538
						29%	556	657
HE2KZ07	1149808	128	blastx.14	(AB004267)	gi|3135197|dbj|BAA28263.1|	92%	17	508
				Ca2+/calmodulin-
				dependent protein kinase I
				beta 2 [Rattus norvegicus]
HE2KZ07	909948	438	HMMER	PFAM: Eukaryotic protein	PF00069	115.19	5	289
			1.8	kinase domain
			blastx.14	(AB004267)	gi|3135197|dbj|BAA28263.1|	96%	17	433
				Ca2+/calmodulin-		56%	418	507
				dependent protein kinase I
				beta 2 [Rattus norvegicus]
HSIGN57	1105444	129	blastx.14	(AB033615)	gi|6705987|dbj|BAA89457.1|	96%	3	962
				phospholipase C-L2 [Mus		70%	982	1041
				musculus]
HSIGN57	910078	439	HMMER	PFAM:	PF00387	159.3	131	484
			2.1.1	Phosphatidylinositol-
				specific phospholipase C,
				Y domain
			blastx.2	PHOSPHOLIPASE C-L2.	sp|Q9QYG1|Q9QYG1	83%	2	754
HLHBC30	1106654	130	blastx.14	1-phosphatidylinositol-	pir|S14113|S14113	85%	9	332
				4,5-bisphosphate		77%	408	512
				phosphodiesterase 1		85%	155	175
HLHBC30	910079	440	HMMER	PFAM: C2 domain	PF00168	104.78	45	305
			1.8
			blastx.2	1-phosphatidylinositol-	pir|S14113|S14113	83%	9	332
				4,5-bisphosphate		74%	408	512
				phosphodiesterase 1
HFBDJ13	1195217	131	blastx.14	SH3 domains-containing	pir|T09071|T09071	90%	178	1182
				protein POSH - mouse		56%	1171	1365
						26%	598	699
						39%	272	370
						57%	898	939
						41%	514	600
						28%	823	897
						30%	315	383
HFBDJ13	911264	441	HMMER	PFAM: SH3 domain	PF00018	78.6	105	269
			2.1.1
			blastx.2	(AF030131) Plenty of	gb|AAC40070.1|	78%	3	473
				SH3s; POSH [Mus
				musculus]
HTPGG25	911282	442	HMMER	PFAM: Eukaryotic protein	PF00069	114.02	72	353
			1.8	kinase domain
			blastx.2	(AL117482) hypothetical	emb|CAB55955.1|	94%	9	353
				protein [Homo sapiens]		92%	350	622
						63%	2	58
HSSMT34	911294	133	HMMER	PFAM: Eukaryotic protein	PF00069	53.16	95	292
			1.8	kinase domain
HWWDN34	1152430	134	blastx.14	(AF144094)	gi|6224683|gb|AAF05903.1|	45%	350	814
				unconventional myosin-15		51%	128	349
				[Homo sapiens]		66%	800	880
						37%	72	152
						56%	87	134
						80%	96	125
						28%	28	207
						37%	69	140
						57%	178	219
						29%	216	287
						46%	354	398
						33%	339	401
						30%	99	197
						50%	452	487
HWWDN34	911357	443	HMMER	PFAM: Src homology	PF00018	14.09	686	853
			1.8	domain 3
			blastx.2	(AF053130)	gb|AAC40124.1|	42%	56	874
				unconventional myosin		66%	788	868
				MYO15 [Mus musculus]
HCEPW85	911374	135	HMMER	PFAM: Eukaryotic protein	PF00069	83.52	3	260
			1.8	kinase domain
			blastx.14	predicted using	gi|3875903|emb|CAA94127.1|	87%	3	260
				Genefinder; Similarity to
				111 cDNA
HMTAW83	1071602	136	blastx.14	(AF230904) c-Cbl-	gi|7188749|gb|AAF37854.1|	94%	1	354
				interacting protein [Homo 1	AF230904_1	48%	7	168
						51%	88	210
						59%	7	87
						61%	298	351
						75%	425	460
						62%	425	448
HMTAW83	911385	444	HMMER	PFAM: Src homology	PF00018	76.18	1	159
			1.8	domain 3
			blastx.2	(AF230904) c-Cbl-	gb|AAF37854.1|AF230904_1	94%	1	354
				interacting protein [Homo		52%	7	210
				sapiens]		48%	7	168
						61%	298	351
						75%	425	460
HDMAV01	911386	445	HMMER	PFAM: Src homology	PF00018	52.13	264	413
			1.8	domain 3
			blastx.2	unnamed protein product	emb|CAB42388.1|	73%	111	410
				[unidentified]		100%	3	116
HDPSR74	911396	138	HMMER	PFAM: Src homology	PF00018	47.19	293	460
			1.8	domain 3
			blastx.2	(AF104246) enhancer of	gb|AAD11795.1|	48%	281	553
				filamentation 1 homolog
				[Gallus gallus]
HHEZT58	911416	446	HMMER	PFAM: Src homology	PF00018	80.7	277	444
			1.8	domain 3
			blastx.14	myosin I heavy chain	gi|167839|gb|AAA33229.1|	47%	277	435
				[Dictyostelium
				discoideum]
HTLDU05	911649	140	HMMER	PFAM: Actins	PF00022	141.45	125	469
			1.8
			blastx.2	ACTIN-LIKE-7-BETA.	sp|Q9Y614|Q9Y614	72%	2	580
HTLET56	1189721	141	blastx.14	actin [Filobasidiella	gi|508701|gb|AAC49074.1|	52%	192	854
				neoformans]		48%	932	1291
						30%	837	986
HTLET56	911654	447	HMMER	PFAM: Actins	PF00022	262.03	134	703
			1.8
			blastx.2	actin 1 - Trypanosoma	pir|A27724|A27724	53%	134	715
				brucei		39%	718	963
						40%	942	1022
HTLCA95	911655	142	HMMER	PFAM: Actin	PF00022	345.2	170	1096
			2.1.1
			blastx.2	actin - Phaffia rhodozyma	pir|S70377|S70377	40%	2	1096
HTEJT86	1090517	143	blastx.14	actin [Diphyllobothrium	gi|1098579|gb|AAA82604.1|	50%	142	684
				dendriticum]		52%	670	1119
						55%	22	129
HTEJT86	911656	448	HMMER	PFAM: Actin	PF00022	106.8	4	366
			2.1.1
			blastx.2	ACTIN.	sp|Q9UVF3|Q9UVF3	44%	25	369
						66%	366	410
HTEMA54	1134919	144	blastx.14	(AF113526) actin-like-7-	gi|5524058|gb|AAD44109.1|	94%	55	1359
				alpha [Homo sapiens]	AF113526_1
HTEMA54	911666	449	HMMER	PFAM: Actin	PF00022	320.7	247	1161
			2.1.1
			blastx.2	ACTIN-LIKE-7-ALPHA.	sp|Q9Y615|Q9Y615	92%	55	1167
						82%	1121	1360
HTLGJ17	1135518	145	blastx.14	(AF191277) cytoplasmic	gi|6478616|gb|AAF13923.1|	59%	360	440
				actin [Cavia porcellus]	AF191277_1	44%	521	574
HTLGJ17	915136	450	HMMER	PFAM: Actins	PF00022	25.12	237	317
			1.8
			blastx.2	DJ63M2.2 (similar to	sp|CAC08484|CAC08484	81%	93	413
				ACTIN) (Fragment).		76%	403	465
HOUES64	918119	146	HMMER	PFAM: Aldehyde	PF00171	138.5	3	278
			2.1.1	dehydrogenase family
			blastx.2	lactaldehyde	pir|A38165|A38165	98%	3	275
				dehydrogenase (EC
				1.2.1.22) aldA -
				Escherichia coli
HMSCD15	982250	147	blastx.14	FBP 17 [Mus musculus]	gi|1255033|gb|AAC52479.1|	93%	453	635
HMSCD15	918133	451	HMMER	PFAM: Src homology	PF00018	41.06	453	599
			1.8	domain 3
			blastx.2	(AK000975) unnamed	dbj|BAA91451.1|	98%	453	635
				protein product [Homo		29%	387	479
				sapiens]		28%	80	175
HDQDX20	919027	452	HMMER	PFAM: PX domain	PF00787	73.4	246	569
			2.1.1
			blastx.14	serine/threonine protein	gi|294637|gb|AAA42137.1|	78%	633	974
				kinase [Rattus norvegicus]		44%	465	578
HLTHP86	1110457	149	blastx.14	(AF161420) HSPC302	gi|6841254|gb|AAF28980.1|	92%	498	1349
				[Homo sapiens]	AF161420_1	76%	1351	1833
						100%	1811	1849
						52%	1295	1351
HLTHP86	919354	453	HMMER	PFAM: TBC domain	PF00566	69.4	855	1274
			2.1.1
			blastx.2	(AF161420) HSPC302	gb|AAF28980.1|AF161420_1	89%	456	1352
				[Homo sapiens]		99%	1309	1974
						52%	1253	1309
HMSOL52	921126	454	HMMER	PFAM: EF hand	PF00036	12.43	276	359
			1.8
			blastx.2	CG11041 PROTEIN.	sp|Q9V8Z6|Q9V8Z6	45%	102	464
HAHGD33	921782	455	HMMER	PFAM: Eukaryotic protein	PF00069	83.68	4	564
			1.8	kinase domain
			blastx.14	(AF145690)	gi|5052670|gb|AAD38665.1|	68%	1	297
				BcDNA.LD28657	AF145690_1	56%	412	609
				[Drosophila melanogaster]		60%	304	426
						39%	676	804
HHEHC53	921783	152	HMMER	PFAM: Eukaryotic protein	PF00069	58.81	507	797
			1.8	kinase domain
			blastx.14	(AF145690)	gi|5052670|gb|AAD38665.1|	79%	567	803
				BcDNA.LD28657	AF145690_1	70%	321	563
				[Drosophila melanogaster]
HE2PB01	921850	456	HMMER	PFAM: Actin	PF00022	35.9	29	616
			2.1.1
			blastx.2	HSPC281 (Fragment).	sp|AAF28959|AAF28959	100%	2	541
HOUDP52	1219522	154	blastx.14	CG7846 PROTEIN.	sp|Q9VX09|Q9VX09	43%	27	491
						52%	1218	1361
						35%	501	752
						35%	1002	1202
HOUDP52	922102	457	HMMER	PFAM: Actin	PF00022	32	760	1095
			2.1.1
			blastx.2	CG7846 PROTEIN.	sp|Q9VX09|Q9VX09	36%	208	1104
						46%	23	190
HHGAE47	1127881	155	blastx.14	(AF187305) calmodulin	gi|5932428|gb|AAD56955.1|	45%	59	499
				[Myxine glutinosa]	AF187305_1
HHGAE47	922194	458	HMMER	PFAM: EF hand	PF00036	16.77	171	257
			1.8
			blastx.2	calmodulin [validated] -	pir|S48728|MCHU	48%	310	576
				human		48%	138	260
HMCGL45	1165349	156	blastx.14	(AF187305) calmodulin	gi|5932428|gb|AAD56955.1|	45%	464	904
				[Myxine glutinosa]	AF187305_1
HMCGL45	922195	459	HMMER	PFAM: EF hand	PF00036	26.6	460	546
			2.1.1
			blastx.2	CALMODULIN.	sp|Q9U6D3|Q9U6D3	45%	460	867
HELEF11	1153884	157	blastx.14	gamma-glutamyl	gi|1552811|gb|AAB08663.1|	100%	1283	531
				phosphate reductase
				[Escherichia coli]
HELEF11	926930	460	HMMER	PFAM: Pyridoxal-	PF00282	202.9	146	565
			2.1.1	dependent decarboxylase
				conserved domain
			blastx.2	glutamate decarboxylase	pir|B43332|B43332	81%	131	721
				(EC 4.1.1.15) beta -		100%	45	152
				Escherichia coli		56%	595	780
						47%	564	620
HETJX04	1212235	158	blastx.14	GRANUPHILIN-A.	sp|Q9R0Q1|Q9R0Q1	94%	6	683
						64%	685	810
						87%	804	827
HETJX04	927120	461	HMMER	PFAM: C2 domain	PF00168	150.4	9	260
			2.1.1
			blastx.2	GRANUPHILIN-A.	sp|Q9R0Q1|Q9R0Q1	94%	6	683
						57%	685	831
						48%	719	859
HSOBC04	927280	462	HMMER	PFAM: EF hand	PF00036	23.5	278	346
			2.1.1
			blastx.2	hypothetical protein	pir|T42709|T42709	88%	41	388
				DKFZp586I0821.1 -
				human (fragment)
HE8PW83	1069980	160	blastx.14	(AB002584) beta-alanine-	gi|1944136|dbj|BAA19549.1|	86%	4	546
				pyruvate aminotransferase 1
HE8PW83	927532	463	HMMER	PFAM:	PF00202	139.27	4	465
			1.8	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.2	ALANINE -	sp|Q64565|AGT2_R	83%	4	546
				GLYOXYLATE	AT
				AMINOTRANSFERASE
				2 PRECURSOR (EC 11
HWLEA48	927676	161	HMMER	PFAM: Eukaryotic protein	PF00069	32.82	190	381
			1.8	kinase domain
			blastx.2	(AF169034) protein	gb|AAF12757.2|AF169034_1	59%	154	429
				kinase [Homo sapiens]		100%	89	166
						51%	287	415
HNHNP81	1129143	162	blastx.14	(AF091575) olfactory	gi|3769641|gb|AAC64595.1|	62%	618	896
				receptor [Rattus		61%	236	505
				norvegicus]		72%	502	621
HNHNP81	928378	464	HMMER	PFAM: 7 transmembrane	PF00001	58.09	233	511
			1.8	receptor (rhodopsin
				family)
			blastx.2	OLFACTORY	sp|Q9Z231|Q9Z231	61%	236	505
				RECEPTOR		52%	502	618
				(FRAGMENT).
HFIDL68	1123641	163	blastx.14	G protein-coupled	gi|438129|emb|CAA80651.1|	44%	945	742
				receptor [Lymnaea		46%	1086	997
				stagnalis]
HFIDL68	928475	465	HMMER	PFAM: 7 transmembrane	PF00001	50.42	8	319
			1.8	receptor (rhodopsin
				family)
			blastx.2	CG5042 PROTEIN.	sp|Q9VBP0|Q9VBP0	38%	8	397
HUJCT05	1165261	164	blastx.14	(AF155116) NY-REN-60	gi|5360127|gb|AAD42882.1|	100%	1277	1540
				antigen [Homo sapiens]	AF155116_1
HUJCT05	929264	466	HMMER	PFAM: EF hand	PF00036	11.52	359	433
			1.8
			blastx.2	CG8334 PROTEIN	sp|Q9VW49|Q9VW49	59%	56	499
				(FRAGMENT).
HTEGO05	932583	165	HMMER	PFAM: Eukaryotic protein	PF00069	50.8	3	233
			2.1.1	kinase domain
			blastx.14	male germ cell-associated	gi|205278|gb|AAA41562.1|	85%	3	395
				kinase (mak) [Rattus		64%	489	761
				norvegicus]		85%	768	848
						38%	1023	1100
HRDBH58	1226719	166	blastx.14	probable aldehyde	pir|II83136|H83136	38%	1320	1637
				dehydrogenase PA4073		40%	2124	2309
				[imported] - Pseudomonas		56%	675	770
				aeruginosa (strain PAO1)		31%	462	635
						27%	2328	2471
						23%	894	1094
						40%	1101	1196
						30%	354	461
						50%	831	872
						25%	1125	1184
HRDBH58	933364	467	HMMER	PFAM: Aldehyde	PF00171	175.49	536	1558
			1.8	dehydrogenases
			blastx.2	probable aldehyde	pir|H83136|H83136	29%	569	1528
				dehydrogenase PA4073		34%	244	450
				[imported] - Pseudomonas
				aeruginosa (strain PAO1)
HSDGW22	934467	167	HMMER	PFAM: Eukaryotic protein	PF00069	44	145	318
			2.1.1	kinase domain
			blastx.14	(AF071071) protein	gi|5305333|gb|AAD41593.1|	96%	145	318
				kinase Myak-S [Mus	AF071071_1	100%	9	143
				musculus]		100%	303	326
HNTMD79	1126594	168	blastx.14	(AB037134) IRE homolog	gi|6729348|dbj|BAA89784.1|	58%	232	603
				1 [Arabidopsis thaliana]		66%	157	228
HNTMD79	934522	468	HMMER	PFAM: Eukaryotic protein	PF00069	130.82	203	586
			1.8	kinase domain
			blastx.14	LATS [Drosophila	gi|903942|gb|AAA70336.1|	52%	239	586
				melanogaster]		33%	76	156
						57%	169	210
						22%	64	240
HCE5J51	1197900	169	blastx.14	SRG1.	sp|P97610|P97610	98%	11	703
HCE5J51	934524	469	HMMER	PFAM: C2 domain	PF00168	82.59	338	604
			1.8
			blastx.14	Srg1 [Rattus norvegicus]	gi|1772658|gb|AAC53019.1|	94%	12	302
						86%	293	622
						88%	625	702
HHEFQ42	1151482	170	blastx.14	(AB025258) granuphilin-a	gi|5926736|dbj|BAA84656.1|	40%	57	428
				[Mus musculus]		56%	810	980
						48%	618	815
						42%	630	743
						31%	186	299
						46%	567	605
HHEFQ42	934527	470	HMMER	PFAM: C2 domain	PF00168	128.8	203	472
			2.1.1
			blastx.14	(AB025258) granuphilin-a	gi|5926736|dbj|BAA84656.1|	40%	128	505
				[Mus musculus]		57%	887	1057
						46%	695	892
						39%	707	820
						31%	263	376
						46%	644	682
						38%	572	610
						75%	107	130
HLQDC55	1082368	171	blastx.14	(AK002037) unnamed	gi|7023676|dbj|BAA92048.1|	49%	332	496
				protein product [Homo		42%	149	253
				sapiens]
HLQDC55	934528	471	HMMER	PFAM: C2 domain	PF00168	81.1	1	216
			2.1.1
			blastx.2	CG15078 PROTEIN.	sp|Q9V8M4|Q9V8M4	34%	7	441
						43%	1	234
						64%	444	494
HFPHI62	1195825	172	blastx.14	rabphilin-3A - bovine	pir|A48097|A48097	95%	184	1119
						68%	4	90
HFPHI62	934529	472	HMMER	PFAM: C2 domain	PF00168	106.44	27	293
			1.8
			blastx.2	rabphilin-3A - mouse	pir|JX0338|JX0338	90%	3	410
HE8QH09	1152238	173	blastx.14	(AB000893)	gi|1840399|dbj|BAA19204.1|	95%	28	591
				synaptotagmin 3 [Mus		96%	585	923
				musculus]		39%	46	228
						33%	193	351
						39%	453	521
HE8QH09	934532	473	HMMER	PFAM: C2 domain	PF00168	168.2	77	337
			2.1.1
			blastx.14	(AB000893)	gi|1840399|dbj|BAA19204.1|	92%	56	568
				synaptotagmin 3 [Mus		98%	564	830
				musculus]		42%	407	556
						33%	573	731
						32%	170	328
						34%	56	205
						100%	21	53
						39%	430	498
HFAAX29	1128791	174	blastx.14	(AF000423)	gi|2130632|gb|AAB58344.1|	99%	25	570
				synaptotagmin XI [Rattus		35%	385	510
				norvegicus]		25%	169	333
						47%	331	387
HFAAX29	934540	474	HMMER	PFAM: C2 domain	PF00168	115.2	194	463
			2.1.1
			blastx.2	SYNAPTOTAGMIN XI.	sp|O08835|O08835	98%	8	550
						32%	149	490
HHFOC79	1182276	175	blastx.14	(AF081251) putative eps	gi|3415099|gb|AAC31599.1|	97%	84	296
				protein [Rattus
				norvegicus]
HIIFOC79	935406	475	HMMER	PFAM: EF hand	PF00036	13.96	186	263
			1.8
			blastx.2	EH domain containing 2.	sp|AAF40470|AAF40470	98%	54	248
HOGEQ43	935465	476	HMMER	PFAM: Src homology	PF00018	28.13	58	132
			1.8	domain 3
			blastx.2	(AF132480) Ese2 protein	gb|AAD19748.1|	93%	37	132
				[Mus musculus]
IICECQ23	938398	177	HMMER	PFAM: CUB domain	PF00431	53.7	567	433
			2.1.1
			blastx.2	seizure-related protein	pir|I52657|I52657	93%	810	370
				SEZ-6 precursor - mouse		90%	335	237
						29%	765	370
						35%	744	571
						30%	747	574
						27%	687	484
						27%	537	409
HTGAU79	1178621	178	blastx.14	(AL157917) similarity to	gi|7106102|emb|CAB76028.1|	50%	745	966
				endopeptidases 1		38%	361	561
						52%	607	720
						52%	313	363
HTGAU79	940369	477	HMMER	PFAM: Eukaryotic protein	PF00069	31.25	315	779
			1.8	kinase domain
			blastx.2	(AL157917) similarity to	emb|CAB76028.1|	45%	324	977
				endopeptidases
				[Schizosaccharomyces 1
HE9FI33	1156432	179	blastx.14	putative integral	gi|3004482|emb|CAA71076.1|	59%	14	286
				membrane transport		61%	1153	1206
				protein [Rattus
				norvegicus]
HE9FI33	941348	478	HMMER	PFAM: Sugar (and other)	PF00083	17.62	210	422
			1.8	transporters
			blastx.2	putative integral	emb|CAA71076.1|	53%	3	428
				membrane transport
				protein [Rattus
				norvegicus]
HNHCP79	941862	480	HMMER	PFAM: 7 transmembrane	PF00001	118.47	2	670
			1.8	receptor (rhodopsin
				family)
			blastx.14	(AF102533) olfactory	gi|3983394|gb|AAD13325.1|	55%	2	658
				receptor F7 [Mus
				musculus]
HTLIY52	1194806	181	blastx.14	TESTIS-SPECIFIC	sp|Q61241|Q61241	46%	624	956
				SERINE/THREONINE		48%	126	398
				KINASE.		45%	411	563
						42%	549	605
HTLIY52	942161	481	HMMER	PFAM: Eukaryotic protein	PF00069	251.19	166	933
			1.8	kinase domain
			blastx.2	serine/threonine kinase	gb|AAA99535.1|	44%	133	936
				[Mus musculus]
HRAED74	942527	182	HMMER	PFAM: Eukaryotic protein	PF00069	59.6	406	612
			1.8	kinase domain
			blastx.2	(AB023658)	dbj|BAA75246.1|	97%	71	346
				Ca/calmodulin-dependent		81%	388	648
				protein kinase kinase		71%	342	425
				alpha, CaM-kinase kinase		88%	662	688
				alpha [Rattus norvegicus]
HFKKN77	943757	183	HMMER	PEAM: 7 transmembrane	PF00001	80.79	274	573
			1.8	receptor (rhodopsin
				family)
			blastx.2	G-protein coupled	pir|JC7289|JC7289	82%	160	714
				receptor, SREB3 - human
HTEMU66	1205381	184	blastx.14	MEK KINASE ALPHA.	sp|O96611|O96611	51%	714	962
						66%	633	668
HTEMU66	944419	482	HMMER	PFAM: Eukaryotic protein	PF00069	114.85	613	963
			1.8	kinase domain
			blastx.2	MEK Kinase 3 [Mus	gb|AAB03535.1|	49%	604	948
				musculus]		29%	209	340
HWAGU62	1206797	185	blastx.14	Zinc transporter like 1.	sp|AAF43422|AAF43422	95%	264	827
						96%	969	1511
						93%	29	262
						33%	22	111
HWAGU62	945368	483	HMMER	PFAM: Cation efflux	PF01545	152	619	1395
			2.1.1	family
			blastx.2	(AC007231) putative	gb|AAD32753.1|AC007231_1	45%	388	858
				cation transport protein		42%	910	1386
				[Arabidopsis thaliana]		38%	883	951
HFPFB39	1198036	186	blastx.14	CG8745 PROTEIN.	sp|Q9VU95|Q9VU95|	65%	153	614
						60%	693	935
						65%	945	1118
						66%	1332	1412
						35%	1161	1328
						50%	609	686
HFPFB39	946170	484	HMMER	PFAM:	PF00202	235.05	1613	714
			1.8	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.2	hypothetical protein	pir|T25848|T25848	49%	1613	651
				T01B11.2 -
				Caenorhabditis elegans
HPMFI38	1165993	187	blastx.14	(AB005451) RST [Mus	gi|2696709|dbj|BAA23875.1|	51%	30	296
				musculus]		73%	382	438
HPMFI38	946252	485	HMMER	PFAM: Sugar (and other)	PF00083	32.16	860	564
			1 .8	transporters
			blastx.2	renal organic anion	emb|CAB09724.1|	43%	15	488
				transporter
				[Pseudopleuronectes
				americanus]
HBXDJ07	946830	188	HMMER	PFAM: Synaptophysin/	PF01284	406.7	125	604
			2.1.1	synaptoporin
			blastx.2	synaptoporin - rat	pir|JH0300|JH0300	90%	125	643
						91%	610	921
HOFMS43	1152417	189	blastx.14	porcine membrane	gi|1018989|dbj|BAA20476.1|	62%	325	738
				cofactor protein [Sus		47%	7	312
				scrofa]		52%	322	378
						29%	673	765
						36%	688	744
						33%	512	574
HOFMS43	947973	486	HMMER	PFAM: Sushi domain	PF00084	64	174	302
			2.1.1	(SCR repeat)
			blastx.2	PORCINE MEMBRANE	sp|O02839|O02839	47%	12	317
				COFACTOR PROTEIN.
HOVCO14	1091087	190	blastx.2	C4BP beta chain, leader	emb|CAA90392.1|	34%	3	434
				[Rattus norvegicus]
HOVCO14	947999	487	HMMER	PFAM: Sushi domain	PF00084	84	21	170
			2.1.1	(SCR repeat)
			blastx.2	UNKNOWN PROTEIN	sp|Q28797|Q28797	33%	21	347
				(FRAGMENT).		34%	21	380
						38%	424	516
						47%	424	474
HTEPE35	1105272	191	blastx.14	1-phosphatidylinositol-	pir|S14113|S14113	53%	1	357
				4,5-bisphosphate		51%	451	750
				phosphodiesterase 1
HTEPE35	948475	488	HMMER	PFAM:	PF00387	163.8	839	507
			2.1.1	Phosphatidylinositol-
				specific phospholipase C,
				Y domain
			blastx.2	1-phosphatidylinositol-	pir|S14113|S14113	48%	839	90
				4,5-bisphosphate
				phosphodiesterase 1
HE8UA52	1229490	192	blastx.14	collagen alpha 3(VI) chain	pir|A37797|A37797	34%	121	729
				precursor - chicken		32%	805	1353
						35%	700	819
						19%	208	330
						44%	814	867
						24%	196	306
						50%	808	861
						26%	208	330
						30%	395	484
HE8UA52	948509	489	HMMER	PFAM: von Willebrand	PF00092	57.11	208	561
			1.8	factor type A domain
			blastx.2	collagen alpha 3(VI) chain -	pir|S32605|S32605	41%	121	576
				mouse (fragment)
HOUBE50	1090776	193	blastx.14	neuroligin 3 [Rattus	gi|1145791|gb|AAA97871.1|	74%	376	1140
				norvegicus]		67%	31	252
						77%	277	381
						68%	1134	1181
HOUBE50	948519	490	HMMER	PFAM: Carboxylesterases	PF00135	55.97	16	243
			1.8
			blastx.2	Neuroligin 3 isoform	sp|AAF71231|AAF71231	70%	31	243
				HNL3s (Fragment).
HAJAV28	1165229	194	blastx.14	(AK000544) unnamed	gi|7020711|dbj|BAA91243.1|	95%	96	1118
				protein product [Homo		100%	1064	1345
				sapiens]
HAJAV28	948630	491	HMMER	PFAM: Actin	PF00022	35.9	120	230
			2.1.1
			blastx.2	Uncharacterized	sp|AAF67655|AAF67655	97%	96	458
				hypothalamus protein
				HARP11.
HAQBZ89	1083554	195	blastx.14	strong similarity to class-	gi|1707274|gb|AAB37999.1|	49%	249	578
				III of 1 elegans]		38%	594	881
						52%	873	992
						54%	1	72
						58%	186	221
HAQBZ89	949061	492	HMMER	PFAM:	PF00202	62.49	68	325
			1.8	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.2	CG8745 PROTEIN.	sp|Q9VU95|Q9VU95	52%	8	316
HELHF07	949067	196	HMMER	PFAM:	PF00202	38.85	95	295
			1.8	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.14	4-aminobutyrate	gi|1742132|dbj|BAA14871.1|	85%	83	295
				aminotransferase (EC		92%	21	98
				2.6.1.19) 11		45%	246	311
				aminotransferase).		100%	1	18
				[Escherichia coli]
HE9QQ22	1127726	197	blastx.14	(AB002584) beta-alanine-	gi|1944136|dbj|BAA19549.1|	77%	92	418
				pyruvate aminotransferase 1		80%	418	585
						85%	587	628
						100%	677	697
HE9QQ22	949080	493	HMMER	PFAM:	PF00202	105.1	285	545
			2.1.1	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.2	ALANINE -	sp|Q64565|AGT2—	51%	3	1070
				GLYOXYLATE	RAT	43%	545	1003
				AMINOTRANSFERASE		49%	682	999
				2 PRECURSOR (EC 11
HSDSB06	949151	494	HMMER	PFAM: SH3 domain	PF00018	249.3	483	647
			2.1.1
			blastx.2	(AL133047) hypothetical	emb|CAB61374.1|	98%	3	863
				protein [Homo sapiens]		30%	6	848
						33%	222	848
HACAD35	949199	199	HMMER	PFAM: von Willebrand	PF00092	70.8	1461	1174
			2.1.1	factor type A domain
			blastx.2	SIMILAR TO COCH-	sp|Q9UDN0|Q9UDN0	99%	1464	952
				5B2.		100%	947	648
						95%	657	457
						22%	944	663
						50%	1005	952
HEQAP17	949358	200	HMMER	PFAM: 7 transmembrane	PF00001	94.57	741	436
			1.8	receptor (rhodopsin
				family)
			blastx.2	Orphan seven-	sp|AAF59827|AAF59827	84%	786	295
				transmembrane receptor.
HMTBB17	950884	495	HMMER	PFAM: EF hand	PF00036	15.74	285	202
			1.8
			blastx.2	CDNA FLJ10466 FIS,	sp|BAA91628|BAA91628	100%	513	100
				CLONE NT2RP1001665.
HKGDE58	945039	496	blastx.2	CDNA FLJ10466 FIS,	sp|BAA91628|BAA91628	86%	17	835
				CLONE NT2RP1001665.		30%	281	691
						55%	697	825
						36%	690	914
						35%	32	208
HKGDE58	950885	497	HMMER	PFAM: EF hand	PF00036	15.98	304	221
			1.8
			blastx.14	(AJ133836) calmodulin 2	gi|4581211|emb|CAB40132.1|	28%	337	179
				[Branchiostoma floridae]		37%	166	119
HCHMW40	1144323	203	blastx.14	calmodulin [Plasmodium	gi|385234|gb|AAA29508.1	60%	376	564
				falciparum]		49%	136	348
						38%	349	573
						36%	157	345
						32%	481	564
HCHMW40	951518	498	HMMER	PFAM: EF hand	PF00036	129.9	486	572
			2.1.1
			blastx.2	Calmodulin-like skin	sp|AAF66821|AAF66821	98%	135	572
				protein.
HE8QZ34	1143411	204	blastx.14	predicted using	gi|3875264|emb|CAB01132.1|	39%	941	1201
				Genefinder; similar to EF		50%	437	595
				hand (2 domains)		40%	695	877
				[Caenorhabditis elegans]		32%	227	412
						26%	1082	1183
HE8QZ34	952283	499	HMMER	PFAM: EF hand	PF00036	12.97	543	617
			1.8
			blastx.2	CG4662 PROTEIN.	sp|Q9VDT8|Q9VDT8	38%	249	980
						42%	249	878
						33%	977	1084
HWAFG04	1227627	205	blastx.14	PRO1038.	sp|AAF71042|AAF71042	56%	5	550
						44%	536	745
HWAFG04	952878	500	HMMER	PFAM: Eukaryotic protein	PF00069	93.74	1655	945
			1.8	kinase domain
			blastx.14	(AC002343) Ser/Thr	gi|2262107|gb|AAB63615.1	41%	1655	1383
				protein kinase isolog		48%	1319	1185
				[Arabidopsis thaliana]		42%	1046	933
						75%	1355	1332
HTEKT33	953308	501	HMMER	PFAM: Eukaryotic protein	PF00069	200.58	428	1393
			1.8	kinase domain
			blastx.2	(AC007661) putative	gb|AAD32787.1|AC007661_24	41%	722	1009
				protein kinase		36%	1070	1243
				[Arabidopsis thaliana]		29%	428	628
HBXDM07	953622	502	HMMER	PFAM: Sec1 family	PF00995	96.7	267	575
			2.1.1
			blastx.2	Vacuolar protein sorting	sp|AAF91174|AAF91174	83%	141	728
				33B.		97%	1	141
						35%	587	706
HFPFA83	955614	208	HMMER	PFAM: 7 transmembrane	PF00001	107.6	316	681
			1.8	receptor (rhodopsin
				family)
			blastx.2	G-protein coupled	pir|JC7289|JC7289	98%	202	735
				receptor, SREB3 - human
HKADO36	956115	503	HMMER	PFAM: Sugar (and other)	PF00083	44.03	2	277
			1.8	transporters
HFXKG51	956596	210	HMMER	PFAM: Sugar (and other)	PF00083	121.54	506	147
			1.8	transporters
			blastx.2	No definition line found	gb|AAB18499.1|	100%	560	982
				[Escherichia coli]
HFPHR82	957528	504	HMMER	PFAM: Actin	PF00022	91.7	1322	357
			2.1.1
			blastx.2	Uncharacterized	sp|AAF67655|AAF67655	100%	1523	273
				hypothalamus protein
				HARP11.
HISAF59	959140	212	HMMER	PFAM: Eukaryotic protein	PF00069	89.46	340	771
			1.8	kinase domain
			blastx.14	(AC002343) Ser/Thr	gi|2262107|gb|AAB63615.1|	39%	460	768
				protein kinase isolog		33%	397	468
				[Arabidopsis thaliana]
HCEHD66	1136122	213	blastx.14	neuronal calcium sensor	gi|498032|gb|AAA88510.1|	98%	2	562
				[Rattus norvegicus]
HCEHD66	959160	505	HMMER	PFAM: EF hand	PF00036	64.2	311	397
			2.1.1
			blastx.2	Neuronal calcium sensor-1.	sp|AAD01642|AAD01642	100%	14	583
HE8UY74	1163590	214	blastx.14	(AF080119) contains	gi|3600036|gb|AAC35524.1|	38%	13	291
				similarity to protein		68%	367	441
				kinase 1		61%	464	502
HE8UY74	960914	506	HMMER	PFAM: Eukaryotic protein	PF00069	36.37	114	407
			1.8	kinase domain
			blastx.14	(AF080119) contains	gi|3600036|gb|AAC35524.1|	36%	117	290
				similarity to protein		45%	13	111
				kinase 1		73%	366	410
						37%	467	553
HAHIY08	962113	215	HMMER	PFAM: Eukaryotic protein	PF00069	74.92	39	278
			1.8	kinase domain
			blastx.14	similar to tyrosine kinase	gi|470364|gb|AAC47047.1|	44%	192	278
				[Caenorhabditis elegans]		64%	18	92
						58%	108	179
H2CBH45	963811	507	HMMER	PFAM: Src homology	PF00018	13	194	310
			1.8	domain 3
			blastx.2	Kryn [Mus musculus]	dbj|BAA19686.1|	85%	2	373
						79%	381	467
						87%	460	483
						70%	131	160
HMVAM09	963814	508	HMMER	PFAM: Src homology	PF00018	4.79	728	802
			1.8	domain 3
			blastx.2	(AK001580) unnamed	dbj|BAA91769.1|	96%	20	802
				protein product [Homo
				sapiens]
HFPEN04	1199663	218	blastx.14	CG8745 PROTEIN.	sp|Q9VU95|Q9VU95	65%	156	617
						60%	696	938
						65%	948	1121
						66%	1335	1415
						35%	1164	1331
						50%	612	689
HFPEN04	964824	509	HMMER	PFAM:	PF00202	33.54	259	489
			1.8	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.2	CG8745 PROTEIN.	sp|Q9VU95|Q9VU95	62%	148	492
HSLJD02	1104452	219	blastx.14	UhpC protein [Escherichia	gi|148114|gb|AAA24722.1|	95%	145	927
				coli]
HSLJD02	965826	510	HMMER	PFAM: Sugar (and other)	PF00083	19.53	464	874
			1.8	transporters
			blastx.2	UhpC protein [Escherichia	gb|AAA24722.1|	100%	56	907
				coli]
HDPFZ30	1220164	220	blastx.14	Sulfate transporter.	sp|CAC05432|CAC05432	55%	1684	1517
						48%	1433	1335
						32%	1154	996
						50%	180	139
						35%	1199	1140
HDPFZ30	966752	511	HMMER	PFAM: Sulfate transporter	PF00916	60.2	1496	1233
			2.1.1	family
			blastx.2	(AF180728) sulfate	gb|AAD53951.1|	28%	175	807
				transporter [Drosophila		52%	14	196
				melanogaster]
HPJCR33	966758	512	HMMER	PFAM: C2 domain	PF00168	31.15	13	267
			1.8
			blastx.2	E3 UBIQUITIN LIGASE	sp|Q9UJT8|Q9UJT8	89%	7	375
				SMURF1 (FRAGMENT).
HTOAK34	966800	513	HMMER	PFAM: Eukaryotic protein	PF00069	32.41	1020	1190
			1.8	kinase domain
			blastx.14	(AF084205)	gi|3452473|gb|AAC71014.1|	75%	954	1190
				serine/threonine protein
				kinase TAO1 [Rattus
				norvegicus]
HE8NI24	971296	223	HMMER	PFAM: 7 transmembrane	PF00001	61.74	453	707
			1.8	receptor (rhodopsin
				family)
			blastx.2	G-protein coupled	pir|T47131|T47131	93%	345	707
				receptor, SREB2 - human		88%	722	748
HAMFM39	1055532	224	blastx.14	(AK001509) unnamed	gi|7022807|dbj|BAA91729.1|	53%	3860	3432
				protein product [Homo		100%	4171	4106
				sapiens]
HAMFM39	971347	514	HMMER	PFAM: Src homology	PF00018	67.14	1136	1306
			1.8	domain 3
			blastx.2	(AK001509) unnamed	dbj|BAA91729.1|	59%	4511	4017
				protein product [Homo
				sapiens]
HBGMG39	971414	515	HMMER	PFAM: EF hand	PF00036	10.69	61	141
			1.8
			blastx.2	45 KDA CALCIUM-	sp|Q61112|CB45_MOUSE	94%	7	165
				BINDING PROTEIN
				PRECURSOR
				(STROMAL 1
HSXBV89	1128699	226	blastx.2	TYPE I	sp|Q9UJ47|Q9UJ47	93%	7	2037
				TRANSMEMBRANE		29%	313	1044
				RECEPTOR		29%	742	1464
				PRECURSOR.
HSXBV89	971821	516	HMMER	PFAM: Sushi domain	PF00084	43.6	123	290
			2.1.1	(SCR repeat)
			blastx.2	TYPE I	sp|Q9UJ47|Q9UJ47	82%	3	635
				TRANSMEMBRANE		32%	96	536
				RECEPTOR
				PRECURSOR.
HBIOZ10	1143756	227	blastx.14	(AF003134) strong	gi|2088685|gb|AAB54139.1|	43%	3	497
				similarity to the
				CDC2/CDX 1
HBIOZ10	973131	517	HMMER	PFAM: Eukaryotic protein	PF00069	121.1	3	365
			1.8	kinase domain
			blastx.2	(AF003134) strong	gb|AAB54139.1|	60%	3	305
				similarity to the
				CDC2/CDX subfamily of
				ser/thr protein kinases
				[Caenorhabditis elegans]
HTLEJ11	1085651	228	blastx.14	(AF144573) Mx-	gi|4868443|gb|AAD31319.1|	69%	35	268
				interacting protein kinase	AF144573_1	40%	437	592
				PKM [Mesocricetus		42%	293	397
				auratus]		38%	877	939
HTLEJ11	973302	518	HMMER	PFAM: Eukaryotic protein	PF00069	55.9	44	223
			2.1.1	kinase domain
			blastx.14	(AF144573) Mx-	gi|4868443|gb|AAD31319.1|	69%	35	268
				interacting protein kinase	AF144573_1	40%	437	592
				PKM [Mesocricetus		42%	293	397
				auratus]		38%	877	939
HAWAM69	1207835	229	blastx.14	SPARC-RELATED	sp|Q9WVN9|Q9WVN9	63%	580	972
				PROTEIN.		53%	193	438
						53%	961	1224
						52%	49	198
						48%	223	333
						46%	640	756
						23%	382	624
						34%	343	411
						50%	604	657
						33%	760	831
						28%	1025	1120
						38%	2238	2300
HAWAM69	943104	519	blastx.2	SPARC-RELATED	sp|Q9WVN9|Q9WVN9	51%	31	261
				PROTEIN.
HAWAM69	973465	520	HMMER	PFAM: EF hand	PF00036	10.13	97	26
			1.8
			blastx.14	(AF070470) SPARC-	gi|5305327|gb|AAD41590.1|	62%	133	5
				related protein [Mus	AF070470_1
				musculus]
HSCKD11	1056288	230	blastx.14	(AJ243342) nicotinic	gi|6688136|emb|CAB65091.1|	98%	1292	1831
				acetylcholine receptor		88%	2347	2886
				alpha 9 subunit [Homo		100%	54	203
				sapiens]		33%	3000	3107
						35%	2938	2988
HSCKD11	973894	521	HMMER	PFAM: Neurotransmitter-	PF00065	31.56	147	257
			1.8	gated ion-channel
			blastx.2	(AJ243342) nicotinic	emb|CAB65091.1|	90%	120	296
				acetylcholine receptor
				alpha 9 subunit [Homo
				sapiens]
HDPLT62	973945	522	HMMER	PFAM: Neurotransmitter-	PF00065	102.12	417	746
			1.8	gated ion-channel
			blastx	GABA receptor rho-3	dbj|BAA09322.1|	78%	414	797
				subunit precursor [Rattus		92%	262	411
				norvegicus]
HTPFX16	974296	232	HMMER	PFAM: PMP-	PF00822	50.2	48	299
			2.1.1	22/EMP/MP20/Claudin
				family
			blastx.2	CLAUDIN-18.	sp|P56857|CLDI_MOUSE	67%	39	359
						44%	316	483
HE9NO66	1079624	233	blastx.14	(AB035267) Nck-	gi|6472874|dbj|BAA87066.1|	82%	449	775
				interacting kinase-like		94%	2	283
				embryo specific kinase		80%	748	990
				[Mus musculus]
HE9NO66	974353	523	HMMER	PFAM: Eukaryotic protein	PF00069	121.6	473	757
			1.8	kinase domain
			blastx.14	(AB020741) NIK-related	gi|6009519|dbj|BAA84943.1	73%	449	817
				kinase [Mus musculus]		94%	2	283
						79%	748	990
HSDJI44	1154068	234	blastx.14	(AE000180) 7,8-	gi|1786991|gb|AAC73861.1|	94%	803	1849
				diaminopelargonic acid		98%	1828	2088
				synthetase [Escherichia
				coli]
HSDJI44	974784	524	HMMER	PFAM:	PF00202	511.4	894	1835
			2.1.1	Aminotransferases class-
				III pyridoxal-phosphate
			blastx.14	(AE000180) 7,8-	gi|1786991|gb|AAC73861.1|	99%	795	1841
				diaminopelargonic acid		100%	1837	1860
				synthetase [Escherichia
				coli]
HFXDP53	578868	525	HMMER	PFAM: CUB domain	PF00431	11.77	21	77
			1.8
HWADY66	734565	236	HMMER	PFAM: Eukaryotic protein	PF00069	28.82	1	174
			1.8	kinase domain
HLDBC63	1144557	237	blastx.14	carnitine	gi|755646|gb|AAC41748.1|	99%	3	629
				palmitoyltransferase I
				[Homo sapiens]
HLDBC63	745061	526	HMMER	PFAM: Carnitate	PF00755	258.4	3	410
			2.1.1	acyltransferase
HFIVB68	752981	527	HMMER	PFAM: C2 domain	PF00168	35.53	406	570
			1.8
			blastx.2	hypothetical protein	pir|T12449|T12449	93%	187	615
				DKFZp564E1616.1 -		97%	692	835
				human (fragments)		97%	588	692
						96%	104	184
						68%	3	107
						36%	573	668
						27%	406	543
						36%	397	465
						54%	125	157
HTLAC56	1181355	239	blastx.14	carnitine	gi|755646|gb|AAC41748.1|	54%	6	599
				palmitoyltransferase I
				[Homo sapiens]
HTLAC56	753093	528	HMMER	PFAM: Carnitate	PF00755	143.3	6	422
			2.1.1	acyltransferase
HSSAD41	753094	240	HMMER	PFAM: Carnitate	PF00755	90.8	51	299
			2.1.1	acyltransferase
HCFMT57	765375	529	HMMER	PFAM: Src homology	PF00018	14.55	107	3
			1.8	domain 3
			blastx.2	(AF039571) peripheral	gb|AAD11957.1|	96%	377	3
				benzodiazepine receptor
				interacting protein; PBR-
				IP/PRAX1 [Homo
				sapiens]
HDAAV61	810305	530	HMMER	PFAM: Eukaryotic protein	PF00069	41.11	11	145
			1.8	kinase domain
HDPKD75	1096253	243	blastx.14	(AF191838) TANK	gi|6224868|gb|AAF05989.1|	100%	74	637
				binding kinase TBK1	AF191838_1
				[Homo sapiens]
HDPKD75	810824	531	HMMER	PFAM: Eukaryotic protein	PF00069	98.74	68	433
			1.8	kinase domain
HTEON29	1126312	244	blastx.14	(AB021866) CIB [Homo	gi|4092850|dbj|BAA36281.1|	50%	190	339
				sapiens]		47%	394	501
						57%	103	186
						48%	1	111
HTEON29	815852	532	HMMER	PFAM: EF hand	PF00036	22.29	266	349
			1.8
			blastx.2	CALCIUM-AND	sp|Q9R010|Q9R010	41%	2	496
				INTEGRIN-BINDING
				PROTEIN CIB.
HSKAC24	1121800	245	blastx.14	(AF144573) Mx-	gi|4868443|gb|AAD31319.1|	94%	37	453
				interacting protein kinase	AF144573_1	77%	464	490
				PKM [Mesocricetus		100%	17	43
				auratus]		88%	484	510
HSKAC24	823869	533	HMMER	PFAM: Eukaryotic protein	PF00069	79.36	122	454
			1.8	kinase domain
HTJAA71	846682	534	HMMER	PFAM: S-100/ICaBP type	PF01023	36.3	77	208
			2.1.1	calcium binding domain
			blastx.2	TUMOR RELATED	sp|Q9UBG3|Q9UBG3	70%	68	325
				PROTEIN.
HTEKS20	1124378	247	blastx.14	calcineurin [Bos taurus]	gi|312969|emb|CAA50659.1|	77%	53	562
HTEKS20	846714	535	HMMER	PFAM: EF hand	PF00036	84.7	453	539
			2.1.1
			blastx.2	calcineurin regulatory	pir|A33391|A33391	77%	60	569
				chain - human
HE9TK49	856343	536	HMMER	PFAM: Ion transport	PF00520	77.02	11	256
			1.8	proteins
			blastx.2	(AB012043) NBR13	dbj|BAA36409.1|	95%	2	256
				[Homo sapiens]		50%	256	327
						37%	259	282
HCHAT01	867209	537	HMMER	PFAM: EF hand	PF00036	24.01	1227	1304
			1.8
			blastx.2	AD 3 (FRAGMENT).	sp|Q9UQ32|Q9UQ32	47%	795	1409
						72%	14	367
						57%	472	783
						79%	375	476
HCEEN06	1150867	250	blastx.14	(AB025258) granuphilin-a	gi|5926736|dbj|BAA84656.1|	32%	296	490
				[Mus musculus]		48%	548	652
						47%	242	298
						42%	152	229
HCEEN06	878658	538	HMMER	PFAM: C2 domain	PF00168	51.79	203	466
			1.8
HDPKI83	883382	251	HMMER	PFAM: C2 domain	PF00168	13.47	530	601
			1.8
			blastx.2	MUNC13-4 PROTEIN.	sp|Q9R189|Q9R189	76%	194	631
						95%	735	794
						80%	661	738
HSPBQ12	1152258	252	blastx.14	copine I [Homo sapiens]	gi|1791257|gb|AAC15920.1|	73%	55	570
						63%	570	851
HSPBQ12	884004	539	HMMER	PFAM: C2 domain	PF00168	42.06	352	624
			1.8
HPCID78	886915	253	HMMER	PFAM: Sulfate transporter	PF00916	26.4	265	381
			2.1.1	family
			blastx.2	(AF030880) pendrin	gb|AAC51873.1|	40%	25	375
				[Homo sapiens]
HDTKQ14	886936	254	HMMER	PFAM: Src homology	PF00018	12.87	430	546
			1.8	domain 3
			blastx.2	(AL049683) hypothetical	emb|CAB41255.1|	100%	439	555
				protein [Homo sapiens]		56%	76	291
HRACK83	888037	255	HMMER	PFAM: Eukaryotic protein	PF00069	48.4	211	423
			1.8	kinase domain
HSIAO78	889498	540	HMMER	PFAM: EF hand	PF00036	19.91	389	463
			1.8
			blastx.2	HYPOTHETICAL 22.5 KDA	sp|O43745|O43745	97%	38	622
				PROTEIN.
HWAGS73	894404	257	HMMER	PFAM: Eukaryotic protein	PF00069	64.17	4	273
			1.8	kinase domain
HCMSL08	898203	258	HMMER	PFAM: Calsequestrin	PF01216	1001.1	52	1221
			2.1.1
			blastx.2	calsequestrin precursor,	pir|A60424|A60424	95%	112	1197
				fast skeletal muscle -
				human
HCMSL08	959176	541	HMMER	PFAM: Calsequestrin	PF01216	697.4	1372	569
			2.1.1
			blastx.14	calmitine; calsequestrine	gi|688292|gb|AAB32063.1|	93%	1372	593
				[Homo sapiens]
HLWFN63	1101533	259	blastx.14	(AL049683) hypothetical	gi|4678753|emb|CAB41255.1|	45%	470	937
				protein [Homo sapiens]		75%	989	1024
HLWFN63	908437	542	HMMER	PFAM: Src homology	PF00018	12.81	515	664
			1.8	domain 3
			blastx.2	(AL049683) hypothetical	emb|CAB41255.1|	44%	464	1024
				protein [Homo sapiens]
HPWAY10	908549	543	HMMER	PFAM: KRAB box	PF01352	156.3	206	394
			2.1.1
			blastx.14	zinc finger protein 30	gi|456269|emb|CAA82913.1|	70%	152	325
				[Mus musculus		67%	326	454
				domesticus]
HOUDH19	1153909	261	blastx.14	(AC007842) BC331191_1	gi|5080758|gb|AAD39268.1|	100%	57	335
				[Homo sapiens]	AC007842_3
HOUDH19	908588	544	HMMER	PFAM: KRAB box	PF01352	169.7	241	429
			2.1.1
			blastx.2	(AC007842) BC331191_1	gb|AAD39268.1|AC007842_3	91%	226	549
				[Homo sapiens]
HDPFF24	909232	545	HMMER	PFAM: KRAB box	PF01352	121.3	158	349
			2.1.1
			blastx.2	(AC007228) R31665_2	gb|AAD23606.1|AC007228_1	50%	158	457
				[AA 1-673] [Homo
				sapiens]
HWLFH94	1152278	263	blastx.14	(AK000265) unnamed	gi|7020230|dbj|BAA91041.1|	41%	739	939
				protein product [Homo		53%	595	690
				sapiens]		57%	335	397
HWLFH94	909682	546	HMMER	PFAM: Src homology	PF00018	58.42	308	463
			1.8	domain 3
			blastx.2	(AK000265) unnamed	dbj|BAA91041.1|	40%	215	535
				protein product [Homo
				sapiens]
HWMBM13	1152283	264	blastx.14	(AK000265) unnamed	gi|7020230|dbj|BAA91041.1|	56%	153	296
				protein product [Homo		41%	345	545
				sapiens]
HWMBM13	909683	547	HMMER	PFAM: Src homology	PF00018	59.64	126	281
			1.8	domain 3
			blastx.2	Eps8 [Mus musculus]	gb|AAA16358.1|	35%	33	317
						37%	324	527
HFIUE75	1172525	265	blastx.14	(AB037134) IRE homolog	gi|6729348|dbj|BAA89784.1|	53%	868	1134
				1 [Arabidopsis thaliana]		40%	1126	1251
						28%	526	684
HFIUE75	909758	548	HMMER	PFAM: Eukaryotic protein	PF00069	85.68	377	664
			1.8	kinase domain
			blastx.14	(AD000092) hypothetical	gi|1905906|gb|AAB51171.1|	43%	362	634
				human serine-threonine		46%	632	715
				protein kinase R31240_1		47%	724	774
				[Homo sapiens]
HNTCP13	909770	549	HMMER	PFAM: Eukaryotic protein	PF00069	102.96	445	930
			1.8	kinase domain
			blastx.14	(AC006530) unknown	gi|4809337|gb|AAD30182.1|	55%	463	957
				[Homo sapiens]	AC006530_4
HBIBQ89	909782	550	HMMER	PFAM: SH3 domain	PF00018	49.7	212	376
			2.1.1
			blastx.2	p115 [Homo sapiens]	emb|CAA55394.1|	41%	14	397
HWBEG18	909798	551	HMMER	PFAM: EF hand	PF00036	33.3	505	591
			2.1.1
			blastx.2	RAS ACTIVATOR	sp|Q9UNN9|Q9UNN9	55%	103	684
				RASGRP.		71%	698	889
						48%	2	142
HTAHB43	1221956	269	blastx.14	PUTATIVE RASGAP-	sp|O43374|O43374	99%	153	2174
				ACTIVATING-LIKE		100%	2174	2356
				PROTEIN.		97%	42	164
						34%	45	140
						31%	429	524
						57%	1436	1477
HTAHB43	909845	552	HMMER	PFAM: GTPase-activator	PF00616	61.3	519	731
			2.1.1	protein for Ras-like
				GTPase
			blastx.2	PUTATIVE RASGAP-	sp|O43374|O43374	97%	39	860
				ACTIVATING-LIKE		100%	1	33
				PROTEIN.
HSYBX32	909846	270	HMMER	PFAM: C2 domain	PF00168	41.14	46	189
			1.8
			blastx.2	PUTATIVE RASGAP-	sp|O43374|O43374	98%	49	228
				ACTIVATING-LIKE
				PROTEIN.
HCEHE35	909937	553	HMMER	PFAM: Eukaryotic protein	PF00069	30.78	210	347
			1.8	kinase domain
			blastx.14	protein kinase PRK2	gi|914100|gb|AAB33346.1|	66%	204	365
				[human, DX3 B-cell
				myeloma cell line,
				Peptide, 984 aa] [Homo
				sapiens]
HFCBB56	1204971	272	blastx.14	inositol 1,4,5-	pir|S62358|S62358	44%	280	387
				trisphosphate-binding		31%	439	612
				protein, 130K - rat		26%	598	744
HFCBB56	910073	554	HMMER	PFAM: EF hand	PF00036	23.95	431	514
			1.8
			blastx.2	1-phosphatidylinositol-	pir|S14113|S14113	36%	275	565
				4,5-bisphosphate
				phosphodiesterase 1
HAMFL82	910074	273	HMMER	PFAM: C2 domain	PF00168	73.4	9	212
			1.8
			blastx.2	PHOSPHOLIPASE C-L2.	sp|Q9QYG1|Q9QYG1	97%	3	317
HBXCM38	1174533	274	blastx.14	unnamed protein product	gi|6740727|emb|CAB69447.1|	97%	405	1349
				[unidentified]		87%	13	396
HBXCM38	910086	555	HMMER	PFAM: Src homology	PF00018	55.89	1062	1232
			1.8	domain 3
			blastx.2	unnamed protein product	emb|CAB69447.1|	92%	402	1316
				[unidentified]		87%	13	396
						77%	1295	1348
HLHCR16	910123	275	HMMER	PFAM: Sushi domain	PF00084	744.9	197	358
			2.1.1	(SCR repeat)
			blastx.2	complement receptor 1 -	pir|I36936|I36936	29%	710	1600
				chimpanzee (fragment)		30%	1166	1921
						31%	818	1636
						30%	1958	2764
						28%	710	1513
						29%	1163	1921
						29%	1757	2632
						28%	1766	2632
						31%	911	1636
						26%	1970	3031
						27%	1754	2605
						28%	1166	1921
						30%	2378	3031
						36%	20	562
						29%	1244	1921
						26%	2210	3163
						26%	2210	3163
						32%	11	571
						32%	11	571
						32%	710	1204
						32%	11	562
						32%	710	1204
						30%	23	595
						30%	992	1630
						32%	710	1204
						29%	23	595
						36%	23	460
						33%	20	460
						27%	32	844
						29%	728	1387
						30%	983	1549
						28%	728	1387
						31%	713	1246
						32%	2657	3124
						31%	860	1387
						30%	518	1228
						31%	713	1246
						33%	713	1117
						32%	701	1114
						32%	113	574
						32%	113	574
						31%	2417	2983
						30%	1811	2242
						32%	2642	3109
						34%	80	460
						32%	1244	1639
						33%	701	1111
						31%	95	547
						29%	2219	2983
						31%	2681	3130
						29%	2618	3109
						30%	734	1171
						31%	1109	1537
						32%	80	451
						31%	2219	2761
						32%	725	1114
						25%	1721	2452
						29%	113	574
						31%	725	1114
						28%	1550	2113
						26%	2474	3319
						30%	1472	2026
						27%	1424	2113
						25%	2474	3100
						25%	1721	2452
						27%	1100	1639
						29%	893	1363
						35%	11	364
						26%	1721	2326
						27%	2555	3322
						26%	1721	2449
						33%	182	574
						26%	1100	1630
						29%	2549	2938
						30%	1997	2401
						30%	38	424
						32%	1241	1657
						30%	626	1015
						30%	734	1090
						25%	1250	1852
						24%	1250	1852
						30%	38	370
						31%	95	382
						31%	95	382
						31%	734	1090
						26%	1769	2464
						31%	725	1015
						31%	725	1015
						29%	1799	2056
						25%	1472	1882
						30%	593	847
						22%	371	598
HLHCR16	965511	556	HMMER	PFAM: Sushi domain	PF00084	357.8	197	358
			2.1.1	(SCR repeat)
			blastx.2	furrowed [Drosophila	gb|AAB36703.1|	31%	638	1480
				melanogaster]		28%	254	1228
						34%	737	1387
						28%	254	1120
						35%	89	604
						32%	908	1468
						34%	692	1189
						30%	740	1270
						30%	419	1018
						32%	11	529
						27%	17	916
						27%	17	553
						34%	1100	1480
						28%	11	445
						30%	977	1480
						37%	365	571
						29%	1220	1489
HE6GF02	1153883	276	blastx.14	(AJ007012) Fish protein	gi|3702174|emb|CAA07416.1|	75%	10	192
				[Mus musculus]		66%	202	378
						39%	202	375
						39%	1	192
						38%	13	168
						39%	10	168
						41%	205	378
						38%	223	372
						37%	253	324
						50%	550	609
						50%	273	320
						54%	346	378
HE6GF02	911263	557	HMMER	PFAM: Src homology	PF00018	51.15	10	174
			1.8	domain 3
			blastx.2	(AJ007012) Fish protein	emb|CAA07416.1|	77%	10	186
				[Mus musculus]		44%	201	275
HOUFT36	1162680	277	blastx.14	(AF162130) MAGUK	gi|6997272|gb|AAD45919.2|	100%	868	1563
				protein TEM-61 [Homo	AF162130_1	98%	422	868
				sapiens]		87%	31	426
HOUFT36	911293	558	HMMER	PFAM: PDZ domain	PF00595	35.3	322	558
			2.1.1	(Also known as DHR or
				GLGF).
			blastx.2	(AF162130) MAGUK	gb|AAD45919.2|AF162130_1	91%	196	846
				protein TEM-61 [Homo		98%	23	193
				sapiens]
HAGGF84	911312	559	HMMER	PFAM: Eukaryotic protein	PF00069	105.85	10	318
			1.8	kinase domain
			blastx.14	calmodulin-dependent	gi|3241849|dbj|BAA28870.1|	88%	10	363
				protein kinase II-delta		87%	366	413
				dash [Oryctolagus		100%	320	364
				cuniculus]
HTTKP07	1119031	279	blastx.14	(AL049683) hypothetical	gi|4678753|emb|CAB41255.1|	63%	8	205
				protein [Homo sapiens]		58%	263	451
HTTKP07	911390	560	HMMER	PFAM: Src homology	PF00018	15.82	47	196
			1.8	domain 3
			blastx.2	(AL049683) hypothetical	emb|CAB41255.1|	51%	8	289
				protein [Homo sapiens]		56%	292	450
HE9SE62	911476	561	HMMER	PFAM: Src homology	PF00018	47.65	268	435
			1.8	domain 3
			blastx.2	(AK000007) FLJ00007	dbj|BAA92232.1|	43%	4	435
				protein [Homo sapiens]		64%	877	927
HUJAD24	1162674	281	blastx.14	serine/threonine kinase	gi|2052191|emb|CAB06295.1|	34%	457	777
				[Rattus norvegicus]		48%	363	512
						34%	797	928
						57%	285	362
						51%	141	233
						72%	1679	1732
						42%	9	71
						24%	75	224
						72%	229	261
						42%	180	236
HUJAD24	911498	562	HMMER	PFAM: Eukaryotic protein	PF00069	34.73	9	215
			1.8	kinase domain
			blastx.14	AMP-activated protein	gi|758783|gb|AAA64850.1|	45%	336	467
				kinase homolog [Homo		45%	123	215
				sapiens]		37%	267	338
						54%	211	243
						41%	45	95
HWLFG75	1228123	282	blastx.14	DJ63M2.4 (novel protein).	sp|CAC08483|CAC08483	81%	472	861
						91%	862	1074
						100%	1140	1163
HWLFG75	916563	563	HMMER	PFAM: EF hand	PF00036	24.1	187	273
			2.1.1
			blastx.2	DJ63M2.4 (novel protein).	sp|CAC08483|CAC08483	89%	720	1058
						75%	457	717
						100%	1123	1146
HT3BG12	921593	564	HMMER	PFAM: Eukaryotic protein	PF00069	27.09	109	183
			1.8	kinase domain
			blastx.14	CYCLIN-DEPENDENT	gi|3715669|emb|CAA03585.1|	85%	1	246
				KINASE (CDK)8
				[unidentified]
HTLJC71	922923	284	HMMER	PFAM: Src homology	PF00018	9.14	1152	1340
			1.8	domain 3
			blastx.2	(AL133030) hypothetical	emb|CAB61362.1|	94%	3	1355
				protein [Homo sapiens]
HCOMM05	1194701	285	blastx.14	epidermal growth factor	pir|I38728|I38728	44%	455	721
				receptor kinase substrate -		59%	188	370
				human		46%	722	850
						23%	53	232
						36%	125	190
						63%	1080	1112
HCOMM05	925952	565	HMMER	PFAM: Src homology	PF00018	59.48	178	342
			1.8	domain 3
			blastx.2	epidermal growth factor	gb|AAA62280.1|	46%	445	840
				receptor kinase substrate		43%	115	435
				[Homo sapiens]		23%	43	222
HSLJE54	926924	566	HMMER	PFAM: Pyridoxal-	PF00282	35.8	342	536
			2.1.1	dependent decarboxylase
				conserved domain
			blastx.2	CYSTEINE SULFINIC	sp|Q9UNJ5|Q9UNJ5	98%	198	548
				ACID		92%	542	739
				DECARBOXYLASE-		85%	721	885
				RELATED PROTEIN 4.		100%	885	908
HTGED07	927411	287	HMMER	PFAM: Sec1 family	PF00995	128.9	34	297
			2.1.1
			blastx.2	VESICLE TRANSPORT-	sp|Q9Y6A8|Q9Y6A8	89%	25	309
				RELATED PROTEIN.
HOFNH30	928365	288	HMMER	PFAM: 7 transmembrane	PF00001	24.58	9	248
			1.8	receptor (rhodopsin
				family)
			blastx.2	CALCIUM-	sp|Q9UBY5|Q9UBY5	75%	18	263
				MOBILIZING		54%	265	375
				LYSOPHOSPHATIDIC
				ACID RECEPTOR 1
HWNCY05	1179767	289	blastx.14	GOK [Homo sapiens]	gi|2264346|gb|AAC51627.1|	65%	10	951
HWNCY05	928789	567	HMMER	PFAM: EF hand	PF00036	12.55	18	101
			1.8
			blastx.2	GOK.	sp|Q13586|Q13586	60%	6	1292
HDPDA47	929193	290	HMMER	PFAM: Src homology	PF00018	12.52	691	810
			1.8	domain 3
			blastx.2	(AL049683) hypothetical	emb|CAB41255.1|	69%	145	1026
				protein [Homo sapiens]		53%	945	1022
HWMEV63	931154	291	HMMER	PFAM: 7 transmembrane	PF00001	53.4	2	262
			2.1.1	receptor (rhodopsin
				family)
			blastx.2	7 transmembrane G-	sp|AAG09275|AAG09275	75%	2	391
				protein coupled receptor.
HCFAT25	1052857	292	blastx.14	(AF096300) HPK/GCK-	gi|4322936|gb|AAD16137.1|	72%	2	412
				like kinase HGK [Homo
				sapiens]
HCFAT25	932068	568	HMMER	PFAM: Eukaryotic protein	PF00069	26.6	136	231
			2.1.1	kinase domain
			blastx.14	(AF096300) HPK/GCK-	gi|4322936|gb|AAD16137.1|	63%	91	456
				like kinase HGK [Homo		72%	60	158
				sapiens]		25%	232	312
HHEQV39	1165420	293	blastx.14	(AF037261) SH3-	gi|3004948|gb|AAC09244.1|	50%	517	606
				containing adaptor		41%	625	696
				molecule-1 [Homo		40%	396	470
				sapiens]		36%	141	215
HHEQV39	932851	569	HMMER	PFAM: Src homology	PF00018	30.41	526	708
			1.8	domain 3
HHFJH79	933308	570	HMMER	PFAM: von Willebrand	PF00092	12.76	62	232
			1.8	factor type A domain
			blastx.2	R31181_2, PARTIAL	sp|O95783|O95783	99%	14	316
				PROTEIN
				(FRAGMENT).
HUCOW17	1155190	295	blastx.2	RHOGAP PROTEIN.	sp|Q98935|Q98935	61%	4	441
						62%	787	987
HUCOW17	933357	571	HMMER	PFAM: Src homology	PF00018	20.28	647	739
			1.8	domain 3
			blastx.2	Graf protein [Homo	emb|CAA71414.2|	67%	1	261
				sapiens]		50%	608	751
						83%	756	809
						40%	187	246
HFKIT06	934019	572	HMMER	PFAM: Eukaryotic protein	PF00069	34.65	160	270
			1.8	kinase domain
			blastx.14	p58 galactosyltransferase-	pir|A38282|A38282	51%	178	270
				associated protein kinase -		40%	74	118
				human
HDTBY88	1104159	297	blastx.14	(AF130372) serine-	gi|7108631|gb|AAF36509.1|	87%	186	491
				threonine protein kinase 1	AF130372_1	98%	3	170
						100%	497	535
HDTBY88	934472	573	HMMER	PFAM: Eukaryotic protein	PF00069	93.6	3	302
			2.1.1	kinase domain
			blastx.14	p56 KKIAMRE protein	gi|1517820|gb|AAC50918.1|	82%	3	170
				kinase [Homo sapiens]		35%	192	458
						100%	492	509
HWLHS82	1082268	298	blastx.2	(AC005581) R31237_1,	gb|AAC33487.1|	93%	162	902
				partial CDS [Homo		88%	1049	1237
				sapiens]		100%	96	170
HWLHS82	934505	574	HMMER	PFAM: Eukaryotic protein	PF00069	147.2	2	319
			2.1.1	kinase domain
			blastx.2	(AC005581) R31237_1,	gb|AAC33487.1|	90%	68	364
				partial CDS [Homo		100%	2	76
				sapiens]		40%	306	422
HDPNC96	1081629	299	blastx.14	HUMAN NDR	gi|2304746|emb|CAA03387.1|	92%	3	734
				[unidentified]
HDPNC96	934520	575	HMMER	PFAM: Eukaryotic protein	PF00069	206.63	3	734
			1.8	kinase domain
			blastx.14	HUMAN NDR	gi|2304746|emb|CAA03387.1|	92%	3	734
				[unidentified]
HCE5I78	1197899	300	blastx.14	rabphilin-3A - bovine	pir|A48097|A48097	95%	191	1126
						68%	11	97
HCE5I78	934531	576	HMMER	PFAM: C2 domain	PF00168	49.14	213	413
			1.8
			blastx.2	rabphilin-3A - bovine	pir|A48097|A48097	83%	135	404
						61%	3	41
HISDS62	1159625	301	blastx.14	(AJ250425) Collybistin I	gi|6706318|emb|CAB65966.1|	90%	185	892
				[Rattus norvegicus]
HISDS62	935932	577	HMMER	PFAM: RhoGEF domain	PF00621	51.3	229	486
			2.1.1
			blastx.2	(AJ250425) Collybistin I	emb|CAB65966.1|	96%	1	483
				[Rattus norvegicus]
HDQDV69	937850	578	HMMER	PFAM: Eukaryotic protein	PF00069	212.5	68	598
			2.1.1	kinase domain
			blastx.2	(AF169035) protein	gb|AAF12758.1|AF169035_1	98%	68	829
				kinase [Homo sapiens]
HEMBT61	939957	303	HMMER	PFAM: Eukaryotic protein	PF00069	76.6	16	285
			2.1.1	kinase domain
			blastx.2	(AD000092) hypothetical	gb|AAB51171.1|	71%	13	441
				human serine-threonine
				protein kinase R31240_1
				[Homo sapiens]
HRODZ70	1088554	304	blastx.2	kinase like protein	emb|CAB10257.1|	39%	254	544
				[Arabidopsis thaliana]		50%	524	601
HRODZ70	942673	580	HMMER	PFAM: Eukaryotic protein	PF00069	78.2	33	248
			2.1.1	kinase domain
			blastx.2	kinase like protein	emb|CAB10257.1|	39%	33	323
				[Arabidopsis thaliana]		50%	303	380
HHERQ79	944057	581	HMMER	PFAM: Eukaryotic protein	PF00069	83.4	133	474
			1.8	kinase domain
			blastx.2	(AB016589) inducible	dbj|BAA85154.1|	90%	109	471
				IKappaB kinase [Mus
				musculus]
HCECM90	945088	582	HMMER	PFAM: Src homology	PF00018	53.06	392	568
			1.8	domain 3
HWHGW72	945692	583	HMMER	PFAM: ATP P2X receptor	PF00864	438.5	247	855
			2.1.1
			blastx.2	(AF190822) P2X2A	gb|AAF19170.1|AF190822_1	91%	190	939
				receptor [Homo sapiens]
HPCRV84	1219890	308	blastx.14	MATERNAL	sp|Q61846|Q61846	94%	138	839
				EMBRYONIC LEUCINE
				ZIPPER KINASE
				(SERINE/THREONINE 1
HPCRV84	945856	585	HMMER	PFAM: Eukaryotic protein	PF00069	75.57	157	384
			1.8	kinase domain
			blastx.2	similar to protein kinase	dbj|BAA11492.1|	78%	127	483
				of X. laevis, has putative 1
HNSAA28	946988	309	HMMER	PFAM: SH3 domain	PF00018	149	757	915
			2.1.1
			blastx.2	(AF146277) adapter	gb|AAD34595.1|AF146277_1	82%	4	1554
				protein CMS [Homo
				sapiens]
HNSAA28	972348	586	blastx.14	(AF146277) adapter	gi|4960047|gb|AAD34595.1|	88%	21	449
				protein CMS [Homo	AF146277_1
				sapiens]
HLWAR77	947484	310	HMMER	PFAM: 7 transmembrane	PF00001	214.2	1287	553
			1.8	receptor (rhodopsin
				family)
			blastx.2	G-protein coupled	sp|AAF87078|AAF87078	100%	1287	292
				receptor HLWAR77.
HTTJW49	1127477	311	blastx.14	(AF118838) citrin; adult-	gi|5052319|gb|AAD38501.1|	94%	516	1244
				onset type II citrullinemia	AF118838_1	97%	101	532
				protein [Homo sapiens]		90%	1232	1381
						100%	1408	1500
						37%	1244	1378
						40%	1411	1476
						40%	1200	1244
						60%	1143	1172
						33%	383	481
						33%	597	695
HTTJW49	948107	587	HMMER	PFAM: EF hand	PF00036	11.98	283	348
			1.8
			blastx.2	CITRIN.	sp|Q9UNI7|Q9UNI7	84%	94	627
HWAFS18	1155193	312	blastx.14	(AF156884) RIP-like	gi|5059425|gb|AAD39005.1|	89%	165	1718
				kinase [Homo sapiens]	AF156884_1
HWAFS18	948434	588	HMMER	PFAM: Eukaryotic protein	PF00069	115.98	225	632
			1.8	kinase domain
			blastx.14	(AF156884) RIP-like	gi|5059425|gb|AAD39005.1|	91%	165	632
				kinase [Homo sapiens]	AF156884_1	66%	702	773
						100%	632	661
HFCBA44	1082762	313	blastx.14	(AB010633)	gi|2810987|dbj|BAA24523.1|	61%	184	639
				carboxylesterase precursor
				[Macaca fascicularis]
HFCBA44	948533	589	HMMER	PFAM: Carboxylesterases	PF00135	34.24	315	485
			1.8
			blastx.2	thiolesterase B (EC 3.—.—.—)	pir|A47162|A47162	56%	2	208
				precursor - mallard		60%	423	482
						48%	184	264
HVADT77	1180374	314	blastx.14	alpha-3 collagen type VI	gi|211622|gb|AAA03201.1|	55%	12	119
				[Gallus gallus]
HVADT77	948886	590	HMMER	PFAM: Kunitz/Bovine	PF00014	74.41	169	321
			1.8	pancreatic trypsin
				inhibitor domain
			blastx.2	alpha-3 collagen type VI	gb|AAA03201.1|	43%	130	330
				[Gallus gallus]
HUFCN91	1189013	315	blastx.14	copine I [Homo sapiens]	gi|1791257|gb|AAC15920.1|	54%	103	540
						48%	561	782
						71%	874	936
						75%	540	587
						64%	783	833
HUFCN91	949137	591	HMMER	PFAM: von Willebrand	PF00092	9.83	529	729
			1.8	factor type A domain
			blastx.14	copine I [Homo sapiens]	gi|1791257|gb|AAC15920.1|	56%	103	588
						48%	971	1333
						48%	562	783
						57%	1332	1430
						45%	899	1009
						64%	784	834
HAGBX32	951351	316	HMMER	PFAM: PMP-	PF00822	182.3	3	476
			2.1.1	22/EMP/MP20/Claudin
				family
			blastx.2	VOLTAGE-	sp|O60359|CCG3_HUMAN	89%	12	551
				DEPENDENT
				CALCIUM CHANNEL
				GAMMA-3 SUBUNIT 1
HWMIB81	955336	593	HMMER	PFAM: Eukaryotic protein	PF00069	122.85	1458	934
			1.8	kinase domain
			blastx.2	(AK000528) unnamed	dbj|BAA91232.1|	100%	3	572
				protein product [Homo
				sapiens]
HCEMU86	1156430	318	blastx.14	p87 = transporter-like	gi|259174|gb|AAB24028.1|	91%	10	795
				protein [cattle, Peptide,
				742 aa] [Bos taurus]
HCEMU86	956864	594	HMMER	PFAM: Sugar (and other)	PF00083	24.49	2124	1738
			1.8	transporters
			blastx.2	p87 = transporter-like	gb|AAB24028.1|	99%	3	788
				protein [cattle, Peptide,
				742 aa] [Bos taurus]
HRDAF83	1153911	319	blastx.14	(AF137378) integrin alpha	gi|5915662|gb|AAD51919.2|	93%	42	338
				11 subunit precursor	AF137378_1
				[Homo sapiens]
HRDAF83	957143	595	HMMER	PFAM: von Willebrand	PF00092	89.99	72	332
			1.8	factor type A domain
			blastx.2	(AF137378) integrin alpha	gb|AAD51919.2|AF137378_1	92%	36	332
				11 subunit precursor
				[Homo sapiens]
HUVGZ88	1204719	320	blastx.14	PRO1038.	sp|AAF71042|AAF71042	50%	527	988
						44%	974	1183
						50%	444	593
						30%	732	851
						75%	713	736
HUVGZ88	959020	597	HMMER	PFAM: Eukaryotic protein	PF00069	31.12	182	439
			1.8	kinase domain
HSCKS55	961074	598	HMMER	PFAM: C2 domain	PF00168	4.41	931	993
			1.8
HOEET48	963290	322	HMMER	PFAM: EF hand	PF00036	26	656	727
			2.1.1
			blastx.2	Reticulocabin precursor.	sp|AAG09692|AAG09692	96%	47	1030
HBODE51	964235	599	HMMER	PFAM: Mitochondrial	PF00153	235.26	995	1834
			1.8	carrier proteins
			blastx.14	aralar1 [Homo sapiens]	gi|3559910|emb|CAA74834.1|	93%	20	2053
HHFCK09	965304	324	HMMER	PFAM: TBC domain	PF00566	179.1	2305	1655
			2.1.1
			blastx.2	(AL022238) dJ1042K10.2	emb|CAA18266.1|	97%	2635	1268
				(supported by		98%	1276	389
				GENSCAN, FGENES and
				GENEWISE) [Homo
				sapiens]
HCOOZ11	965306	600	HMMER	PFAM: Src homology	PF00018	5.22	179	214
			1.8	domain 3
			blastx.2	(AL022238) dJ1042K10.2	emb|CAA18266.1|	100%	182	589
				(supported by
				GENSCAN, FGENES and
				GENEWISE) [Homo
				sapiens]
HDPPO35	1119032	326	blastx.14	(AL049683) hypothetical	gi|4678753|emb|CAB41255.1|	63%	561	758
				protein [Homo sapiens]		65%	816	980
						71%	84	146
						65%	300	359
						45%	1080	1139
						25%	117	245
HDPPO35	966248	601	HMMER	PFAM: Src homology	PF00018	14.07	600	749
			1.8	domain 3
			blastx.2	(AL049683) hypothetical	emb|CAB41255.1|	39%	84	1148
				protein [Homo sapiens]
HLWDZ53	968602	602	HMMER	PFAM: Actin	PF00022	291.1	77	1111
			2.1.1
			blastx.2	Actin-related protein 3-	sp|AAC98904|AAC98904	99%	95	1126
				beta.		100%	54	98
HEOPL36	968826	603	HMMER	PFAM: Src homology	PF00018	79.81	316	483
			1.8	domain 3
			blastx.2	(AL049758) dJ437M21.3	emb|CAB51395.1|	99%	178	486
				(protein kinase C and
				casein kinase substrate in
				neurons 2) [Homo
				sapiens]
HMCFS02	1152252	329	blastx.14	(AK000482) unnamed	gi|7020600|dbj|BAA91194.1|	59%	72	725
				protein product [Homo		40%	716	781
				sapiens]
HMCFS02	969326	604	HMMER	PFAM: C2 domain	PF00168	8.05	347	457
			1.8
			blastx.2	CDNA FLJ20475 FIS,	sp|BAA91194|BAA91194	59%	116	496
				CLONE KAT07206.
HDPSR15	969666	605	HMMER	PFAM: Eukaryotic protein	PF00069	87.19	351	626
			1.8	kinase domain
			blastx.2	(AB026289) protein	dbj|BAA85045.1|	95%	631	1158
				kinase SID6-1512 [Homo		89%	240	692
				sapiens]
HNTAV78	971315	606	HMMER	PFAM: 7 transmembrane	PF00001	23.92	3	143
			1.8	receptor (rhodopsin
				family)
			blastx.2	Cysteinyl leukotriene	sp|BAB03601|BAB03601	100%	3	266
				CysLT2 receptor.
HFKDR14	1145842	332	blastx.14	(AF128625) CDC42-	gi|5006445|gb|AAD37506.1|	98%	90	1277
				binding protein kinase	AF128625_1	100%	1279	1320
				beta [Homo sapiens]
HFKDR14	974255	607	HMMER	PFAM: Eukaryotic protein	PF00069	244.21	297	1097
			1.8	kinase domain
			blastx.2	(AF128625) CDC42-	gb|AAD37506.1|AF128625_1	98%	72	1733
				binding protein kinase		22%	1572	1706
				beta [Homo sapiens]
HDPBI30	974711	333	HMMER	PFAM: 7 transmembrane	PF00001	171.31	386	1096
			1.8	receptor (rhodopsin
				family)
			blastx.2	G PROTEIN-COUPLED	sp|Q9UNW8|Q9UNW8	93%	206	1312
				RECEPTOR.
HODFF88	1094875	334	blastx.2	mixed-lineage protein	pir|S32467|JU0229	73%	89	493
				kinase 1 - human		81%	763	969
HODFF88	974911	608	HMMER	PFAM: Eukaryotic protein	PF00069	101.43	98	370
			1.8	kinase domain
			blastx.14	mixed-lineage protein	pir|S32467|JU0229	74%	131	493
				kinase 1 - human		81%	763	921
						30%	751	915

[0049] Table 2 further characterizes certain encoded polypeptides of the invention, by providing the results of comparisons to protein and protein family databases. The first column provides a unique clone identifier, “Clone ID NO:”, corresponding to a cDNA clone disclosed in Table 1A. The second column provides the unique contig identifier, “Contig ID:” which allows correlation with the information in Table 1A. The third column provides the sequence identifier, “SEQ ID NO:”, for the contig polynucleotide sequences. The fourth column provides the analysis method by which the homology/identity disclosed in the Table was determined. The fifth column provides a description of the PFAM/NR hit identified by each analysis. Column six provides the accession number of the PFAM/NR hit disclosed in the fifth column. Column seven, score/percent identity, provides a quality score or the percent identity, of the hit disclosed in column five. Comparisons were made between polypeptides encoded by polynucleotides of the invention and a non-redundant protein database (herein referred to as “NR”), or a database of protein families (herein referred to as “PFAM”), as described below.

[0050] The NR database, which comprises the NBRF PIR database, the NCBI GenPept database, and the SIB SwissProt and TrEMBL databases, was made non-redundant using the computer program nrdb2 (Warren Gish, Washington University in Saint Louis). Each of the polynucleotides shown in Table 1A, column 3 (e.g., SEQ ID NO:X or the ‘Query’ sequence) was used to search against the NR database. The computer program BLASTX was used to compare a 6-frame translation of the Query sequence to the NR database (for information about the BLASTX algorithm please see Altshul et al., J. Mol. Biol. 215:403-410 (1990); and Gish and States, Nat. Genet. 3:266-272 (1993). A description of the sequence that is most similar to the Query sequence (the highest scoring ‘Subject’) is shown in column five of Table 2 and the database accession number for that sequence is provided in column six. The highest scoring ‘Subject’ is reported in Table 2 if (a) the estimated probability that the match occurred by chance alone is less than 1.0e-07, and (b) the match was not to a known repetitive element. BLASTX returns alignments of short polypeptide segments of the Query and Subject sequences which share a high degree of similarity; these segments are known as High-Scoring Segment Pairs or HSPs. Table 2 reports the degree of similarity between the Query and the Subject for each HSP as a percent identity in Column 7. The percent identity is determined by dividing the number of exact matches between the two aligned sequences in the HSP, dividing by the number of Query amino acids in the HSP and multiplying by 100. The polynucleotides of SEQ ID NO:X which encode the polypeptide sequence that generates an HSP are delineated by columns 8 and 9 of Table 2.

[0051] The PFAM database, PFAM version 2.1, (Sonnhammer et al., Nucl. Acids Res., 26:320-322, 1998)) consists of a series of multiple sequence alignments; one alignment for each protein family. Each multiple sequence alignment is converted into a probability model called a Hidden Markov Model, or HMM, that represents the position-specific variation among the sequences that make up the multiple sequence alignment (see, e.g., Durbin et al., Biological sequence analysis. probabilistic models of proteins and nucleic acids, Cambridge University Press, 1998 for the theory of HMMs). The program HMMER version 1.8 (Sean Eddy, Washington University in Saint Louis) was used to compare the predicted protein sequence for each Query sequence (SEQ ID NO:Y in Table 1A) to each of the HMMs derived from PFAM version 2.1. A HMM derived from PFAM version 2.1 was said to be a significant match to a polypeptide of the invention if the score returned by HMMER 1.8 was greater than 0.8 times the HMMER 1.8 score obtained with the most distantly related known member of that protein family. The description of the PFAM family which shares a significant match with a polypeptide of the invention is listed in column 5 of Table 2, and the database accession number of the PFAM hit is provided in column 6. Column 7 provides the score returned by HMMER version 1.8 for the alignment. Columns 8 and 9 delineate the polynucleotides of SEQ ID NO:X which encode the polypeptide sequence which show a significant match to a PFAM protein family.

[0052] As mentioned, columns 8 and 9 in Table 2, “NT From” and “NT To”, delineate the polynucleotides of “SEQ ID NO:X” that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth column. In one embodiment, the invention provides a protein comprising, or alternatively consisting of, a polypeptide encoded by the polynucleotides of SEQ ID NO:X delineated in columns 8 and 9 of Table 2. Also provided are polynucleotides encoding such proteins, and the complementary strand thereto.

[0053] The nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, the nucleotide sequences of SEQ ID NO:X are useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA contained in Clone ID NO:Z. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling immediate applications in chromosome mapping, linkage analysis, tissue identification and/or typing, and a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO:Y may be used to generate antibodies which bind specifically to these polypeptides, or fragments thereof, and/or to the polypeptides encoded by the cDNA clones identified in, for example, Table 1A.

[0054] Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).

[0055] Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X, and a predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing cDNA Clone ID NO:Z (deposited with the ATCC on Oct. 5, 2000, and receiving ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on Jan. 5, 2001, and having depositor reference numbers TS-1, TS-2, AC-1, and AC-2; and/or as set forth, for example, in Table 1A, 6 and 7). The nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods. Further, techniques known in the art can be used to verify the nucleotide sequences of SEQ ID NO:X.

[0056] The predicted amino acid sequence can then be verified from such deposits. Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.

[0057] RACE Protocol For Recovery of Full-Length Genes

[0058] Partial cDNA clones can be made full-length by utilizing the rapid amplification of cDNA ends (RACE) procedure described in Frohman, M. A., et al., Proc. Nat'l. Acad. Sci. USA, 85:8998-9002 (1988). A cDNA clone missing either the 5′ or 3′ end can be reconstructed to include the absent base pairs extending to the translational start or stop codon, respectively. In some cases, cDNAs are missing the start codon of translation, therefor. The following briefly describes a modification of this original 5′ RACE procedure. Poly A+ or total RNA is reverse transcribed with Superscript II (Gibco/BRL) and an antisense or complementary primer specific to the cDNA sequence. The primer is removed from the reaction with a Microcon Concentrator (Amicon). The first-strand cDNA is then tailed with dATP and terminal deoxynucleotide transferase (Gibco/BRL). Thus, an anchor sequence is produced which is needed for PCR amplification. The second strand is synthesized from the dA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), an oligo-dT primer containing three adjacent restriction sites (XhoI, SalI and ClaI) at the 5′ end and a primer containing just these restriction sites. This double-stranded cDNA is PCR amplified for 40 cycles with the same primers as well as a nested cDNA-specific antisense primer. The PCR products are size-separated on an ethidium bromide-agarose gel and the region of gel containing cDNA products the predicted size of missing protein-coding DNA is removed. cDNA is purified from the agarose with the Magic PCR Prep kit (Promega), restriction digested with XhoI or SalI, and ligated to a plasmid such as pBluescript SKII (Stratagene) at XhoI and EcoRV sites. This DNA is transformed into bacteria and the plasmid clones sequenced to identify the correct protein-coding inserts. Correct 5′ ends are confirmed by comparing this sequence with the putatively identified homologue and overlap with the partial cDNA clone. Similar methods known in the art and/or commercial kits are used to amplify and recover 3′ ends.

[0059] Several quality-controlled kits are commercially available for purchase. Similar reagents and methods to those above are supplied in kit form from Gibco/BRL for both 5′ and 3′ RACE for recovery of full length genes. A second kit is available from Clontech which is a modification of a related technique, SLIC (single-stranded ligation to single-stranded cDNA), developed by Dumas et al., Nucleic Acids Res., 19:5227-32 (1991). The major differences in procedure are that the RNA is alkaline hydrolyzed after reverse transcription and RNA ligase is used to join a restriction site-containing anchor primer to the first-strand cDNA. This obviates the necessity for the dA-tailing reaction which results in a polyT stretch that is difficult to sequence past.

[0060] An alternative to generating 5′ or 3′ cDNA from RNA is to use cDNA library double-stranded DNA. An asymmetric PCR-amplified antisense cDNA strand is synthesized with an antisense cDNA-specific primer and a plasmid-anchored primer. These primers are removed and a symmetric PCR reaction is performed with a nested cDNA-specific antisense primer and the plasmid-anchored primer.

[0061] RNA Ligase Protocol for Generating The 5′ or 3′ End Sequences to Obtain Full Length Genes

[0062] Once a gene of interest is identified, several methods are available for the identification of the 5′ or 3′ portions of the gene which may not be present in the original cDNA plasmid. These methods include, but are not limited to, filter probing, clone enrichment using specific probes and protocols similar and identical to 5′ and 3′ RACE. While the full length gene may be present in the library and can be identified by probing, a useful method for generating the 5′ or 3′ end is to use the existing sequence information from the original cDNA to generate the missing information. A method similar to 5′ RACE is available for generating the missing 5′ end of a desired full-length gene. (This method was published by Fromont-Racine et al., Nucleic Acids Res., 21(7):1683-1684 (1993)). Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of a population of RNA presumably containing full-length gene RNA transcript and a primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest, is used to PCR amplify the 5′ portion of the desired full length gene which may then be sequenced and used to generate the full length gene. This method starts with total RNA isolated from the desired source, poly A RNA may be used but is not a prerequisite for this procedure. The RNA preparation may then be treated with phosphatase if necessary to eliminate 5′ phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase if used is then inactivated and the RNA is treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5′ ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the 5′ end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase. This modified RNA preparation can then be used as a template for first strand cDNA synthesis using a gene specific oligonucleotide. The first strand synthesis—reaction can then be used as a template for PCR amplification of the desired 5′ end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5′ end sequence belongs to the relevant gene.

[0063] The present invention also relates to vectors or plasmids which include such DNA sequences, as well as the use of the DNA sequences. The material deposited with the ATCC (deposited with the ATCC on Oct. 5, 2000, and receiving ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on Jan. 5, 2001, and receiving ATCC designation numbers TS-1, TS-2, AC-1, and AC-2; and/or as set forth, for example, in Table 1A, Table 6, or Table 7) is a mixture of cDNA clones derived from a variety of human tissue and cloned in either a plasmid vector or a phage vector, as described, for example, in Table 7. These deposits are referred to as “the deposits” herein. The tissues from which some of the clones were derived are listed in Table 7, and the vector in which the corresponding cDNA is contained is also indicated in Table 7. The deposited material includes cDNA clones corresponding to SEQ ID NO:X described, for example, in Table 1A (Clone ID NO:Z). A clone which is isolatable from the ATCC Deposits by use of a sequence listed as SEQ ID NO:X, may include the entire coding region of a human gene or in other cases such clone may include a substantial portion of the coding region of a human gene. Furthermore, although the sequence listing may in some instances list only a portion of the DNA sequence in a clone included in the ATCC Deposits, it is well within the ability of one skilled in the art to sequence the DNA included in a clone contained in the ATCC Deposits by use of a sequence (or portion thereof) described in, for example Tables 1A or 2 by procedures hereinafter further described, and others apparent to those skilled in the art.

[0064] Also provided in Table 7 is the name of the vector which contains the cDNA clone. Each vector is routinely used in the art. The following additional information is provided for convenience.

[0065] Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into E. coli strain XL-1 Blue, also available from Stratagene.

[0066] Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59-(1993). Vector lafmid BA (Bento Soares, Columbia University, New York, N.Y.) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR®2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991).

[0067] The present invention also relates to the genes corresponding to SEQ ID NO:X, SEQ ID NO:Y, and/or the deposited clone (Clone ID NO:Z). The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.

[0068] Also provided in the present invention are allelic variants, orthologs, and/or species homologs. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of genes corresponding to SEQ ID NO:X or the complement thereof, polypeptides encoded by genes corresponding to SEQ ID NO:X or the complement thereof, and/or the cDNA contained in Clone ID NO:Z, using information from the sequences disclosed herein or the clones deposited with the ATCC. For example, allelic variants and/or species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for allelic variants and/or the desired homologue.

[0069] The polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.

[0070] The polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below). It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification, such as multiple histidine residues, or an additional sequence for stability during recombinant production.

[0071] The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of a polypeptide, including the secreted polypeptide, can be substantially purified using techniques described herein or otherwise known in the art, such as, for example, by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988). Polypeptides of the invention also can be purified from natural, synthetic or recombinant sources using techniques described herein or otherwise known in the art, such as, for example, antibodies of the invention raised against the polypeptides of the present invention in methods which are well known in the art.

[0072] The present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA sequence contained in Clone ID NO:Z. The present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X or a complement thereof, a polypeptide encoded by the cDNA contained in Clone ID NO:Z, and/or the polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B. Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X, a polypeptide encoded by the cDNA contained in Clone ID NO:Z, and/or a polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B are also encompassed by the invention. The present invention further encompasses a polynucleotide comprising, or alternatively consisting of, the complement of the nucleic acid sequence of SEQ ID NO:X, a nucleic acid sequence encoding a polypeptide encoded by the complement of the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA contained in Clone ID NO:Z.

[0073] Moreover, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in Table 1B column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in Table 1B column 6, or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

[0074] Further, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1), or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1), or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

[0075] Further, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2), or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2), or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (See Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

[0076] Moreover, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of Table 1B column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1B column 6, or any combination thereof. In preferred embodiments, the polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1B column 6, wherein sequentially delineated sequences in the table (i.e. corresponding to those exons located closest to each other) are directly contiguous in a 5′ to 3′ orientation. In further embodiments, above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

[0077] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1B, column 2) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

[0078] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. In preferred embodiments, the delineated sequence(s) and polynucleotide sequence of SEQ ID NO:X correspond to the same Clone ID NO:Z. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

[0079] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. In preferred embodiments, the delineated sequence(s) and polynucleotide sequence of SEQ ID NO:X correspond to the same row of column 6 of Table 1B. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

[0080] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:X are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0081] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X are directly contiguous Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0082] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of the sequence of SEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0083] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides, are also encompassed by the invention.

[0084] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0085] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 corresponding to the same Clone ID NO:Z (see Table 1B, column 1) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0086] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one sequence in column 6 corresponding to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0087] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 corresponding to the same row are directly contiguous. In preferred embodiments, the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B is directly contiguous with the 5′ 10 polynucleotides of the next sequential exon delineated in Table 1B, column 6. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0088] Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. Accordingly, for each contig sequence (SEQ ID NO:X) listed in the fourth column of Table 1A, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, b is an integer of 15 to the final nucleotide of SEQ ID NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a +14. More specifically, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a−b, where a and b are integers as defined in columns 4 and 5, respectively, of Table 3. In specific embodiments, the polynucleotides of the invention do not consist of at least one, two, three, four, five, ten, or more of the specific polynucleotide sequences referenced by the Genbank Accession No. as disclosed in column 6 of Table 3 (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone). In no way is this listing meant to encompass all of the sequences which may be excluded by the general formula, it is just a representative example. All references available through these accessions are hereby incorporated by reference in their entirety.

TABLE 3
	SEQ
Clone ID	ID	Contig	EST Disclaimer
NO: Z	NO: X	ID:	Range of a	Range of b	Accession #'s
HTPAD46	11	1048901	1-1561	15-1575	AW026547, AL119230, AI992054,
					AI968455, AW193784, AW193801,
					AA386091, AA386130, AI825443,
					AA004475, and Z79235.
HCWFF88	12	1092566	1-639	15-653
HSSAX53	13	1198889	1-348	15-362
HCEPH71	14	522739	1-432	15-446	AA326209, AA383931, AL365319, and
					AL390715.
HTEDF74	15	1083405	1-1265	15-1279	AI948732, AW023798, AA058811,
					AA148838, C01936, and AA663155.
HTTEK47	16	1134534	1-1221	15-1235	AI651805, AI989837, AI718022,
					AA400005, AI458374, AA401437,
					AW205244, AA883445, AI478808,
					AW134723, AI689951, AI269389,
					AA865056, AI640798, H11911, R44433,
					AI688852, AI183700, AA424180,
					AI277599, R46805, and AA771819.
HTOBE75	17	1163883	1-1797	15-1811	AW192827, AA595431, AI251121,
					AI923335, AI284016, H30141, T70540,
					T90549, AI432106, AA953436, H27466,
					R50714, R50249, AI540363, T70809,
					AI659868, AW370667, Z99572, I36305,
					AL022146, M87861, M72332, M60235,
					L39075, M60230, M60228, M60231,
					M60229, M60232, M60227, and M60234.
HCFAT05	18	1156310	1-2145	15-2159	AL133816, AA811374, AI095381,
					M38217, M55515, L23499, M85217,
					X16001, M30312, M31744, AR050270,
					U38240, U38182, U96110, and U45979.
HFIAH37	19	1189001	1-1712	15-1726	AL134903, AI912243, AA976922,
					AI742663, AW028771, AW043595,
					AA478697, AA837145, W49831,
					AI354405, AA412384, AA602982, N62994,
					AA013476, AI674206, AA115419,
					AI377356, AW270325, AI479159,
					AA169423, AA133086, AA326624,
					H83962, R76363, AA587840, AI224540,
					H67227, H81547, AA665443, AA018206,
					AA662495, AW298791, AA251488,
					AA301274, AA132987, AI192416,
					AI300307, AA722928, AA478563, R76688,
					AA579347, AA501519, AA629042,
					AI299974, H70300, AI865166, AA252018,
					N79902, AI867958, AI300195, AA251195,
					AA251787, H65133, AW246148,
					AA644296, AA115418, AC004381, and
					AF227510.
HFTDF15	20	1084887	1-715	15-729	AA837715, AI623899, AA775049,
					AA317045, AA581914, AA679872,
					T03203, AA780929, AI634323, AA604843,
					AA904275, AW440633, AA362395,
					AA468486, AI582890, AA640979,
					AL046746, AA721615, H67866,
					AA632960, AI561116, AL120976,
					AI978792, AA663306, AF034193,
					AW302293, AF108083, AC005486,
					AL109985, AC007229, U47924,
					AC008249, AL031289, AC004031,
					AC003029, AC005899, AL022721,
					AC003982, Z97053, AC004134,
					AC004883, AC005839, AC003670,
					AC005746, AP000018, AL135744,
					AC005037, AL021808, Z95889,
					AC006071, AC005480, AC004815,
					AP000159, AC007551, AL031670,
					AC000117, I59642, AC005346, L39891,
					AF039906, AC008372, AL034420,
					AL078611, AC007055, AF134726,
					AL049643, AL121769, AL031447,
					AC003038, AL096701, AL031257,
					AL035690, AL050318, AL035681,
					AL049745, AL031589, AC005412,
					AC007792, AL049636, AL008583,
					AL021878, AL049569, AC007536,
					AF165926, AC005234, AL022237,
					AL031848, AL022149, AC004990,
					AC006501, AL023553, AC007363,
					AC005696, AL035455, AC006120,
					AL031282, AL050309, AC016830,
					AC005881, AC005529, AC004929,
					AC006459, AC007308, AC002319,
					AC002477, AL031277, AC003669,
					AC002470, AF196969, Z82215, AC006039,
					AL049780, AC006578, AF111168,
					AF207550, AF064864, AF165176,
					AL033521, AC004821, AC003663,
					AC004655, AF205588, AL096757,
					AC002429, AC005527, AL034402,
					AL031775, AC002077, AC009498,
					AC006006, AJ011930, AC005082,
					AL031650, AC005695, AL109627,
					AC000003, AC005264, AC007934,
					AC005086, Z83838, AC005777,
					AL133304, Z97630, AC003101,
					AC004034, AC004672, AL022320,
					AP000475, AC004905, Z98052, AL078581,
					AC004517, AL021997, AC006139,
					AC005996, AC005380, AC002395,
					AC006023, Z82244, AL034423, AF001550,
					AL031685, AL008723, AC005102,
					AC007199, AC007151, AC003043,
					AF037222, AL008710, AC007193,
					AC005081, AC004921, AL022329,
					AC005520, AC005039, AL035587,
					Z98051, AC020663, AC016027,
					AC006211, AC003104, Z69921,
					AL133246, AC005049, AL049869,
					AC002091, AC005225, and AL033504.
HPFCU80	21	1017593	1-328	15-342	AC005344.
HSVAW49	22	1153916	1-991	15-1005	AF146277, U95740, AL008731,
					AC002551, and AL079342.
HWHQC94	23	1116463	1-904	15-918	AI366191, AC004472, AC005259, and
					AW469987.
HRSMD49	24	1065458	1-442	15-456	AA136820.
HFTDY67	25	1151220	1-1523	15-1537	AI335266, AI751901, AI751815,
					AI750604, AI040116, AW067945,
					AW239149, AI572373, N42174, N22119,
					N71503, AF182316, AF182317, AB033033,
					AR018882, and AB026436.
HYABL89	26	1090733	1-700	15-714
HCUEV29	27	1137791	1-703	15-717	AI570209, AA583494, AW337550,
					AW087991, AI027766, H17041,
					AW410192, AI669151, T30350,
					AA335428, C16961, AA878169,
					AW411072, AW410900, T24722,
					AA365566, AA365567, AI418046,
					AA350018, AW246233, and AL031283.
HCESP56	28	1121751	1-506	15-520	AW247740, AW247029, AW204207,
					W39269, AA325536, R14422, W52568,
					Y16752, AL022170, and Z65186.
HLQDT35	29	1154064	1-1308	15-1322	AI659435, AW006450, AI380742,
					AI953510, AI078578, AA707183,
					AI453381, AI445431, AW136858,
					AA807157, AW196880, AA131680,
					AI569636, AI140912, AA530976,
					AA410746, AA134742, AA152440,
					AA807317, AA283695, N66180, AI082380,
					AI269183, AA480063, AA635830,
					AA433870, AI631995, AI167742,
					AA292134, AA131985, AA923686,
					AI580936, N30879, AI358691, AA631878,
					AA485099, AA485100, AA165214,
					AA253107, H92198, AI160395, AA830846,
					AI753274, AA253052, AA152441,
					AA879095, R08557, R11497, AA358765,
					AA706241, AA134743, AI424722,
					AI800536, R08654, R10421, N99172,
					T89988, AA804424, W16996, AI934059,
					AA481922, AA292133, AA746933,
					N56752, AA290907, AI091625, and
					AL137699.
HDPBS64	30	846624	1-743	15-757	AA888874, AA992389, and AI767840.
HTBAB41	31	1052388	1-785	15-799	AA382198, H48825, H58945, and
					AI359780.
HTLGE31	32	870247	1-519	15-533	AA714179, AW051497, AI971919,
					AI094911, AW055123, AA293722,
					AI094408, and AA631985.
HWLHK29	33	1152279	1-941	15-955	AA243837, AA588755, AW137873,
					AI351894, AA360896, AI903764, R33743,
					AL045500, AL039086, AL036802,
					AL046849, AI906328, AL042628,
					AW129106, AL036638, AL119791,
					AI312428, AL036396, AW163554,
					AL041562, AI690887, AL079963,
					AL036631, AL037463, AL135661,
					AI581033, AW020397, AW022682,
					AL134598, AW238730, AW105601,
					AI349772, AW023338, AI349937,
					AI623941, AI537677, AA225339,
					AA470491, AW059828, AW020419,
					AL110306, AI279925, AI929108,
					AI580290, AI624859, AI538885,
					AI207510, AW268253, AL042166,
					AI312152, AL046944, AI613038,
					AI446373, AI590423, AA572758,
					AL041016, AI678446, AL042544, N29277,
					AL042382, AI340519, AI340603,
					AI580190, AI345111, AI907070,
					AL119748, AW044029, AI866691,
					AA640779, AL041150, AI433157,
					AI281867, AA641818, AI886594,
					AI345347, AI366974, AW162194,
					AI345415, AI473451, AI348897,
					AW020710, AI539800, AW149876,
					AI624943, AI251221, AI349933,
					AA420722, AI923989, AI284517,
					AA580663, AI500061, AI628325,
					AL135025, AW021717, AI868204,
					AI440263, AI699143, AI247193,
					AW051059, AI345735, AL042745,
					AL037454, AI344910, AI863014,
					AL047344, AW020693, AI538637,
					AI433976, AL121328, AW074869,
					AW189301, AW162189, AI801793,
					AI244249, AI064830, AL047042,
					AI445430, AW020460, AI357599,
					AI349256, AW021140, AI277008,
					AW022861, AW068845, AI698391,
					AI687568, AI815232, AW050578,
					AW023859, AI149592, AI307708,
					AL046931, AI680498, AA579232,
					AA635382, AL119399, AI340627,
					AW167918, AI349645, AW089572,
					AL120307, AL040241, AI690946,
					AW150578, AW151136, AI953765,
					AW403717, AI559752, AL121270,
					AI436429, AI590043, AI452857,
					AI798456, N57346, AI802542, AL042191,
					AA806719, AI567582, AI540674,
					AL038575, AL043070, AL040694,
					AA494167, AI916419, AW058233,
					AI573026, AI471227, AL118781,
					AI920968, AI589668, AI345612,
					AI345688, AW082532, F37439, AI610362,
					AL120736, AL036664, AL043168,
					AL119836, AI866465, AW074993,
					AW268072, AL043345, AI554343,
					AW191003, AL038605, AI866608,
					AI345608, AW268261, AI471898,
					AL036240, AW021373, AW020561,
					AL041772, AI114703, AI475371,
					AI582912, AL036736, AA693314,
					AI554821, AI287446, AI307569,
					AI345253, AA848053, AL048323,
					AA613907, AI345416, AW268067,
					AI313320, AW081383, AI624548,
					AL048340, AI343030, N22276,
					AW020095, AI310606, F35428, AL135022,
					AL036274, AW151138, AI915295,
					AL047422, AI345370, AW166645,
					AI312146, AI560012, AI312339,
					AI890907, AL036403, AW059638,
					AI921254, AW161202, AW022102,
					AI348854, AI345258, AI249946, W48671,
					AL119511, AL040243, AA528822,
					AI434223, AL037582, AL037602,
					AI612885, AW080402, AI801325,
					AA070889, AI273791, AW274192,
					AW163834, I48978, S78214, I48979,
					AR013797, AF090934, Y11587,
					AL133640, AF078844, AC006313,
					AF113691, AL137479, AL133016,
					AL050393, AL117457, AF215669,
					AL137459, AL137478, AF090900,
					AF118064, AL133075, AF081197,
					AF081195, A58524, A58523, AJ012755,
					AF126247, AF090943, AL117460, X84990,
					D16301, I89947, AF090901, U75932,
					Y10655, AL049938, AF118070, AL137529,
					AF090896, AL133606, AL122123, X99257,
					A08916, AF125949, AL137429, AL122050,
					AL122100, AL050146, A18777, I03321,
					AF111851, AL117629, I09499, AF158248,
					AF113013, X06146, X82434, Y16645,
					A08910, AF113019, A08909, AL049382,
					A08913, AL137705, AL122093,
					AL110196, AL049314, AL137527, I89931,
					AL137538, S61953, AF097996, E05822,
					E06743, L31396, AL050138, E02221,
					L31397, AJ242859, X70514, AF114170,
					AF090903, AL137294, AL080060, A08907,
					A08908, U77594, X80340, AL122111,
					AB007812, AL096744, AF039138,
					AF039137, AL133113, AF061573, X72889,
					I49625, AJ000937, AF069506, AF176651,
					AL137558, A93016, AL122110, AF113690,
					AF100931, AF017437, S78453, A65340,
					AL133093, AL080154, AL110197,
					AL117416, A07647, AL122118, AF030513,
					AR034821, AL137555, A03736,
					AR011880, AR038854, AL110159, S75997,
					Y11254, AF118090, AJ238278, AF017152,
					X65873, U42766, AF061943, AL050277,
					AF100781, AL050024, AF132676,
					AL122106, AF061836, AL122098,
					AF026124, AF057300, AL110225,
					AF057299, AL050092, AL096751,
					AF036941, AL133067, E02349, A08912,
					AL137548, AL110280, AF113694, S36676,
					A77033, A77035, AR000496, AF113699,
					U39656, X89102, U55017, X67688,
					AL133557, AL117649, I66342, AL137550,
					AL137656, S77771, AF106657, E01614,
					E13364, AF079765, AL137292, AB019565,
					U51587, AF113677, X59414, AL080158,
					U87620, AL050116, Z97214, AL137533,
					AF177401, AL117435, U72620, AL133560,
					AF113689, AL137526, AL080074, I33392,
					AL137271, AF192557, U96683, AF146568,
					AL137488, AL137521, X63574, AF102578,
					S76508, I89934, AF026816, A65341,
					AL049283, AL049466, AF200464,
					AF079763, AF111849, AL117585,
					AL049452, E07108, AL050108, A21101,
					AF180525, A52563, AL133619, L04504,
					X53587, A18788, AL080124, AL117648,
					AL137557, AF065135, AR038969,
					AL049430, X55446, AF090886, Y09972,
					AL133112, U00763, E03671, AL133080,
					X70685, U58996, AL137648, AL133565,
					AF104032, AL133081, AF031147,
					M96857, AL080137, X57961, AL133665,
					I68732, U66059, D83032, AF162270,
					AC004200, Y10080, AF111112, S83456,
					AL136884, AF003737, AL049300,
					AL117432, and AL050366.
HHEGG20	34	1106816	1-958	15-972	AF084205, and AW473942.
HDPRU43	35	1217035	1-2939	15-2953	AI912020, AI738591, AI673200,
					AW195629, AI914327, AW207103,
					AI858984, AI016102, AI948562,
					AI021976, AA515654, AA824295,
					AI288261, AW003109, AA029227,
					AI332790, AI863407, AW271426,
					AA447206, AW197033, AI673222,
					AA846300, AI093417, AW274813,
					AA917651, AI989749, AI198249,
					AI933079, AW337461, AA149282,
					AA476264, AA029228, N89854, AI650694,
					Z28929, AA149376, R53155, AA805734,
					AI862408, AW374891, AA010232,
					AW137892, AW250017, AA077657,
					H43959, AA077229, AI400383, AA077669,
					AI971136, AA076731, AW405369,
					AI862409, AW386712, AW386708,
					R49809, R43152, H22270, AA077893,
					AA889934, F00253, AF139794, M91506,
					AA077980, AI282751, AA077825,
					AA010157, F01048, AW393714,
					AA078429, AA077544, AI768799,
					AA076983, AA076893, AI125178,
					AW205906, AW373785, AI963990,
					AB011110, AC004084, and AC004985.
HE8PK12	36	1227647	1-3678	15-3692	AI675352, AA404223, N21458,
					AW377007, AW055240, AW376965,
					W72194, AI744480, AW377009,
					AA460033, AA689223, AI151138,
					AW367398, AI204462, AW367559,
					AI814765, AA514481, AA514486,
					AL041934, AI378530, AI127602,
					AI805975, AI816548, AA459944,
					AI079813, H99690, N69075, AI220492,
					AI924878, AA894562, AA227526,
					AW440516, AA652186, W78757,
					AI769346, AI223789, AA663829, R74386,
					AI129571, AI679615, T08944, W80492,
					N35223, AI366554, AA884120, AA227665,
					W04635, AI025087, AI141989, AI276061,
					AI131356, AI057082, N76793, AW089172,
					AA758991, AI149095, AW089170,
					N69065, H82484, AI366370, W31730,
					N44887, R78350, AI868614, M85694,
					T07736, AA404607, AI167295, H13964,
					AI351984, AA704854, AI832531, Z43566,
					AW008608, T30004, T35144, AW023452,
					R62595, R83633, AA978218, R77974,
					R62643, R84838, R73944, D62538,
					C04805, W77830, Z39632, AA663708,
					AA258404, AA904920, AI915380, T30003,
					T30824, AA016152, AA296029, AI139527,
					H22033, AA555134, AA776071, D50973,
					AA216002, AW148599, AA249464,
					H22108, AA369404, AA194728,
					AW367406, D79628, AI800441,
					AL117472, AL122082, U58883, AF136380,
					AF136381, AF078667, and AF078666.
HE9HV92	37	1227519	1-3422	15-3436	AW451462, AW389371, AA469982,
					AW389370, AW389367, AI625782,
					N62808, AW389369, AW367986,
					AW389368, AW389596, AW389606,
					AW044368, AA679038, AI493173,
					AW083020, AI280052, AI634922,
					AA402837, AW377678, AW389366,
					N33240, AI805314, AW004651, AI141651,
					N93923, AI000968, AF114067, AI922980,
					AA910867, AA918883, AW389616,
					H98243, H29386, H29296, H98939,
					AW367988, AW028291, F11743,
					AW002598, AI143427, AI679840,
					AA709068, AA402687, AA927333,
					AI183648, W01827, AW367982, Z45487,
					F06551, T65373, AW367985, AW389594,
					AW367974, AI679265, AW367968,
					AI569013, N79690, AA412251, N70773,
					AA994823, AI588847, AW377594,
					AA886715, AW139939, Z39513, F04059,
					F09403, F04352, AA348028, AI700831,
					R12190, AW139934, AI275660, AI253408,
					AI423822, R35809, AW389634,
					AW389639, Z45167, AW295763,
					AW389633, AW389637, R39914,
					AW389632, AA336725, T65450,
					AW389643, N41955, M78477, AW389640,
					AW389626, N56035, AW083017,
					AA343776, AW389615, AW389623,
					AW389628, AI802303, AW389641,
					AW389630, AW389359, AW389354,
					AA961766, AB007860, I74314, I74317,
					AF069506, AW627522, and AW630555.
HOHCE47	38	1217059	1-2131	15-2145	AI902550, AA852921, AW449324, and
					AB018324.
HSDII69	39	1154067	1-1418	15-1432	AA203346, AA203330, AI024792,
					AI383978, AA489694, AA658936,
					AI912487, AA640288, AW022618,
					AA115749, AA669824, AW296909,
					AW024848, AA133454, AA552781,
					AI332862, T86475, AI332863, AA665267,
					AA640358, AI625278, AA878769, T31809,
					AA318980, T86474, Z24863, and
					AL049423.
HKAKM10	40	1227639	1-3921	15-3935	AW166113, AI762270, AI761800,
					AI968494, AI935006, AI393355,
					AA885443, AA847857, AW044423,
					AI188200, AW085175, T66118, AI935038,
					AW003121, AI356390, AA588552,
					AI475498, AI139170, N63644, AW450561,
					AW088729, R70631, AI203354, AI239443,
					W45495, AA654175, H95337, AI002826,
					AA578373, F10209, AI468683, F09647,
					T83850, AA317152, T65033, AA641861,
					AW196381, AI350190, F12591, AI383380,
					W40418, F12002, T74348, W23298,
					R70529, T89046, N80491, AI474886,
					R88730, AB014530, AF071070, AF170304,
					AF077658, AF170303, and AF071071.
HCEPU56	41	1226120	1-2754	15-2768	AL134903, AW043595, AI912243,
					AA602982, AI674206, AA976922,
					AI224540, AA662495, AI742663,
					AW028771, AA478697, AA837145,
					AI354405, W49831, AA132987,
					AA412384, N62994, AI300307, AA013476,
					AA115419, AA722928, AI377356,
					AA478563, AW270325, AI479159,
					R76688, AA579347, Z43536, AA629042,
					AA169423, AA326624, H83962,
					AA133086, R76363, AA665443,
					AA587840, H67227, H81547, AA018206,
					AW298791, AA251488, AA301274,
					AI300195, AI192416, AI867958,
					AA501519, AI299974, H70300, AA644296,
					AI865166, AA252018, N79902, AA251195,
					AA251787, H65133, T26917, N83883,
					T26928, AL045327, AL045328, AL134524,
					AL134110, AL038878, AL047163,
					AW246148, AL042898, U46344,
					AI318479, AL037295, AL038838,
					AL048677, AL037343, AL038651,
					AI547295, AL038983, AI142134, D29033,
					AL037436, AL037335, AL037323,
					AL135012, AL037727, AL037443,
					AL038532, AL038822, AL038761,
					AL037435, AL040472, AL043941,
					AL039432, AL045494, AL044125,
					AL043923, AL043814, AL047012,
					AL041238, AL044186, AL040617,
					AL043845, AL041347, AL038024,
					AL040576, AL040193, AL045753,
					AL042523, AL041955, AL040463,
					AL047170, AL048657, AL044037,
					AL041635, AL040294, AL044064,
					AL041459, AL041577, AL044162,
					AL040464, AL047219, AL040625,
					AL045684, AL041752, AL046850,
					AL040768, AL045671, AL046994,
					AL048714, AL046914, AL045891,
					AL039360, AL038745, AL040052,
					AL043496, AL040444, AL043538,
					AL040621, AL040510, AL043467,
					AL043677, AL040839, AL043492,
					AL041602, AL044074, AL041730,
					AL041523, AL043627, AL041374,
					AL043848, AL043570, AL047183,
					AL042135, AL042655, AL046442,
					AL041324, AA115418, AL041133,
					AL039643, AL039316, AL041098,
					AL040322, AL046392, AL043089,
					AL040119, AL044272, AL044258,
					AL042420, AL037341, AL042468,
					AL038040, AL041096, AL042096,
					AL045817, AL041168, AL049018,
					AL079852, AL043321, AL041163,
					AL041159, AW363350, AL045920,
					AL040148, AL042741, AL047057,
					AL038041, AL040458, AL044187,
					AL046356, AF227510, AC004381,
					AR066494, AJ238010, A93923, A93916,
					D17247, A93931, AR064707, AL133053,
					AL122101, A85203, AR023813,
					AW611706, and AW769812.
HUSHB54	42	928054	1-343	15-357	AA348022.
HLMDO95	43	928344	1-469	15-483	AC020641.
HHASQ32	44	1198902	1-880	15-894	H00195, AI251764, AL042753,
					AW117882, AI349772, AL047763,
					AL121270, AI868831, AI433976,
					AW162071, AL047042, AI064830,
					AI436456, AI815383, AI433157,
					AL135661, AL036146, AI500077,
					AL119791, AL036396, AW268253,
					AL045500, AL046849, AA640779,
					AI349645, AI500553, AL036802,
					AW071349, AI687376, AI679724,
					AL119049, AI568870, AI863014,
					AI608667, AI690751, AI702406,
					AA613907, AW303152, AL121365,
					AI567351, AI349933, AI920968,
					AW238730, AI207510, AI873731,
					AL040169, AI687728, AI538716,
					AI469532, AI580190, AL036759,
					AI567632, AL119748, AW103371,
					AI673256, AL120854, AI934036,
					AI969601, AW166645, AI340582,
					AW080838, AW089572, AI907070,
					AI687415, AI521012, AI440426,
					AI906328, AW074993, AL036980,
					AI499393, AI349256, AI312152,
					AI753683, AW274192, AI969567,
					AI349937, AW302965, AI349614,
					AI349004, AI349598, AL038605,
					AI889203, AA585422, AI251485,
					AI343112, AL036274, AI343059,
					AL120736, AL036240, AI818683,
					AW132121, AW301409, AI282655,
					AA572758, AI609592, AI678302,
					AW235035, AI285735, AI250293,
					AI799305, AI309401, AI631107,
					AW195957, AI366549, AI281779,
					AW071417, AI149592, AI583316,
					AI690835, AI340519, AI345860,
					AI909666, AI686926, AI345744,
					AI475371, AI345735, AW087445,
					AI696846, AI498579, AI439087,
					AI497733, AI636456, AI813914,
					AI307466, AI366991, AI682743,
					AI907061, AI866608, AI275175,
					AI597918, AI635461, AI345111,
					AI909662, AW169653, AI635942,
					AI624859, AI671679, AA528491,
					AW068845, AI564719, AI699857,
					AI560012, AI568854, AI620284,
					AI220734, AA938383, AI446606,
					AI312428, AI590128, AL040243,
					AI445432, AI625079, AA528822,
					AI697137, AI857296, AI919058,
					AI540832, AI613017, AI249257,
					AI702433, AW148320, AI800453,
					AI800433, AI609580, AI866780,
					AI499463, AL038778, AI610307,
					AI758437, AI597750, AI633419,
					AI866002, AI684265, AA603930,
					AL043326, AW074869, AI224992,
					AL048871, AI687362, AI434281,
					AI281773, AI680113, AI344182,
					AI952114, AI874109, AI862142,
					AI440239, AI271786, AI499131,
					AL038779, AI682841, AI269696,
					AI307558, AL042538, AL036247,
					AI348897, AI475134, AI610645,
					AI682106, AI889839, AI866887,
					AW301300, AI628205, AI800411,
					AI539771, AI500659, AI469811,
					AI754897, AI064787, AI569616,
					AI281762, AI624668, AI580984,
					AA508692, AA528529, AI570384,
					AW075351, AW167776, AI802542,
					AW026882, AL036260, AI907056,
					AL047041, AI921379, AI610756,
					AI886532, AI818206, AI811863,
					AI334902, AI492540, AI445025,
					AL044207, AI636445, AW104724,
					AI439745, AW002342, AI888953,
					AI687375, AI282281, AI620868,
					AL036361, AI493248, AI340603,
					AW085799, AI349226, AW118557,
					AI804585, AI609331, AW268768,
					AI283941, AC005045, AF073770,
					AF168793, U65745, I48979, AF118064,
					AL049430, Y11587, S78214, AL133640,
					AF090934, AL050393, AL133016,
					AF113013, AF078844, AF118070, A93016,
					AF113691, AF090900, AF125949,
					AL050146, AF090901, AF090943, L31396,
					L31397, AJ242859, AL080060, AL110196,
					AF113676, AL133606, AL049938,
					AF104032, AF090903, AL117460,
					AL117457, AL049452, AF113689,
					AL110221, AR059958, AF113694,
					AL137527, I89947, AC002467, A08916,
					S68736, AF091512, AF113690, I89931,
					U95739, AC006371, AL122050,
					AL050149, AF090896, AF106862,
					AC007298, X84990, AL050108, U42766,
					AL096744, AB019565, AC004987,
					AL133075, AL050116, A08913,
					AL049314, AL096776, AL050277,
					AL122093, AF113677, AC005015,
					AF113019, Y16645, AC004690,
					AL049466, AC006336, I48978, AC005242,
					AF113699, AF017152, AL080137, S61953,
					AC006115, AC006944, AF042090,
					AC008394, AL133557, AC005886,
					AC007151, AR011880, E03348,
					AL137283, AL133093, AC005291,
					X63574, AL022147, AC007390,
					AL035587, AL049776, AC004520,
					AL080124, AL133080, AL022315,
					AL137557, AC006480, AC005520,
					AC010072, AF158248, AC005488,
					AL117394, AL034451, AL121934,
					Y11254, AL137459, AL133565,
					AC004686, AC004491, AL031283,
					AF162270, AF097996, AP000013,
					AL030999, U91329, AL122121, AF146568,
					AC004883, AC005175, Z98036, AJ000937,
					Z82206, AC006840, AC004383,
					AL122123, E07361, AF111851, AC007676,
					AP000201, AC009233, AF003737, U66059,
					AC002504, AF196779, AL109827, Z68164,
					AL050138, AF091084, AP000097,
					AL035067, AL033521, AL078593,
					AL008735, AC005048, AL110225,
					AC006157, AF079765, AP000240, and
					X82434.
HARAB87	45	1164340	1-536	15-550	AI733761, AA121199, AA296916,
					AI770025, AI733898, AA366952,
					AA149362, AI288862, AC005669, S76742,
					I26666, and AF075261.
HTNGF69	46	1152268	1-824	15-838	AI139022, AA552953, AI204346,
					AI741884, AI042245, AW205544,
					AI017548, AA258321, AI571085,
					AA478401, AA258530, AA701456,
					AA454012, AA402279, AA873796,
					Z41600, AA688162, AI799203, and
					C00673.
HMSJL96	47	1154788	1-1898	15-1912	U69566, AI478738, AI700975, AW270625,
					AA558431, AI955662, AI796542,
					AA620937, AW073767, AA928103,
					AI087266, AI949116, AI273460,
					AI766325, AW297573, AA873139,
					AI350929, AA770419, AA954532, N64139,
					R75698, N87915, R01072, H26525,
					R01798, AA773665, AI003807, AA318420,
					and AA318524.
HDTBT06	48	1205261	1-1434	15-1448	AA443164, AW020571, AA532437,
					AW118680, AI890631, AI167234,
					AA744921, AI401545, AW152040,
					AW074628, H06431, R74385, AA862392,
					AA649701, AA160546, AI880570, D62917,
					H23246, H46816, AA973615, AI819867,
					H00507, R21742, AA463453, C05953,
					R25958, R26764, AA639080, AW195349,
					AA315526, AW362722, AI494615,
					AW070869, H71752, T84284, AA767232,
					AI824357, and AF161399.
HTTIE47	49	1165363	1-878	15-892	R29204, W60551, and AC004386.
HHFBP47	50	946668	1-1193	15-1207	AW341717, AA001259, AA778598,
					AA203115, AI632467, AA707336, H69425,
					H68732, AI992354, AA346824, AI541205,
					AI557731, AI525500, AI557533,
					AI525556, AI557262, AI541321,
					AI557082, H65400, AI557238, AI557602,
					T18597, AI540890, AW021281, AI541056,
					AI557258, AI541048, AI525856,
					AI557084, AI535660, AI525656, D50992,
					Z32887, AW021585, AI526078, Z33559,
					AI557234, D59751, AI535639, AW023235,
					AI525757, AW022727, AL050350,
					AC002464, AR050070, S68736, A62298,
					A82595, A82593, Z30183, U94592,
					Y08991, A62300, AF006072, U45328, and
					AR025466.
HCCCC81	51	1083553	1-710	15-724	W16450, AL042537, AA367722,
					AI436552, and AA236375.
HPJEV71	52	1197841	1-1830	15-1844	AW239092, AA174017, AA303007,
					AL038072, AW103758, AI923333,
					AA576336, AA704393, AI654285,
					AI859946, AI888468, AA837778,
					AI254913, AW089101, AA584145,
					AA468131, F08230, AA302973,
					AA847952, AI620992, AI923126,
					AI800168, AI278972, AI207465,
					AW023149, H06140, AI751216, AI800180,
					AW131208, AI824706, AW440545,
					AP001037, AC006211, AL080243,
					AL121892, AP000525, AC006480,
					AC006288, AL031321, AL008731,
					AC004466, AC005870, AC008134,
					AC000353, AL117352, AC003049,
					AC007227, AF008191, AC004836,
					AC005041, AC005209, Z98941,
					AL049690, AC005952, AC007216,
					AL034417, AC004851, X05151,
					AC005480, AC006080, AL049830,
					AC004837, U95742, AC003684,
					AC005324, AC005529, AF059650,
					AF050154, Z85987, AL008638, AC005886,
					AL049636, AC007114, AC005368,
					AC007056, AC012099, Z97989,
					AL133249, AP000555, AC007386,
					AC004924, AC005728, AC006946,
					AL133246, AL022323, AC006961,
					AL022302, Z99755, AL031427, Z81014,
					AC002350, AL021918, Z97876, AL035417,
					AC005484, AP000228, Z98750, AC003670,
					AP001054, AL035555, Z83826, AL078463,
					U95743, AC004882, AC004622,
					AL024494, Z69707, U95090, AC006133,
					AL032821, AC007738, AL022238, Z71182,
					AC005920, AL034423, X12919,
					AC004475, AC000066, AC002126,
					AC007011, AC002996, AP000140,
					AF157623, AC005318, AL035659,
					AC002980, AC007537, AC016027,
					AC016830, AL133244, Z82206,
					AC005514, AL096775, AF070718,
					AC004905, AP000035, AC004696,
					AP000350, Z97054, AC005089, AC005587,
					AL031575, AL031281, Z82214, AC006230,
					AC006064, AC001644, AP000466,
					AP000088, AC002325, L29252, AC000082,
					Z73965, AL031767, AC002553, and
					AC007312.
HTEIL07	53	1136121	1-1216	15-1230	AA725842, AW139921, AI651885,
					AI971598, AA453466, AL110422,
					AI027229, AI026797, AA778573,
					AI279962, AI073425, AI208767, H55405,
					AA453966, H55431, AL118498, and
					AL031843.
HTEAG49	54	954614	1-1289	15-1303	AW452652, AI039005, AA780077,
					AW316890, AI337290, AA463229,
					AA463230, AI423317, AI468158,
					AA382497, N66986, AF041822,
					AL390796, AL390796, AL357045, and
					AL357045.
HSLCF96	55	637670	1-1575	15-1589
HNHCI32	56	861673	1-586	15-600	AF112462, and AR035954.
HPMFL08	57	1050684	1-463	15-477	AA555286, AA640814, AI281916,
					AW073979, AI378363, R70468,
					AW242350, AW013856, AA644290,
					AW449140, Z93016, AC012384,
					AL035541, AC005228, AC003662, and
					AC009300.
HTXRA13	58	959622	1-1150	15-1164	AI701008, N92159, AA363885, AI990716,
					AW197467, and AW291923.
HCE3H71	59	1197898	1-2059	15-2073	AI638508, AW139057, AW149807,
					AI654790, AI419465, AI569283, H51217,
					R90888, R85125, H29245, H29244,
					AA488106, AI480182, H05353, AI500178,
					AI873131, AI499775, F11386, H05303,
					AI458144, H51247, F05862, R44423,
					F09051, R14779, R51725, R51648,
					R42549, AA338672, Z40525, F07470,
					R19635, W22746, R49451, R35934,
					R85080, F02105, AW169213, AL046466,
					AW162194, AI352326, AI700159,
					AI955945, AW192701, AI890507,
					AI978703, AI263331, AI800159,
					AI573167, AI571980, AI961589,
					AW169671, AW188693, AI634224,
					AI274507, AI690748, AI758309,
					AI648436, AL039716, AI590043,
					AI911648, AI690687, AW075484,
					AI917963, AI648684, AI698391,
					AI671642, AI619607, AW168031,
					AW168296, AI572787, AI918435,
					AL119863, AI564426, AI814087,
					AI470648, AI452556, AW029611,
					AI921254, AW054960, AI365256,
					AI564234, AI597758, AI919500,
					AI624120, AI686716, AI621341,
					AI309306, AL079799, AW071349,
					AW008781, AI926878, AI564448,
					AW024594, AI933992, AI540676,
					AW051088, AW198075, AI921155,
					AI536685, AI561356, AI922812,
					AI538850, AI468872, AW022699,
					AW089275, AI919593, AW188382,
					AI866770, AI434134, AW264019,
					AA835966, AI690620, AI950729,
					AI564765, AI813868, AI925680,
					AI829327, AI417790, AI540759,
					AI630876, AI570872, AI744279,
					AL046595, AI439452, AI566386,
					AI354630, AI609409, AI681985,
					AL040011, AI784219, AI247193,
					AI590781, AW080746, AI874261,
					AI249877, AA279795, AI470284,
					AI589428, AI445611, AI590415,
					AI620284, AI887389, AI554485,
					AI963625, AI522052, AI654672,
					AI520809, AI889306, AI540674,
					AI783821, AI281757, AI474646,
					AI889376, AA983883, AI567769,
					AA916133, AI670009, AI783504,
					AL047675, AI805671, AI366900,
					AW130307, AI289310, AI553645,
					AW022093, AI797538, AW029197,
					AI696570, AI624293, AI345688,
					AI872423, AI362580, AI580674,
					AW087199, AL135517, AW170725,
					AA687501, AI479577, AI868204,
					AI863241, AW194185, AI572021,
					AI492540, AA502794, AW080346,
					AI419650, AI679550, AI632851,
					AI920835, AW188539, AI241923,
					AI587121, AW163823, AI433611,
					AI697157, AI621209, AW008166,
					AI862139, AI612750, AI147686,
					AA806719, AW102902, AI273901,
					AI306613, AI679672, AW152182,
					AI270295, AI422688, AW024793,
					AI288305, AI695129, AI569945,
					AL036673, AI918449, AW088560,
					AI889189, AW148423, AI620075,
					AI357599, AI269205, AW167228,
					AI277325, AL138386, AI439745,
					AW193467, AI590830, AI623941,
					AW117997, AI797908, AI963224,
					AL038665, AI524179, AI818353,
					AW075413, AI954507, AI683099,
					AI524671, AI635478, AI653578,
					AI623379, AI860783, AW007309,
					AI635639, AI564749, AI830259,
					AW029533, AI627360, AI874166,
					AI582932, D29763, D64009, D64010,
					I89947, AL137271, AF067728, AL137665,
					AR038854, AL050155, AL117435,
					AJ003118, AF177401, AJ005690, I48978,
					AF113690, AL137463, AL050277, A65340,
					AL137479, AL133560, S75997, AF028823,
					S36676, AF111849, E01314, AL080126,
					AL110296, Z97214, U75932, AF151109,
					X52128, AL133606, AF106862, A18777,
					AL137459, AL122100, AF061795,
					AF151685, A45787, AL110225, I32738,
					AR034821, A15345, AL080124,
					AL137550, AL117416, AF183393, E02349,
					A08913, AL137574, AL133568,
					AL137480, AL133112, AL137478,
					A08916, U86379, AL133557, M27260,
					A08912, AL110280, A52563, AL133637,
					I89931, X93495, AL110222, A08910,
					X72889, A21103, I49625, AF091084,
					A08909, AJ238278, AL122098, AL117394,
					AL080148, X63574, AF061573, AF113677,
					A08908, AF031147, AL137533, AL137294,
					AL050138, AJ006417, AF026816, I89934,
					AF017437, AL050149, AL133010, U35846,
					E01614, E13364, AL049339, A07588,
					AL133558, Y11254, Y10655, AL122110,
					AR020905, A65341, A77033, A77035,
					AL137641, AL023657, I48979, S78453,
					AL080159, AF087943, Y14314, AL137558,
					AF158248, AF061981, AL133619,
					AL117463, AF079763, U87620, U80742,
					S76508, AL049314, AL080154, AF111851,
					AL110218, A90832, AL117460, AF094480,
					AF090900, U66274, AL133016, A23630,
					I00734, AF113694, L19437, AF090943,
					AF069506, Z82022, AF017152, AF205861,
					E00617, E00717, E00778, AF016271,
					AF100781, AL137292, AL137537, I89944,
					L04849, X82434, X79812, Y11587,
					AF118070, AL122050, AL117583,
					AF159615, AF017790, I17544, AL137529,
					AL110221, AF090903, Y09972, AF026124,
					U42766, AF051325, D83032, AL049464,
					AL137560, AL137530, AL049452,
					U55017, X67688, A18788, E12747,
					X63410, AF113019, AL137523, AF057300,
					AF057299, AL110171, AF118094,
					AL049283, E04233, X80340, AR059958,
					AL080127, AF125948, AF185576,
					AF113691, A58524, A58523, AL137276,
					AL137429, AL137283, X76228, S63521,
					AL133080, X70685, M30514, E06743,
					AJ242859, AL137256, L31396, U68387,
					AL137656, AF146568, AL122093, L31397,
					U91329, AJ012755, M92439, AF003737,
					AL080163, I96214, AR034830, M86826,
					S82852, AF137367, AF115392, AL122106,
					U00763, AF106697, U57352, S68736,
					AL137488, AL133113, A03736, AF032666,
					AF111112, A08907, Y10823, AL049430,
					AL133640, AF118090, M96857, E07108,
					AL117457, D16301, I66342, AL133665,
					AL050092, AL049465, AR011880,
					A08911, and AL133067.
HUTSF11	60	1134914	1-437	15-451	AI384010, AI288640, Z20435, and
					A74523.
HTEGI48	61	1021235	1-536	15-550	AA102044, H93506, AF140360, and
					AF074606.
HSFAM09	62	1153913	1-281	15-295
HNFHK77	63	1182286	1-1272	15-1286
HFXDO83	64	1012602	1-605	15-619	T03269, D58283, D59859, D80022,
					D80166, D80195, D80193, D59927,
					D59467, D51423, D59619, D80210,
					D51799, D80391, D80164, D59275,
					D80240, D80253, D80043, D59787,
					D80227, D59502, C14331, D80038,
					AW177440, AW378532, AW179328,
					AA305409, D80134, C14389, D51097,
					C75259, AW360811, AW366296,
					AW375405, D58253, AA305578,
					AW375406, AW378534, AW179332,
					AW377672, AW179023, AW178905,
					D80132, AW352170, AW377676,
					AW178906, AW177733, AA033512,
					D89785, D34614, X67155, X82626,
					A84916, A67220, A62300, A62298,
					Y17188, A78862, D26022, D88547,
					AJ132110, A25909, AR018138, AB012117,
					AR025207, A85396, A44171, A85477,
					AR066482, A86792, I19525, X93549,
					AF058696, Y12724, AR008278,
					AB028859, D88507, A94995, AF135125,
					U87250, I18367, U87247, AB033111, and
					AR064240.
HSDIW73	65	1104406	1-1602	15-1616
HFVGD23	66	1199645	1-1842	15-1856	W78862, W19697, H14921, AA576940,
					H14628, H54580, AW119184, T93838,
					AA056294, R53170, R99389, R11968,
					F11919, F11380, T79980, AA043550,
					T65194, R09850, AI948441, AI206824,
					AW190832, AI199930, R55990,
					AA013266, AI097591, AI754286,
					AF073770, AC005045, AF052187,
					AF168793, U65745, U26033, J02844, and
					Z98742.
HMSBZ24	67	1082367	1-706	15-720	H14236.
HWHHB69	68	1217042	1-2892	15-2906	AL045925, AL042685, AW245943,
					AW245500, AI827711, AW247149,
					AI589761, AI422317, AI076031, N94372,
					AA708691, AA702609, AA702730,
					AI912816, AI984055, AL042686,
					AI420887, AL045926, AW272712,
					AW237553, AI469477, AA494501,
					AW374634, AI863106, AA181277,
					T15903, AI476561, R06007, AA380280,
					AA322751, C04187, F36452, AW248180,
					AA883148, AI767541, T82100, AA506918,
					AA227226, C01255, N57562, and
					AJ242655.
HFXLC69	69	1162543	1-1632	15-1646	AA296887, AA297110, AF065216,
					AF121908, and AF065215.
HBXBW40	70	1156765	1-574	15-588	AL023754, AL049688, and D86557.
HCE1L51	71	1140498	1-420	15-434	AA349751.
HRADM45	72	1148046	1-468	15-482	AA418916, AA426580, AJ271722,
					AP000260, AP000036, AF055919,
					AP000099, and AP000098.
HTEFO45	73	1153918	1-899	15-913	AA620907, AA758187, AA015938,
					R84831, AA412093, R58215, and U75361.
HOHBN82	74	1152271	1-1453	15-1467	AI335266, AI751901, AI751815,
					AI750604, AI040116, AW067945,
					AW239149, AI572373, N42174, N22119,
					N71503, AF182316, AF182317, AB033033,
					and AR018882.
HWHGF52	75	1217026	1-2228	15-2242	AW044636, AI216076, AA846742,
					W22035, AW172841, AI291112,
					AI681233, AW080046, AI399893, H28922,
					AA614450, AA536156, AI278855, N39741,
					AI183847, H21177, AA313439, N20038,
					AA470881, AI088477, AA032036,
					AW007815, AA515917, AA348553,
					R86198, AW006990, AI094006, D61068,
					AI282605, R48136, AA971399, AA333772,
					AA365066, N26782, AA034263,
					AA377509, AA804676, AI242834, R48135,
					AA576728, D60948, D60442, H46369,
					R49863, D81590, AI183862, AA894892,
					AA886813, D53429, AA484583, R49862,
					AA907007, AA339653, AI183749,
					AA348552, AI167561, AI869376,
					AA223889, M78928, AI241882,
					AB002360, and Z35654.
HBKDI30	76	1223861	1-1626	15-1640	F37398, AA197072, F22840, AW444680,
					AA196995, F31270, R02824, F37397,
					AA112849, F17211, F37676, F30884,
					F35768, F35763, J05194, and J03886.
HSQFR54	77	1185143	1-2012	15-2026	AA811369, AA873372, AA209183,
					AA304836, W26880, AW189673,
					AI459087, AA326319, T11336, H00191,
					AL120282, and U35244.
HAGBA56	78	1102593	1-1273	15-1287	AA812064, AI803142, AA430303,
					AA430200, AI425013, AA954361,
					AA012835, T07365, AA984341, AI207984,
					AB020641, AF033655, U62391,
					AC000057, AC006036, and AC002458.
HHSAE29	79	1220851	1-1193	15-1207
HMSHO64	80	746582	1-398	15-412
HFPBW22	81	1154786	1-1051	15-1065	AA583561, AI685755, and AI971263.
HTLBH67	82	1224371	1-2872	15-2886	AI700778, AI651596, AA203283,
					AI079116, AI269328, AA766256,
					AA846207, W94671, W95139, AI765522,
					AI123765, AW337193, AI693824, T15539,
					AI269741, W19592, AW449541,
					AW407143, AA045079, AI204381,
					AA045395, AW305104, AI742830,
					AW052085, AI858504, AI587476,
					AW135172, AI887064, AW380082,
					AW295490, AI453541, AI955603,
					AA971802, AA485799, AA287153,
					AI761438, AA485669, AA781274,
					AA214554, AI865011, AA284733,
					AW341388, AA814271, AA447822,
					AA256234, AA368228, AC005368,
					AF086518, and AF059650.
HNTMH70	83	1143523	1-1073	15-1087	AL045099, AL110384, AA477597,
					AA485587, R25821, AL134410, R55476,
					AA584162, H19102, AI383263, AA349309,
					H42360, AA953198, AI688425, W22471,
					AI537054, AA736967, R56322, AA526482,
					H29361, AI699883, F06802, Z78292,
					AA081493, AW168512, AA035215,
					AA078393, AA077854, H21589, AI004027,
					AA836778, D44975, AA581900, R17223,
					H18689, AA507183, AI570959, AL134844,
					R87452, AA569527, AA491053,
					AA077436, R28228, R49752, F00981,
					W38765, AA584770, AA601420,
					AA374571, R87607, AA601480,
					AA310271, R26668, R11721, AW298136,
					AA780824, F12062, AA164247,
					AA062928, AI539135, AI752143, T66331,
					AA868891, AI298079, AA582543,
					AC005726, AC005785, AF196970,
					AL034374, AL049822, Y18000,
					AC005529, AC005288, AC002553,
					AC002395, AF052041, AP000087,
					AL049594, AC015853, AC007999,
					AL049839, AC005531, AC008038,
					AF095725, AC002351, AL034394,
					AC005694, AC004860, AC005343,
					Z98304, AL031650, AL109847, AL021938,
					AP000225, AC002524, AC007372,
					AL050321, AP000555, AC005829,
					AC003663, AL035681, AP000350,
					AL049837, AL118497, AC005013, Z98742,
					AL031685, AC003991, AC006449,
					AB000882, AL031057, U91326,
					AL024507, AC002544, AL109662,
					AC005206, AC006992, AL049632,
					AL133245, AL109837, AC005667,
					AP000506, AL080233, AL117356,
					AC007376, AB014080, AL021154,
					AC004814, AL121653, AC004206,
					AC006236, AL034430, AL121756,
					AL049757, AC004757, AL049552,
					AC004073, AC006557, AL117258,
					AP000514, AL031671, AC004167,
					AJ011930, AC004849, AB000879,
					AL021397, AL049539, AC005535,
					AC004079, AL031668, AL031430,
					AC005971, AC004558, Z69654,
					AL080112, AL096773, AC005681,
					AF165147, AC005006, AP000502,
					AC002525, AC005962, Z83840,
					AC004448, AC007172, AC008372,
					AL031602, Z82976, AL035045, AF129077,
					Z97054, AC007560, AC004021,
					AL121577, AC003005, Z94054, AL023575,
					AC002531, AC005156, AC004196,
					Z94044, AL033527, AF165926, AP000520,
					L09706, AC008249, AC004474, AF029308,
					Z75746, AC006132, Z73900, AC005046,
					AB023056, AF019413, AC007327,
					AF064859, AC005069, AC007126, Z11739,
					AP000510, AL133246, AL021394,
					AC004520, AC002556, AC007066,
					AC003071, AP000553, AC005684, Z11740,
					Z98172, AB023048, AC009516, Z95437,
					AC004065, AC007546, AC004973,
					AL031224, AC006427, AL049842,
					AL022101, AL035078, AC005332, Z83844,
					AC003102, AC004169, AP000694,
					AC004601, AC008417, AC006313,
					AC007967, AL049832, Z83841,
					AC005510, AC004462, AP000501,
					AL133304, AC007387, Z84487, AL096703,
					AC002463, AC004213, AL133243,
					AC004762, AL137191, AC006539,
					AL022476, D10855, AP000354, AL022723,
					AL031391, AC002991, L77570, Z82203,
					AC005067, AC004067, AL022170,
					AC005320, AC005527, AC002400,
					Z75889, AL023875, AC007666, AL135745,
					AC000052, AD000813, AC004144,
					AF187850, AC004019, AC005940,
					AL031229, AF109076, AL049646,
					AC007435, Z82171, AC005570,
					AC004531, AC000025, AL050343,
					AF107885, AC005828, Z82196, AL022332,
					Z93403, AF117829, AL031275, AL021877,
					AC006077, Z98941, AC004858,
					AC000387, AC006222, AC006952,
					AC006001, AL022721, AC004885,
					AL035458, AP000352, AC002402,
					AF109907, AC000003, AC007687, Z97056,
					AC005192, AC005994, AL109802,
					AL008583, AL022400, AL049843,
					AL079342, AC002996, AP001053,
					AC006039, AC005317, AC006008, and
					AL135879.
HCETC59	84	1183334	1-401	15-415	AA346622, AA085022, and U35245.
HE8UX76	85	1161223	1-1763	15-1777	AI863338, AA703679, AI223268, F12220,
					F09849, R22646, H04918, H04815,
					T66347, AB026810, AB026803,
					AB026809, U20105, and Y19241.
HTLEN77	86	1136124	1-1180	15-1194	T89857, T89583, AI349772, AL121365,
					AL047042, AL036396, AL121270,
					AI687376, AL119791, AW238730,
					AW268253, AI636456, AI349004,
					AI868831, AL045500, AI521012,
					AI285735, AW301409, AL135661,
					AL038778, AW103371, AL036802,
					AL047763, AI433976, AI475371,
					AW071349, AI436456, AL036146,
					AI687728, AI064830, AI349645,
					AI445432, AI635461, AI625079,
					AI250293, AI568870, AI702406,
					AI538716, AW195957, AI439087,
					AW162071, AI678302, AI564719,
					AL119049, AI815383, AI620284,
					AI498579, AI433157, AW169653,
					AI340582, AI349933, AI613017,
					AL045903, AL046849, AI866608,
					AL036274, AL040243, AW274192,
					AI590128, AI699857, AW071417,
					AI540832, AI440426, AI697137,
					AI249257, AI275175, AI281779,
					AI857296, AI702433, AW148320,
					AI800453, AI800433, AL038605,
					AI500553, AI920968, AI500077,
					AI580190, AI567351, AW074993,
					AI439745, AI312152, AI345735,
					AI349937, AW089572, AI207510,
					AI906328, AI690751, AW068845,
					AI758437, AI597750, AI499463,
					AI682743, AL120854, AW166645,
					AI497733, AI673256, AI679724,
					AI633419, AI866002, AI863014,
					AI349614, AI499131, AW080838,
					AI686926, AW117882, AL043326,
					AI440239, AI873731, AI567632,
					AW303152, AI282655, AI281773,
					AI610307, AI907070, AI631107,
					AI568855, AI818683, AI499393,
					AI224992, AL036759, AL038779,
					AI343112, AI866887, AA613907,
					AW074869, AI349598, AL120736,
					AI349256, AI608667, AI866780,
					AL048871, AW087445, AI348897,
					AL040169, AI682841, AI271786
					AA572758, AI560012, AI800411,
					AA640779, AI628205, AI597918,
					AI921379, AI690835, AI469532,
					AI568854, AI434281, AW132121,
					AI969601, AI580984, AI366549,
					AI251485, AL036980, AI475134,
					AW268768, AI813914, AI281762,
					AL119748, AW085799, AI811863,
					AI469811, AI862142, AI680113,
					AI889203, AI874109, AI493248,
					AI802542, AW301300, AI687465,
					AW026882, AI934036, AI269696,
					AI889839, AI609592, AI583316,
					AI492540, AI671679, AI570384,
					AA528822, AW167776, AI753683,
					AI610645, AI696398, AW235035,
					AL042753, AI539771, AI969567,
					AI919058, AI500659, AA508692,
					AI445025, AL044207, AI349226,
					AI687375, AW104724, AI591311,
					AI624668, AI754897, AI569616,
					AL121014, AI684265, AI687415,
					AI818206, AI952114, AI149592,
					AI536685, AI872711, AL047041,
					AI318569, AW075351, AI620868,
					AI909666, AI612913, AW118557,
					AI859733, AI609580, AI345860,
					AA585422, AI609331, AI446628,
					AW183130, AI696846, AI343059,
					AI635942, AI432969, AI432229,
					AI690426, AI679764, AI345744,
					AI624859, AI636445, AI334902,
					AI340519, AW302992, AW002342,
					AI619502, AI446606, AA938383,
					AI282281, AI907061, AL119828,
					AI269205, AL036240, AI282903,
					AI800384, AI583445, AI366991,
					AI804585, AI309401, AL041573, I48979,
					AL050393, AF090900, L31396, L31397,
					AF125949, S78214, AF090934, I89947,
					AF113013, AF118070, AF078844,
					AL080060, Y11587, AF090901, AF118064,
					AF113694, AL133016, AF113691,
					AL133640, A93016, AF090943, AL117457,
					AL133606, AF104032, AR059958,
					AL117460, AF090903, AL050146,
					AL137527, AF113689, AL110196,
					AF113690, AL049938, AL049452,
					AL050149, AL110221, S68736, AJ242859,
					AL122050, AB019565, AF090896, I89931,
					AF113676, X84990, AL050108, U42766,
					A08916, AF106862, AL133075, AL050116,
					AF113677, AL049314, AL122093,
					AF113019, AL049466, AL133557,
					AL096744, A08913, AF017152, AL137283,
					AL122121, AL080124, AL080137,
					AL050277, AL133565, E03348, AL137557,
					AL133093, I48978, AF158248, AF113699,
					AL137459, Y16645, Y11254, AJ000937,
					AR011880, AL133080, X63574,
					AF177401, AF111851, E07361, AL049430,
					AL122123, U91329, X82434, AF091084,
					AL050138, AF125948, AF146568,
					AF097996, AL117394, AL110225, E07108,
					AF079765, AL049300, AL137550, I49625,
					AL117583, U00763, AL133560, A65341,
					S61953, AF017437, AL117585, X70685,
					E02349, AJ238278, A08910, AL050024,
					AL117435, AL049464, A08912,
					AL049382, AF067728, AF118094, I33392,
					A58524, A58523, AL133113, AL137538,
					AC007390, AF183393, U72620, A77033,
					A77035, Z82022, E05822, A08909,
					AL122110, AL137271, AL122098,
					A03736, AF091512, AC002467, A12297,
					AL049283, X72889, AL137648,
					AL137463, AF061943, U80742, I03321,
					AF087943, Y09972, I09360, X96540,
					I42402, AL080127, X93495, AL110197,
					AL096776, X57961, U35846, X65873,
					AL080159, U67958, I00734, AL137521,
					AC006336, E00617, E00717, E00778,
					AC006371, AF111112, AL110280,
					X98834, U49908, AC004093, AJ012755,
					AL133014, AL133104, I26207, AR013797,
					AC007172, AL022147, AL133568,
					A93350, E08263, E08264, I17767,
					AC004686, AL133072, AC006840,
					AC004690, L13297, I66342, AL137523,
					AL137560, E15569, AR000496, U39656,
					U58996, AF026816, Y14314, AC007298,
					AL137533, X83508, AC004987,
					AF153205, AF061981, Z37987, AL133077,
					AL137476, AF119337, AL137556,
					AF100931, A08911, AL122049, AL137526,
					Z72491, M30514, U95739, AL133445,
					AF000145, AF057300, AF057299, A45787,
					AL050172, AF026124, and AC004200.
HBGDI80	87	1124695	1-1069	15-1083	AI950010, AW014786, AI694670,
					AA171820, AI862334, AA604593,
					AA171724, AI697768, T11223, R41784,
					AI023823, T10688, and AI802300.
HELHB88	88	1225632	1-3305	15-3319	AI671143, AI580905, AI632369,
					AA773823, AW370310, AA773263,
					AA313515, AA985166, AL121153,
					AI382884, AA181724, AI469456,
					AA024936, AI750406, AAI55593,
					AA024853, AL120063, T78993, T78788,
					T82245, AA155607, AI750407, AL134372,
					AA670080, L25219, AA247838,
					AF114487, AF114488, AF064243,
					AF064244, U61166, AF127798, AF132672,
					AF132478, AF132481, AP000311,
					AP000117, AP000193, AP000049,
					AP000116, AP000050, AP000048,
					AP000308, and AP000115.
HTEMV66	89	1152261	1-847	15-861	AI149647, AA430041, AA430250, and
					AW372558.
HMTAJ73	90	1063989	1-954	15-968	AI831613, AI870169, AI924408,
					AI368905, AI284115, AW168626,
					AA678670, AW068406, AA568895,
					AW198110, AA627558, AA857431,
					AW068493, AI284116, H19069, AJ010119,
					AF074714, and AF074715.
HE9TD31	91	815845	1-941	15-955	AI475682, AI439613, AA815076,
					AB033082, AF132480, and AF132479.
HGBDG55	92	1141363	1-521	15-535	AA368408, and AW614226.
HOUHL51	93	1125914	1-633	15-647	AA431822, AI341790, AW295199,
					AI656610, AW292290, AA037543,
					AA431419, AA974280, AA815270,
					AA037457, AI651702, AA583011,
					AI208605, AI419858, AA620408,
					AA417333, AA417321, W28051,
					AA251183, AI917695, W28536, and
					AI024754.
HEOPP67	94	1020119	1-959	15-973	AA641653, AF181972, AF181973, and
					AL137592.
HKAOV71	95	1165423	1-743	15-757	AF123303, and AF004161.
HDQID90	96	1137752	1-1007	15-1021	AW300598, AA669095, AI948608,
					AI797687, AI718165, AI129358,
					AI765613, AA114888, AA504203,
					AI701050, AI890342, AA974370,
					AI023212, AA504439, AI935316,
					AA252310, AA464174, D57415,
					AA280044, W46279, D54675, AA165321,
					AI420451, T71333, N69756, AA832206,
					AA521314, AA114887, AA877638,
					AW196653, AI027401, AI807828,
					AA863081, AA995204, AI831132, Z28882,
					Z40146, D57019, AA464762, Z25261,
					N87679, Z19443, AI918466, T71487,
					F00129, D56990, AL047889, AA278335,
					AW369458, W46278, AA743770,
					AL047888, AI809238, AA767219,
					AW025464, AL110306, AW302960,
					AW162194, AL036802, AW087445,
					AW071417, AI699865, AW163823,
					AL036274, AL041562, AI254727,
					AL119863, AW238730, AL045500,
					AI783861, AI909697, AI340603,
					AI537677, AI433157, AW163554,
					AI698391, AI929108, AI619502,
					AI802542, AW026882, AI783504,
					AI620284, AW198075, AI860783,
					AL079963, AA640779, AL047344,
					AW051088, AA572758, AL041772,
					AI699011, AI345180, AW082113,
					AW269098, AW268251, AI064830,
					AW161156, AL039086, AW020693,
					AI349645, AW268768, AW300782,
					AI349933, AL036403, AL119828,
					AI923989, AW300889, AL119791,
					AI497733, R36271, AL036396,
					AW172745, AI521012, AL041150,
					AW150578, AL079960, AI340519,
					AL048656, AL135022, AL080046,
					AI610293, AI567351, AW162071,
					AW079572, AW169653, AW074993,
					AI636456, AI284517, AI433976,
					AI697324, AW160916, AW268253,
					AI569583, AL038505, AL040169,
					AI312152, AW301409, AI345735,
					AI468872, AI524671, AI349937,
					AL036638, AA613907, AW089572,
					AI863382, AL047042, AW080402,
					AI270183, AI884318, AL037030,
					AI926878, AW023859, AI890507,
					AI564719, AI568114, AW068845,
					AI815232, AI868931, AW020419,
					AI624293, AI683395, AL039716,
					AI499285, AI886753, AL037582,
					AL037602, AL037463, AI815855,
					AI933589, AW004886, AW161579,
					AI312428, AI538850, AI307604,
					AI702073, AA427700, AI873644,
					AL046931, AW059828, AI499963,
					AI866469, AI610645, AL037454,
					AI349614, AL038605, AI343112,
					AL080045, Z99428, AW129106,
					AL134830, AI348897, AI862144,
					AL040827, AL121014, AI349598,
					AW118518, AI560012, AI473536,
					AI633125, AI307285, AI539153,
					AI627988, AI309401, AI567582,
					AI539771, AI500523, AI335208,
					AI866608, AI537244, AL036146,
					AL119049, AI521560, AI889189,
					AA449768, AI340582, AI500659,
					AI269862, AI287449, AI625464,
					AL121365, AI801325, AA804740,
					AW103371, AW022808, AI358701,
					AI613038, AI859991, AI538980,
					AI754897, AA580663, AI813914,
					AW078839, AA528822, AI866770,
					AI500662, AI917963, AL040241,
					AI349004, AI570807, AI352274, F27788,
					AL046944, AL043975, AI570966,
					AI635492, AL042745, AI682841,
					AI475371, AW149236, AI538716,
					AC002350, AB033082, AF132480,
					AF132479, I48979, U35846, I09499,
					I89947, AL122050, I48978, Y16645,
					AL096744, AF090903, AL110196,
					AL117457, Y11587, AF177401, AF090943,
					S78214, AL122093, A08910, AF100931,
					AL133075, AF146568, AL050116,
					AF090901, AL137550, AF090900, A08916,
					I89931, AL133606, AF078844, A77033,
					A77035, AL137271, AL133560, A08909,
					AL049382, AL137538, E07108, AF090934,
					AF183393, AL133565, AL137557,
					AL133640, AL110221, AL133016,
					A08913, E12747, AF113019, AL133557,
					AF113013, AF090896, AR013797,
					AL049452, AF113691, AF079763,
					AL137533, AF104032, AF113694, U87620,
					AF125949, AF097996, AL049938,
					AL137478, AJ000937, AL049283,
					AF125948, AL050146, I00734, S68736,
					AL117435, AB019565, AL049300, E05822,
					AL137459, AL122100, E00617, E00717,
					E00778, AL080124, AF067728, AL050149,
					AL050277, E06743, AL133080, I33392,
					U58996, AL117460, AL137488,
					AL080148, E02221, AF091084, AF113690,
					X70685, E02349, Y11254, AL137480,
					AL049430, AF111851, L31396, AL137527,
					AL050393, AL137548, L31397, AL122121,
					AF118090, M27260, AL050108, U42766,
					A58524, A58523, AR038854, AF017437,
					I49625, AF118064, A65341, AL050024,
					AF118070, AF111849, X63574, X72889,
					AL080060, AF106862, AR059958,
					AL133113, AF079765, AF057300,
					AF057299, AF017152, AF113699,
					AL050172, Z82022, AJ242859, X84990,
					A12297, AL110225, AL137294, AF032666,
					AL137479, A93016, AL122110,
					AL137283, AF118094, A65340, AF158248,
					AR011880, AL133067, AF031147,
					AL122098, AL137529, A03736,
					AL137521, AF067790, AF087943,
					AL049314, AL117649, Z37987, U80742,
					U91329, X83508, U72620, AL049466,
					AF113677, X79812, A08908, AL096720,
					A08912, X82434, AF113689, AJ238278,
					AF113676, AJ005690, AR020905,
					AL117583, U78525, AF126247, AF153205,
					AF026124, U68387, AF081197, AF081195,
					S61953, AF159615, Y09972, AL050366,
					AL117416, A07647, Y07905, AL122123,
					AF210052, AL080158, AL023657,
					AL080137, AL050138, I68732, AF100781,
					AL137526, X87582, AF054599, U96683,
					AL133568, AF185576, AL117394, A21103,
					AL080074, AF106657, AF030513,
					AL137292, AB016226, A18777,
					AL133093, AL080159, Y14314, AF061981,
					AL050155, X65873, AF119337, E03348,
					U67958, AL137560, AF106697, AF139986,
					AL050092, AL049464, X53587, U88966,
					AL080234, AB007812, AL110222,
					X98834, AL137463, X81464, AJ012755,
					AR038969, X80340, U00763, E15569,
					AJ006417, AF026816, E07361, S36676,
					and AR000496.
HFRBN81	97	1182552	1-4099	15-4113
HFKJW01	98	1187134	1-475	15-489
HSDFL63	99	1219300	1-2578	15-2592	AI811010, AW182310, AI669944,
					AA553658, AI149982, AW002490,
					AI138253, AI015322, AI417803,
					AW262574, AI338004, AW072451,
					AW073593, AI093838, AI027630,
					AI655339, AA922787, AI638037,
					AI095502, AW439551, AA913807,
					AW305307, AL042064, AA977416,
					AI205666, AA036837, AA036780,
					AA447978, AA356059, AA382934,
					AI611255, AI401469, AI280408,
					AI522175, AW263492, AA320515,
					AA382259, AA382933, AW450423,
					AA927003, AI933504, AI990172,
					AA552283, AA330729, AA382258,
					AB015228, AL110274, AL110299,
					AL137418, AB015226, AB015227,
					U60063, and X99273.
HPJET90	100	836503	1-542	15-556	T03269, D58283, D80022, D80195,
					D80193, D59927, D51423, D59619,
					D80210, D51799, D80391, D80240,
					D81030, D80253, D80227, D80196,
					D80188, D59275, D80219, D80366,
					D80043, D80038, D59859, D80166,
					D80212, AI905856, D80269, D50995,
					D59889, C14429, D50979, D80134,
					D80378, D80024, D80045, C75259,
					AW178893, C14014, D59502, D57483,
					D59787, D59610, D51097, D80164,
					D80241, F13647, D80268, C14331,
					D51060, AW177440, D58253, C15076,
					D59467, D80949, D80168, C14227,
					AA305409, AW378532, AW178775,
					AW179328, C14389, AW352117,
					AW352158, AW177501, AW177511,
					D51079, AW178762, D51022, AW366296,
					AW360811, AW176467, AW375405,
					AA305578, AW377671, D59695,
					AW179220, AW360844, AW360817,
					D81026, AW375406, D80248, AW378534,
					AW179332, AW377672, AW179023,
					AW178905, AA514188, D52291, D80251,
					D80132, AW352170, AW352171, D80522,
					AW377676, AW177731, AW178907,
					AW179019, AW179024, AA514186,
					D80133, AW178906, AW177505,
					AW179020, AW178909, AW177456,
					AW179329, AW178980, AW177733,
					AW378528, AW178908, AW178754,
					AW179018, AW179004, AW178914,
					AW178911, AW367967, AA033512,
					AW352174, D80302, AW178774,
					AW177723, D80439, D80247, T48593,
					AW178983, D51103, AI535850,
					AW367950, C14975, AW178986, D45260,
					A67220, A62300, A62298, D34614,
					D26022, X67155, A25909, A84916,
					D89785, A78862, AR025207, D88547,
					AJ132110, AB012117, Y17188, A85396,
					AR066482, X82626, A85477, A86792,
					X93549, I19525, A44171, AR018138,
					X68127, AF135125, U87250, AF058696,
					AR008278, Y12724, AB028859,
					AR064240, A94995, D88507, AR008443,
					AB033111, I18367, I50126, I50132,
					I50128, I50133, AR066488, A82595,
					AR066490, AR016514, D50010, D13509,
					AR060138, A45456, A26615, AR052274,
					Y09669, AR060385, AB002449,
					AR066487, A43192, Z32749, A43190,
					AR038669, A30438, AR008408, U87247,
					U79457, AB023656, AR060133, X93535,
					and AR008382.
HEMFC61	101	836514	1-701	15-715	AB015226, AB015227, AB015228,
					AL110299, X99273, and U60063.
HDTBR50	102	1174351	1-453	15-467
HACCH94	103	847143	1-1399	15-1413	AI093369, AW292321, AA972431,
					N40174, AA746376, AA130392,
					AA286750, AA287684, R71586, R71568,
					R71587, H03136, H03946, R71567,
					AI471079, H97311, AA365025, AF039686,
					AF118670, AR034800, AF081916,
					AL161458, and AL161458.
HE8TI39	104	1223481	1-2820	15-2834	AI681280, AA251688, W60548, Z45463,
					H86769, F07768, H86760, Z42543,
					R15292, AW339546, H86765, Z44339,
					H86774, H86962, AA091738, R58217,
					F06562, AW377760, and R21166.
HEGAP32	105	1140393	1-512	15-526	AI814253, AW338148, AW192239,
					H72014, and AL137708.
HCWFU66	106	853005	1-392	15-406
HUSYI29	107	853149	1-763	15-777	AA209183, AA811369, AA873372,
					AA304836, AW189673, AA326319,
					T11336, AI459087, H00191, and
					AL120282.
HMEFT66	108	1134131	1-919	15-933	AI269592.
HKAAR71	109	863023	1-963	15-977	AW068487, AW239526, T19084, R73854,
					AA984561, AA190644, R22358, R14385,
					AI968382, AA773650, AA425030,
					AW237628, AJ242972, and AJ242971.
H7TBC95	110	865922	1-692	15-706
HAPPX52	111	637493	1-2368	15-2382	T47026.
HBGSJ13	112	1152326	1-744	15-758	W22401, W22336, and W26219.
HFKLX38	113	880220	1-295	15-309	AL136383.
HTLGP15	114	1165362	1-949	15-963	AW173250, T08271, AI372624,
					AA350545, T10079, AA349847,
					AA351693, and AF060173.
HMEGH46	115	1092158	1-713	15-727	AB033054.
HE8PY29	116	1129488	1-710	15-724	AI271550, AI753504, AA809220,
					AW081079, AI264068, AW386283,
					AI219556, AW082138, AA455733,
					AI382746, AA548778, W78099,
					AA431230, AF092137, AF100751, and
					AF040252.
HTDAB17	117	890384	1-591	15-605	AW410520, Z21669, AA334183,
					AW376427, and AC011078.
HCFCF47	118	1199931	1-1842	15-1856	AL038713, AI264673, AI685116,
					AI887321, AI924175, AA189081,
					AI610776, AI818151, AI367384,
					AW157413, AI925647, AA767353,
					AA778304, AI559442, AI147839,
					AI110720, AL133942, AW089655,
					AI811494, W49501, AW084901,
					AI376984, AA085707, AI110640,
					AI132962, AW177120, AA493998,
					AI862874, N64574, AI675848, AI858607,
					N24958, AA807609, AA902828, AI749571,
					AI568919, AW074001, AI827133,
					AI817158, AI561208, AI250812,
					AI983921, AW177226, AI082077,
					AA130536, AI819528, AW139132,
					AA055654, AI027421, AI801377,
					AA724159, AI610326, AA932087,
					AA846188, AA864823, AW085676,
					W58442, AI453790, AI499286, AA659014,
					AW151307, T16214, AW090210,
					AA581433, AW262471, AI973178,
					AI189033, N26540, N76274, AI984510,
					AA709024, AI733728, AA581340,
					AW177317, AL044349, AW167452,
					AA130476, AA160519, AI811854,
					AI921101, AI369914, AW168798,
					AI479035, AA911409, AI346802,
					AI439860, AI034217, AW193992,
					AA493735, AI927861, AA287329,
					AW440317, AA129986, AI683685,
					AW102963, AA854527, AI246569,
					AW177237, AA346162, AA745961,
					T62931, AA889273, AI872415, W85828,
					AA847621, AA946637, AI197934,
					AW167319, AA907819, AA953572,
					AW272376, AL041411, AI862212,
					AI025602, AA092309, AI334099, C17235,
					AI439415, C06012, AI632138, AW130042,
					H20876, AI937684, AI538654, AA470572,
					AW023397, AI061131, AA811111,
					T69889, AA342331, AI874256, AI564253,
					AI440018, AI095849, AA157033,
					AI051341, AA771730, T57073, AA771711,
					AI926394, AI358417, AA174085,
					AI952804, AI860964, AI499811,
					AA368610, AI591332, AA136576,
					AA633390, W58428, AI619818,
					AA782144, AI291353, AA604138,
					AI393148, AA862481, AI863415,
					AA694579, AA176355, AI917243,
					AA169142, W33199, AA643785, W87732,
					AI285660, AA099788, AI955464,
					AI088796, AA347740, AA350922,
					AA961590, AA166854, AI871616,
					AA779937, AI290861, N77920, AA070814,
					AA508451, AI869945, AI051363, T06932,
					AI271865, C17730, AI813517, AI627862,
					AA132716, AI457328, AW235478,
					N20521, AA460715, H06476, AI336355,
					AA121916, AL119355, AA505616,
					AA598990, AI567544, AA559950,
					AW090739, AI949496, AI362951,
					AW168195, AA041332, N94967,
					AI004961, W31567, AA501873,
					AA629837, W19865, AA328438, W04638,
					AI310239, AI540098, AI375417,
					AW272291, AI086865, AI803229,
					AA876415, AA132536, T06365,
					AL031656, AL033379, AC002564,
					AC007381, AC005484, Z84719,
					AL023513, AL049734, AC007514,
					AC003084, AC004069, AL049867,
					AL049635, AC005181, AB017651,
					AC004050, AC004384, AL031407,
					AB019441, AC002349, AC007630,
					AC004650, AC004748, AC006463,
					AB020872, AC009405, AC003029,
					AL078477, AC006327, AL078638,
					AL135960, AJ131016, AC002385,
					AC003001, AL031054, Z98052, AL050348,
					AC006387, AC006198, AL132800,
					AC002079, AF207955, AP000355,
					AC004677, Z95325, AC007677,
					AC007358, AP000365, AL078604,
					AC005562, AC004875, AP000014,
					AB014082, AL121577, Z95328,
					AC003091, AC004022, AP000532,
					AC006396, Z97181, AC006374,
					AC005901, AC003085, AC000119,
					AL110505, AC006370, AL035542,
					AL009029, AL021940, AC007262,
					AC004891, AC003106, AC002122,
					AC004813, U96409, AL035088,
					AC003109, AL035397, AL035555,
					AC002458, AC005682, AC004053,
					AP000946, AJ007973, AC007671, Z70758,
					AL109759, AL121652, AC007402,
					AC008173, Z94721, AC004869, AP000962,
					AC006026, AC004536, AC002416,
					AL034377, AC007649, AC004664,
					AL080239, AC011198, AL033522,
					AC006296, AL109941, U70984,
					AC004822, AL136297, AC004757,
					AC005670, AL031671, AF130343,
					AC002471, AC002528, AC003013,
					AC005374, AC005993, AF117829,
					AL035633, AL049733, AL136018,
					AP000023, AL122007, AF095725,
					AL022100, AC004388, AL121578,
					AC004911, AL008722, AC004381,
					AC004701, AC007392, AC003100,
					AL023806, AF146191, AL033525, Z98304,
					AL022099, AL031115, AC007971,
					AL096867, Z94056, AC006239,
					AC005191, AC005053, AC004111,
					AD000091, AF121898, AC005799,
					AC007364, AC002485, AC002041,
					AC005521, AF130342, AL132994,
					AC004460, AC004999, AL109611,
					Z92542, AC005791, AC005082,
					AC004047, AL022401, AF152364,
					AL022097, AL121767, AL031313,
					AC006525, AJ251973, AC004987,
					AL031285, AC005820, AC006924,
					AC004749, AC006502, AF129078,
					AC005962, AC006971, AL078644,
					AP000473, AL034406, AP000455,
					AL022394, Z93019, AL021877, AC005297,
					AJ239321, AC006986, AF123462,
					AB023056, AC005922, AC007870,
					AC004223, AC003687, AL034399,
					AC007486, AB020868, AC006382,
					AL109659, AL049544, AL008627,
					AF207550, AF044083, AC005367,
					AC011594, AC004909, AL031684,
					AL031430, AL096772, AL050339,
					AC005681, AF055066, AC004894,
					AL049835, AL031737, AC003992,
					AC010722, AC007012, AC002379,
					AC004910, AC002492, AC006581,
					AL033380, AC007436, AC006369,
					AF070718, AC003692, AC004103,
					AC006504, AC006315, Z82212,
					AL009047, AC005284, AC004073,
					AC000114, AC004506, AL136295,
					AC008014, AL035700, AP000949,
					AC000109, U80017, AC006961,
					AP000033, AC003667, AC005913,
					AC005164, Z93018, AC006344,
					AC007377, and AC004178.
HDQHB19	119	1194798	1-1586	15-1600	AW195239, AW149418, AA461376,
					AW005579, AI392913, AI378013,
					AA461199, AA779830, AI860240,
					AI436586, AA576717, AA147800,
					AI276889, AW337924, AA459985,
					AI264931, AI203549, AW104319,
					AA460078, AI377235, AI291778,
					AI925811, AI094031, AI612894,
					AA147758, AA639492, AA037273,
					R61563, AA463275, AA767986, AI289261,
					AA768536, AW166255, AA832298,
					H59980, N47107, AA157070, AA508841,
					AI360737, AA417605, AA628790,
					AA731955, R35919, AI273576, AI301339,
					AI682196, AA463188, AI208175, H59937,
					D20738, AI391726, W42645, R14353,
					AI271983, N30324, T53535, AI073411,
					H57854, N56657, AW001677, R35723,
					N50317, AA514325, AI242094, AA969269,
					AI808646, AI280324, AA360254,
					AI699261, AA263061, T77863, AA551384,
					AA741518, AA906804, AI091790, T11446,
					AI208678, AA031793, AA505982,
					AA214523, AA428834, T12550, T11445,
					AB026289, and AR044150.
HAGDN53	120	1129154	1-1553	15-1567	AI671311.
HUFDB74	121	1162672	1-1535	15-1549	AW411339, AI978930, AW090612,
					AI521584, C05134, AA025277, AI281896,
					AA190389, R80748, F13061, AA190814,
					T75371, R80747, AA074211, AI570569,
					AA296815, AA024667, F10653, AI370565,
					AW197990, AI254860, AC002117,
					AC002425, AC004671, AC005736,
					AC005899, AC005757, AL034549,
					AC003048, AF001552, AL031591,
					AC007637, AC009363, AC005837,
					AC004813, Z83822, AC005568,
					AC003101, AC005669, AC003010,
					AC004887, AL035684, AC008079,
					AC006312, AL022319, AC002302,
					M19364, AL109758, AL008583,
					AF111168, AC005071, AC004916,
					AC005088, AC002565, AP000252,
					AC005363, AC007685, AL009051,
					AL034417, AC007565, Z82245, Y14768,
					AC005606, L34079, AL022396, AL034423,
					AP000505, AL049871, AL117337,
					AC004104, AL024509, AC006026,
					AC002314, AC002352, AC005295,
					AL080243, AC009288, AC004963,
					AC004876, U63721, AL031737, Z82206,
					AC005666, AL021977, AC002472,
					AC004216, U91321, AP000501,
					AC006040, AC005183, Z98200,
					AL049709, AC007981, AC009464,
					Z97054, and AC005585.
HNHFH24	122	1092567	1-1015	15-1029	AW023111, AI792578, AA570740,
					AA483606, AW069227, AI634187,
					AA515728, AA084609, AA565911,
					AI457313, AA568204, AI187148,
					AA856961, AA644090, AA557136,
					W96522, AI192440, AI440117, AI369580,
					AI610468, AW161016, AI054419,
					AI245693, N34689, AW189113, AI889579,
					AW245860, AA602906, AI583142,
					AI275982, AI494417, AI679294,
					AI755057, AI679871, AA126005,
					AA502207, AI362442, AA653823,
					AI342183, AL037714, AI636734,
					AA622801, AI866970, AI185394,
					AA469282, F28845, AA526099,
					AA714011, AA501461, AA133332,
					AA449997, AA635433, AW274072,
					AA191418, AI434513, R98218, AI925869,
					AA808861, AA279649, AA598892,
					AC004656, AC005736, AL049831,
					AC007371, AC005777, AC007993,
					AC002470, AF124523, AL117694,
					AC004975, AF104455, AL078477,
					AC003043, AL049539, AC005037,
					AF196972, AC005274, AC007542,
					AL109984, D87675, AC007917,
					AC005209, U78027, AC005696, U47924,
					AC005920, AC007298, AC005701,
					AC005500, AL035420, AL035422,
					AC005399, AC008064, AC006006,
					AL034423, AC004491, Z94056,
					AC005523, AC003982, AP000103,
					AP000032, AC007546, AC005972,
					AC005295, AP000555, AL035209,
					AF111169, AC004919, AC002091,
					AC004905, AC006486, AC005324,
					AL133448, AC003108, AC005004,
					AC004659, AC000025, AC004816,
					AC005527, AC005591, AC007690,
					AC004815, AC007327, Z82244, U91322,
					AL021154, AC006961, AC005529,
					AC004551, AC003110, AC005536,
					AC005730, AL031767, AL022313,
					AC006354, AC003681, AC005189,
					AC007386, AL049570, AP000263,
					AC006285, AC005280, AC005599,
					AP000100, AC005277, AL031228,
					AP000210, AP000132, AL022334,
					AC007934, AL121769, AL109801,
					AF196779, AL050343, AP000503,
					AL049776, AC005200, AC005075,
					AL031597, AP000193, AC006312,
					U62293, AC009247, Z93241, AC004983,
					AC005726, AL136295, AL035697,
					AC007731, AP000117, AC005952,
					AL031431, AL109952, Z84466, AC002301,
					Z93023, AC005513, AP000036, AC005409,
					AP000313, AP000050, AC008012,
					AC007437, Z82206, AC007242,
					AL034402, AC004020, AC006487,
					AC005901, AC006480, AL035683,
					AP000141, AC005330, AC004647,
					AF134726, AF031078, AC002316,
					AC007842, AF030876, AC005225,
					AC002476, AC006057, AC005067,
					AC006271, AC004796, AC004813,
					AL022394, AC003029, AL078611,
					AC005251, AC007041, AC007421,
					Z83844, AL034549, AC004383,
					AC003035, AC005180, AC005625,
					AP000228, AP000140, AP000088, U89337,
					AC005231, AC004805, AC004967,
					AC002477, U76667, AC007664,
					AL022476, Z49236, AL035086, AC004526,
					AP000212, AP000134, Z84467, AL033397,
					AL034421, AP000248, AC007773,
					AL109963, AF064857, AF042484,
					AP000497, AC007021, AL035684,
					AL021546, AC006597, AC004025,
					AP000302, AC004859, AC000134,
					AC006449, Z97630, AC003665, Z99714,
					AC004033, AC005095, AC005915,
					AP000558, AC005837, AL117352,
					AC000111, AC007938, AC005300,
					AL022326, AL033527, AL078584,
					AL033521, AL023553, AC005318,
					AC004673, AC004821, U73630,
					AC006255, AP000114, AP000046,
					AC002559, AC007052, AP000694,
					AC005682, AC003046, AC005531,
					AC006211, AL031589, AC005484,
					Z97876, AL050341, Z98036, AL049757,
					AC005245, AC004106, AC006077,
					AC003070, AC005013, AL049643,
					AC005332, AC005058, and AC006035.
HBGQT03	123	1188175	1-1204	15-1218	AW193981, AA576536, AW439879,
					AA218860, AA587394, AW206358,
					AI735027, AI075695, AI749755,
					AW328242, AI073515, AI828816,
					AI283940, AA452508, AI741698, F25077,
					AA454093, AI280249, AI826261,
					AI567379, AA350150, AI251129, F26225,
					AI354257, AW129660, AA171893,
					AI357160, F26293, F36700, H24638,
					AI270014, AI952189, AA834233,
					AI689497, AI688448, F17480, Z38509,
					T11668, N93072, AW362737, T11669,
					AW273866, N93071, AW328241, and
					AF130979.
HETLF29	124	1103959	1-469	15-483	AA960957, AI001155, and AC004664.
HOUGD29	125	1204931	1-2274	15-2288	AW243053, AI674036, AI160750,
					AA426073, AI299702, AI079952,
					AA405859, AI805286, AI828341,
					AW022161, W24408, AI421345,
					AW206919, AA351454, AW118669,
					AI263265, AA640181, AW134737,
					R13311, AW135904, AW008702,
					AA041245, R40791, T16675, AI418741,
					AI572229, AA040806, AI057025, N93105,
					AA954204, AF117948, and AL050031.
HTEMV09	126	1128254	1-1347	15-1361	AI818734, AA454060, AW268879,
					AA453640, AI377304, AI818733,
					AI681535, AI818743, AI741915,
					AA948041, AI198872, AW341578,
					AI267885, AA767746, AI677678,
					AI829855, AI677729, AW129267,
					AA947425, AA297313, AL041049,
					N67346, and AA889773.
HNTNB14	127	1128964	1-713	15-727	F12661, T74243, R60839, AA349498,
					AA082976, and L22557.
HE2KZ07	128	1149808	1-695	15-709	AA114993, AI696123, AI141657,
					AI986390, AI307294, AB004267,
					AF181984, AB023027, and D86556.
HSIGN57	129	1105444	1-1086	15-1100	AW408450, T78839, and AB029015.
HLHBC30	130	1106654	1-770	15-784	AI366170, W21960, AA047627, W22094,
					AA047570, W22769, AA359453,
					AA359449, AA128575, AI220321, and
					W22833.
HFBDJ13	131	1195217	1-1355	15-1369	AI637673, AI982948, M86084, AW161837,
					AA568170, AA044809, AW157364,
					AI686957, AA191323, AI161414,
					AI140787, AI752687, R17699, AA742642,
					and AF030131.
HTPGG25	132	1217208	1-2771	15-2785	AI681123, AI741848, AI636347,
					AI973055, AI554720, AI768326,
					AI871117, AI333117, AI745311,
					AW340966, AW192924, AA706712,
					AI091179, AI677802, AI889659,
					AI688189, AI804323, AI298377,
					AA535027, AI830304, AI139157,
					AW089901, AA018361, AA410579,
					AA416567, AW073842, AW316637,
					AI827376, AA417232, AI372513,
					AA411560, AW001905, AI796719,
					AI400032, AI334363, AI452964,
					AI085075, AI888902, AI400560,
					AA308319, T33187, AI372512, AI332395,
					AA877699, AA485507, AA017127,
					R85136, H94860, T33188, AW016699,
					AA324901, AA988884, R18537, AI925753,
					AA993373, AI263531, W05059,
					AA282629, F29641, AA378627,
					AA625328, H58095, R17859, AA354334,
					AW337874, AI559961, AA282410,
					AA126985, AI014243, AI671403, F07835,
					R01402, AA485352, R41526, Z39066,
					F04091, R43109, W04796, R01401,
					Z42943, AA128150, AW375092, C04525,
					T25085, F17839, N74669, AW371533,
					AW058382, AW371557, AL117482,
					Z61430, AW612722, and AW662030.
HSSMT34	133	911294	1-540	15-554	AA378627, F07835, and AL117482.
HWWDN3	134	1152430	1-1254	15-1268	AI671062, AI023330, AW243448,
					AI990947, AW081367, AW391909,
					AA448391, AI984688, AA448394,
					AI283270, AW014216, AI344135,
					AA127530, AA335984, AA377148,
					Z42084, R12430, and AA400585.
HCEPW85	135	911374	1-302	15-316	N83965, AA326737, and H14153.
HMTAW83	136	1071602	1-487	15-501	AI908321, AA831896, AR058970,
					AR058968, A68194, and AR058969.
HDMAV01	137	1194697	1-1796	15-1810	AA639636, AI631313, AW295120,
					AA182022, AW085587, AI805706,
					AA181842, AA732237, AW275826,
					AI215758, AA482475, AI802881, N50527,
					AI582673, AI581648, AA687232,
					AA742653, AI678872, AI937512,
					AA043083, N95362, AA130860,
					AW303909, N50583, AA186576,
					AW149048, AA743626, AA972227,
					R82179, AA988476, H19646, AA872660,
					AA476734, AA040856, AA074515,
					W93062, AA649136, AA186539,
					AA443881, AW021342, AI039487,
					AA252656, H22712, AW006472,
					AI342673, N72971, AW316519, H01103,
					R82221, AW079113, W02736, H19647,
					H43529, F23483, AI681977, AA989257,
					AA357239, H01104, W21036, AA872966,
					AI908321, N93561, R57677, AA984133,
					AA306556, AI423661, AL120709, D19838,
					AW295339, AW403073, AA100099,
					H38954, AA297943, AA130916,
					AW007473, A68194, AR058970,
					AR058968, and AR058969.
HDPSR74	138	911396	1-709	15-723
HHEZT58	139	1160657	1-2197	15-2211	AI653410, AI808115, AW103846,
					AI954664, AI809351, AL038027,
					AW365646, AA598677, AW118178,
					AA461436, AA461119, AI915224,
					AI452666, AI962619, AA384806,
					AA021033, AA317505, AW179253,
					AA054648, AI949041, R59010, H21414,
					AW450327, AI084523, AA813068,
					AW021195, AI242505, AA768247,
					AL046262, AL138455, AL035847,
					AA714441, AL042853, AI570389,
					AI821062, AA804728, AA760655,
					AA665057, AL042753, AL045943,
					AI493858, AW079656, AI027175,
					AA504562, AL049552, AF162270,
					AC004834, AP000208, AP000130,
					AP000247, AL049557, D83989, AL022315,
					AC009501, AL031281, AL109758,
					AC006313, AC002464, AC005291,
					AC002565, AC004837, AL022313,
					AL031393, AC007172, AC018767,
					AL021393, AL022165, AF222686,
					AC004987, AC005091, AC006112,
					AL110269, AC006115, AC011331,
					AC005156, AC002430, AC005088,
					AC004686, AC007384, AC005902,
					AP000697, AC004883, AC006501,
					AC006039, L30117, AL035458, AL035461,
					AC010206, AL035067, AL034417,
					AC005057, AC002472, AP000009,
					U96629, Z83840, AF053356, AC004383,
					AF091512, AP000344, U67211, U66059,
					AC000004, AC003070, AL096791,
					Z82206, AC005081, AC008067,
					AL034400, and AC007284.
HTLDU05	140	911649	1-589	15-603	AA437044, AF113527, AB023062, and
					AF113520.
HTLET56	141	1189721	1-1390	15-1404	AI968198, AI655275, AL044119,
					AW003563, AA397903, AL044168,
					AL044118, AW016204, AA625705, and
					Z74696.
HTLCA95	142	911655	1-1148	15-1162	AI028227, AI798166, AI968058,
					AI962770, AC012616, and AC012616.
HTEJT86	143	1090517	1-1644	15-1658	AI290635, AI097065, AI811210,
					AI655508, AI655489, AA402182,
					AA373381, AA948283, Z21336, AI984919,
					AI825441, Z21335, and AW467143.
HTEMA54	144	1134919	1-1483	15-1497	AI954673, AI220421, AA813119,
					AA382989, AI024406, AF113526,
					AB023063, and AF113519.
HTLGJ17	145	1135518	1-573	15-587
HOUES64	146	918119	1-304	15-318
HMSCD15	147	982250	1-642	15-656	AA864599, AA828277, AW270419,
					AA761244, AA262754, AA779760,
					W37119, AA206843, Z42584, AA206842,
					and AB011126.
HDQDX20	148	1223474	1-2688	15-2702	AI905612, N63562, N75655, N94726,
					AA297704, N64807, AW265468,
					AA601376, AW162314, AW162332,
					AI318548, AW410844, AL042753,
					AL121039, AI702049, AI547110,
					AI919048, AA845690, AW021674,
					AA280886, AW328185, AI076729,
					AW327673, AL138455, AA526542,
					AL118628, AW148821, AI754926,
					AI344906, AI064968, AW419201,
					AI065031, AI129421, AL041924,
					AI090377, AI252005, AI254463,
					AW409621, AA313025, AA610644,
					AA760655, AI797998, AI821901,
					AA557945, AA595661, AI860423,
					AA831426, AW021399, AA765899,
					AI174827, AI251024, AL042667,
					AL042670, AI003068, AW439224,
					AL042377, AI567676, AL134524,
					AI905408, AI570067, AA527633,
					AW022796, AI025355, AA525753,
					AI133355, AI224583, AI609992, N95424,
					AI281622, AI446618, AI745666,
					AA632355, AI791659, AW085626,
					AI815425, AI819419, AI884404,
					AA828840, AA631915, AI049845,
					AA133568, AI921744, AI114755,
					AL044966, W27084, AA524604,
					AL039436, AA084439, AI279417,
					AW023975, AW239465, AI753131,
					AW275432, AA847341, AW177869,
					AW192930, AW409626, AI049643,
					AW338525, AI828721, AA935827,
					AI857834, AI348780, AI744963, F35374,
					AI434103, AA601712, AL138262,
					AL138431, AW272815, AI445699,
					AI270280, AI888050, AW029626,
					AI150934, AL042731, AI003391,
					AL044701, AI924950, AA535558, H86399,
					AI733523, AW020612, AW069769,
					AA568433, H47461, AA167656,
					AL079698, H62123, AA196994, T03928,
					AI078409, AA015948, AI049892,
					AI815770, AW303052, AA558488,
					AA315052, AF169035, AF085233,
					AL049694, AC006084, AC006581,
					U93163, AC007298, AL022315,
					AC007050, L78810, AF196779, AC005081,
					AL031680, AC004891, AF113676,
					AC004895, AC005921, AC005015,
					AC005701, AC005291, AF207550, Z98941,
					AC006079, Z83844, U95739, AC005553,
					AL031846, AL021391, AC004263,
					AC004808, Z99716, AL008582,
					AC006312, Z93241, AC005519,
					AL121603, AC006115, AL080317,
					AL049538, AC002558, AL121595,
					AC004703, AC007172, AC006441,
					AL022238, AC007227, Z82206,
					AC004702, AP000116, AC007392, Z98752,
					AC005730, AL031311, AL022165,
					AC005039, AL021155, AL035551,
					AC005829, AC007055, AP000555,
					AC007237, AC005484, AF053356,
					AC005365, AC003982, AF038458,
					AL137100, AC004966, Z95152, AL049872,
					AL122020, AL049869, AL049557,
					AC005224, AC004797, AC005971,
					U85195, AC006538, AL078463,
					AC005585, AL031283, AL034549,
					AC007193, AF001549, AE000658,
					AC008372, AC006978, AC005251,
					AC007536, AC005695, Z82184,
					AL022723, AC007384, Z98949, AP000692,
					AL035587, AC006953, AL096701,
					AC005409, AC006013, AC005944,
					AL031433, AC005911, AL096703,
					AC005839, AP000210, AP000132,
					AC003108, AC006039, Z93017, AP000516,
					AC004659, AC006111, AL022721,
					Z77249, AF111168, Z94721, AP000212,
					AP000134, AL050338, AC005527,
					AC007390, AC005216, AF187320,
					AC002036, AC009510, AC005666,
					AC004673, AL021808, AC005225,
					AC004213, AL021453, AL008725,
					AC007242, AL008726, AP001046,
					AC005618, AC007878, AL031575,
					AC002350, AL049699, AL121653,
					AC003013, AC006966, AL031228,
					AL109984, AC002351, AC006509,
					AC005175, AL049569, AC006211,
					AC003037, Z98200, AC004805, AP000201,
					AL031229, AC006196, AC004913,
					AP000248, Z84466, AL022476, AL034379,
					AC005327, AL008712, AC004663,
					AC005017, AL021579, Z95114,
					AC002477, AC007537, U91322,
					AC007676, AC005900, AC002565,
					AP000097, AP000348, AC006277,
					AC011311, AC007546, U07563, L44140,
					AC007684, Z68284, AC003111,
					AC005529, AC005368, U07561,
					AC004000, AC004883, AL022316,
					AC005500, AC005369, Z82976,
					AC006571, AP000505, AC005821,
					AL034369, AC007057, AP000049,
					AL034421, AC007510, AL031594,
					AC005041, AC004821, AP000338,
					AC005071, AC008134, AP000030,
					AP000104, AL035086, AL132712,
					AL096803, AF064862, AC004383,
					D84401, AC003689, AF024533,
					AC002980, Z82211, AC005156,
					AC006539, AC007731, AC000090,
					AP000511, AP000211, AP000133,
					AC002306, AC003029, AD000092,
					AC003043, AC006275, AP000216,
					AC006157, Z84474, Z82208, AC005048,
					AC002133, AC006458, and AC005697.
HLTHP86	149	1110457	1-1837	15-1851	AA663589, H16878, R56761, H84971,
					H16267, Z44040, Z44727, AA363673,
					T95749, H09671, AA809486, R91239,
					N50504, AA834548, N58608, AA872305,
					and AF161420.
HMSOL52	150	1182715	1-1289	15-1303	AI911515, AI360955, AW028045,
					AI796049, AI609712, AW195544,
					AI184337, AI470056, AI361065, N34939,
					AI017177, AI038779, AI440241,
					AI651451, AA789292, AA854683,
					AI765258, AI702748, and AA384884.
HAHGD33	151	1219819	1-2211	15-2225	AA058874, AA778668, AW408302,
					AA205441, AI127967, AI887424,
					AI479839, AI697118, AI313146,
					AI992196, W01185, AI828049, AA196613,
					AA988948, AW410815, AI569584,
					W44348, AI754108, AI858157,
					AW161181, AI809391, AI418172,
					AW378448, AW378426, AI554365,
					AA064738, N41640, AI129499,
					AW080159, AI079282, AI624100, Z43369,
					N29634, AA160313, AI476090, AI748939,
					H40577, W52734, AI828528, AA984486,
					AA723784, W73106, AI811703, AI982708,
					AA610087, H45144, AA975653, D31100,
					AA064739, AA226860, W79308,
					AA976982, AA961166, T35036,
					AA044358, AA969553, AW380268,
					AA961174, AW380277, AA192146,
					AA348984, C21229, R16767, AA348983,
					AI536815, W59987, AI632654, T35774,
					AW292300, T08259, AI368455, AI701960,
					AI969407, AI559435, AI285876,
					AI243806, AA232389, AI476704,
					AW410816, AA588076, AA918087,
					AA989405, AA639598, AA862740,
					AA160321, AI904952, Z39439, H46434,
					R10018, AA227210, N78192, AA977128,
					F35561, R40005, AW050898, H14918,
					AA852243, AA043840, N74228,
					AA719438, W45701, AI879824,
					AA249020, H79060, AA852244, T80752,
					H45445, AA353126, AA320390, R45977,
					AI187729, AW385198, AI364441,
					AI284294, AA862396, T81225, H46980,
					AA642250, R57404, H14625, AA295773,
					W79389, T12193, W52140, T81300,
					R13945, AI918467, T47464, AA043841,
					Z43504, AA404490, AA627362, D45662,
					AA205277, AA196528, C21486, AI739190,
					AI123849, AI205909, AI025702, and
					AF113249.
HHEHC53	152	921783	1-896	15-910	AW408302, AW410815, AW161181,
					AA160313, AA226860, AA044358,
					AI632654, AA232389, Z43369, AA249020,
					T35774, AA852244, AA064738,
					AA295773, D31100, R13945, AA205277,
					T47464, T08259, AI904952, AF113249,
					AC009427, AC009427, and AC009427.
HE2PB01	153	1206665	1-1753	15-1767	AA443164, AW020571, AA532437,
					AA315526, AW118680, AI167234,
					AI890631, AA744921, AI401545,
					AW195349, AW152040, AW074628,
					H06431, R74385, AA862392, H23357,
					AA649701, AW362722, AA160546,
					AI880570, D62917, AA973615, H23246,
					H46816, AI819867, H00507, AA329368,
					R21787, R21742, AA463453, C05953,
					R25958, R26764, AA639080, AI494615,
					AW070869, H71752, T84284, AA767232,
					AA160663, AI824357, and AF161399.
HOUDP52	154	1219522	1-1735	15-1749	AA126458, AI091270, AA535353,
					AW129933, AI653554, AA809485,
					AI638693, AI208921, R73542, AW088345,
					R72907, AW105725, AA483641,
					AI828781, AI350843, AI970412,
					AI971578, AA121009, AI989884,
					AI671096, AI962165, AI632336,
					AI241787, AI580332, AA991236,
					AI587241, AA317304, AI655218,
					AA853441, and AI971684.
HHGAE47	155	1127881	1-733	15-747	AW025529, AI475932, AW026010,
					AA886335, AA662803, AI056120,
					AW050607, AI885090, AI244837,
					AW449834, AI375435, AA878578,
					AA922036, AW197722, AA161103,
					AW058170, AI393408, AI056614,
					AA643750, AI560410, AI749095,
					AI720931, AI446208, AI913781, N52768,
					AI268967, AI277003, AA657904,
					AI914599, AA910277, AA485405,
					AI192693, AW050712, N52783, AI673692,
					AA631339, AA485566, AA158820,
					AI619710, AI560351, AI919380, N57590,
					AI832600, and N57604.
HMCGL45	156	1165349	1-1136	15-1150	AW025529, AW026010, AI475932,
					AA886335, AA662803, AI056120,
					AI885090, AW050607, AI375435,
					AW449834, AI244837, AA878578,
					AI056614, AA922036, AW058170,
					AW197722, AI393408, AA161103,
					AI560410, AA643750, AI749095,
					AI720931, AI446208, AI913781, N52768,
					AA910277, AI277003, AI268967,
					AA657904, AI914599, AI192693,
					AA485405, AI673692, N52783,
					AW050712, AA158820, AA631339,
					AA485566, AI619710, AI560351,
					AI919380, N57590, AI832600, N57604,
					T25136, and AA299927.
HELEF11	157	1153884	1-1324	15-1338
HETJX04	158	1212235	1-844	15-858	AA853282, AA370481, AA625156,
					AB025258, and AB025259.
HSOBC04	159	1165357	1-1194	15-1208	AA115298, AI741325, AI688227,
					AI819333, AA452504, AI742595,
					AI925664, AI174530, AA115338,
					AA563582, AA461615, AA807844,
					N94422, W58424, AA569395, AI095261,
					AI142563, AA687480, AI567500,
					AA479551, AA582573, AA779677,
					N24393, AI280806, AI081428, AI863187,
					AA988617, AA834079, AW302361,
					AI362861, AW273442, AA553678,
					AA150123, AI752480, AI312661, W52661,
					AI298150, AA463418, W72509,
					AA024450, W72139, W79868, AI037968,
					H39596, AI028169, AA477651, W02690,
					AI198327, AI952450, AA926794,
					AI087245, W74236, H98040, AW004736,
					AI870989, AI689546, W76066, AI332748,
					AA150031, AI349417, W80872, H99144,
					AI334346, W52767, AA496878,
					AW166280, R40403, H25985, AI357863,
					R55375, AA363023, AA378409,
					AA595996, AW104147, AI687489,
					AI376184, T32290, AI979074, N26307,
					H97338, N95244, W77880, AI917258,
					W25604, AA024802, AI536791,
					AA577352, AA328156, AA359865,
					AA367475, AA358275, AA461442,
					W80763, T09474, AA987427, AI611160,
					AA888165, AA595303, AI918172,
					W30769, AI201782, W21074, AAI87662,
					AA411955, AA090719, AA411956,
					AA935961, AA451977, AI371307,
					AW074526, N79974, N39751, AI635472,
					AI612934, AA478489, AA102215,
					AI802295, AI750502, AA496836,
					AL133116, and L07063.
HE8PW83	160	1069980	1-1219	15-1233	AA203427, AW024967, AA707382,
					N74230, AA875830, AI051580, AA975082,
					AI650913, AI651056, AA707184, N69106,
					AA938679, N69120, AA704705, AI283739,
					T72088, AW135507, R10286, R10287,
					AA010205, AW296131, AI085405,
					AA333931, AA873194, W01187,
					AF121182, AB002584, D38100, and
					AW611663.
HWLEA48	161	927676	1-415	15-429	AA130828, AF169034, Z98752, and
					AF169033.
HNHNP81	162	1129143	1-1036	15-1050	AW366296, D80045, AW375405, D51060,
					C14014, D58283, AA305409, D80253,
					D80024, D80166, D59619, D80210,
					D80240, D80366, AA514186, C14389,
					D80043, D81030, D80133, D80247,
					D59859, D80212, D51799, D80164,
					D80219, D51423, D80022, D80391,
					D59787, D80195, D80188, D80248,
					C14331, D59502, D59467, D57483,
					D59275, D59610, D80227, D81026,
					D50995, D80196, T48593, D80439,
					D80251, D80269, D59889, D51022,
					AI905856, D50979, D80268, D80522,
					C15076, D59927, AA305578, D80038,
					D80193, D80241, AA514188, AW375406,
					AW360811, D80378, AW177440, D80302,
					C05695, C14429, AW178893, AW377671,
					D80157, T03269, C75259, AW178906,
					AW179328, AW360844, AW360817,
					D59373, D51103, AW378534, AW179332,
					AW377672, AW179023, AW178905,
					D51759, AW360841, AW378532,
					AW177731, AW177501, AW177511,
					D58253, AW352171, AW377676,
					AW352170, AW178907, AW378528,
					AW178762, AW179019, D80132,
					AW179024, D80134, D51250, AW176467,
					AW178983, AW177505, D59653,
					AW179020, AW178775, AW178909,
					AW177456, AW179329, AW178980,
					AW178914, AW177733, AW178908,
					AW178754, AW179018, C06015,
					AW367967, AW352158, AW369651,
					AW352117, AW178774, AW352120,
					D45260, AW179004, D80949, AW179012,
					D81111, AW378525, D59695, AW352163,
					D52291, AW360834, D59627, D51079,
					AW378543, D80064, AW177728, H67854,
					D80168, AW179009, AI525923, C14298,
					AW352174, D80258, AW367950,
					AW178911, AW177722, AI910186,
					AW378540, C03092, H67866, C14227,
					AA809122, D51221, D59503, AW178781,
					D58246, T11417, D58101, AW177508,
					F13647, AI525917, C14407, AW178986,
					T03116, D80228, AI535686, Z21582,
					C14077, AW177497, D59317, D80014,
					D59474, AW177734, AI525920,
					AW177723, C14973, AI535850, C14344,
					AW378533, AA514184, D51213, D59551,
					D45273, C14957, AI525215, D60010,
					AI525235, D60214, AI525227, C14046,
					AI557774, AI525912, AI525925, D51097,
					AI525242, T03048, AA285331,
					AW378542, AI557751, AI525222,
					AW378539, Z30160, C16955, C05763,
					Z33452, T02974, D51053, AW360855,
					H67858, AI525237, C04682, T02868,
					C13958, A62298, A62300, AB028859,
					A82595, AR018138, A94995, AJ132110,
					A84916, AR008278, Y17188, AF058696,
					AR016514, AR060385, Y17187,
					AB002449, A43190, X67155, D26022,
					Y12724, A25909, D89785, AR038669,
					A67220, A78862, D34614, AR008443,
					A30438, I50126, I50132, I50128, I50133,
					D88547, AR066488, AR060138, A45456,
					A26615, AR052274, X82626, Y09669,
					A43192, AR066487, I14842, AR025207,
					AR054175, D50010, AR066490,
					AR008277, AR008281, A63261, I18367,
					AR008408, AR062872, A70867,
					AR016691, AR016690, U46128, D13509,
					AR060133, AB012117, A64136, A68321,
					I79511, X68127, U79457, AF123263,
					AR032065, Z82022, A63887, and
					AR008382.
HFIDL68	163	1123641	1-1148	15-1162	AI805323, AI375172, AL119457,
					AL119399, AL119511, AL119324,
					AL134524, AL042544, AL043152, Z99396,
					AL042382, AL043168, AI431323,
					AI582910, AL038837, AL079794,
					AL037051, AL036725, AL037081,
					AL046052, AA631969, AL039074,
					AW151132, AL036418, AL042866,
					AW058275, AL045413, AI282249,
					AL119443, AL039085, AL039564,
					AL039456, AA580663, AL036858,
					AL039156, AW151974, AI927233,
					AL039108, AL038509, AI539771,
					AI432644, AI537677, AI494201,
					AL039109, AI804505, AI500659,
					AI815239, AL039128, AI446536,
					AI866465, AI815232, AI866691,
					AI801325, AI500523, AI538850,
					AW392670, AI358271, AI887775,
					AI582932, AI923989, AI590043,
					AI872423, AI284517, AI500706,
					AI635082, AI445237, AI491776,
					AW151138, AI289791, AI926593,
					AI889189, AI521560, AI500662,
					AI285417, AI582912, AI284509,
					AI539800, AW172723, AI440263,
					AI538885, AI889168, AI866573,
					AI633493, AI434256, AI866469,
					AI805769, AI434242, AI888661,
					AI500714, AI284513, AI888118,
					AI285439, AI859991, AI436429,
					AI889147, AI355779, AI623736,
					AI581033, AI371228, AI932794,
					AI491710, AI440252, AI431307,
					AI440238, AW089844, AI567971,
					AI866786, AI860003, AI610557,
					AI431316, AI242736, AI539260,
					AI828574, AI698391, AI887499,
					AW151979, AI539781, AI702065,
					AI539707, AI801286, AI885949,
					AI638644, AW089557, AI285419,
					AI559957, AI521571, AI469775,
					AI866581, AW074057, AI567953,
					AI815150, AI446495, AI867068,
					AI952433, AI889191, AI225248,
					AI698352, AI371229, AL036924,
					AW151136, AI440260, AI584130,
					AI355126, AI440236, AA761608,
					AL036241, AW189301, AI623302,
					AI866458, AI431238, AI469784,
					AW194509, AI370623, AL079741,
					AL042365, AI345688, AI436438,
					AI890907, AI357672, AI623941,
					AI554821, AI561170, AI586931,
					AI859644, AI924051, AI690946,
					AI371251, AI869377, AI866510,
					AI648567, AL119791, AL047849,
					AI866461, AI923046, AI433157,
					AI457113, AI434240, AI632036,
					AL047422, AI954200, AA641818,
					AI345010, AL048403, AW023072,
					AI610714, F36033, AL037094, AI250282,
					AL047398, AI648699, AI610616,
					AI887163, AW384394, AI049850,
					AI469764, AI284516, AL045166,
					AW019988, AI354981, AL039659,
					AI798359, AL038531, AI653829,
					AW074651, AI383510, AW238753,
					AI469754, AW075382, AW083572,
					AI371243, AI419455, AI537925,
					AW151970, AI049859, N25033,
					AL036196, AL119863, AW162194,
					AI560954, AL135012, AI439995,
					AI887785, AL039390, AI493559,
					AI963849, AI955221, AI566386,
					AI559976, AI250353, AI274759,
					AI432666, AL049048, T66952, N29277,
					AW245729, AI866419, AI433976,
					AW363220, AL038986, AL047611,
					AI349256, AI798456, AR060234,
					AR066494, AR023813, U77594, A81671,
					AR064707, AR069079, S75997, L10353,
					Y11587, AL133084, AF115410, AL133559,
					S82852, M85164, U72621, U30290,
					AL137479, AC002464, AF090943,
					AL133070, AJ005690, AF176651,
					AJ238278, AL137529, AF132676,
					AF061836, I09499, U83172, AR029490,
					AL133016, X70685, E12580, AL137533,
					AL122101, AL133049, AL049423,
					AB007812, AF180525, Z35309, AF013214,
					AF079763, AL023657, AR038854,
					AL133640, AL133655, AF090900,
					AF043642, AL110199, AF113694,
					AL122104, AL133053, AF060866, I25049,
					A03736, AL049276, AR020905,
					AF161699, AF067728, E04233, AL137554,
					AF146568, E13998, AL137521, M79462,
					AL133560, AF119336, I28326, D44497,
					Y09972, A07647, AL049466, A08910,
					AL110218, S54890, X61970, AF002985,
					A08909, U49434, AR034821, AL080129,
					U49908, A60092, A60094, AF031572,
					AF077051, A08908, X66862, AL110196,
					A77033, A77035, AF113699, X63162,
					AF068615, U51123, AF177401, S69407,
					AL117435, AL137268, AF098162,
					AL137550, AL049447, AL136884,
					AF113677, AB028451, AL133557,
					AL133015, AL133608, S53987, I32738,
					A18777, AF076633, AF067790, M19658,
					Y16645, AL080159, AL050172, AF106697,
					S77771, AR068466, AL133619, E02221,
					Z97214, AL080118, E05822, AL117587,
					E12579, A08913, AF080622, I89947,
					AL117443, AL110269, AF182215,
					AR068751, AL122049, Y10823,
					AF131821, AF112208, X67813, AC004213,
					AF026816, A08907, U76419, Z13966,
					A08912, AF090903, I25048, AL110280,
					M80340, D83032, A08911, AC004200,
					E12747, AB016226, AL133067, I48978,
					Y11254, AL122050, AL117460, AF061795,
					A58545, AF151685, I03321, AL137292,
					AF032666, AF090896, AF047716, I89931,
					AF113690, AL117438, I42402, Y10080,
					Z82022, AL117582, AF100931, AL137281,
					AL133062, AJ010277, AF016271,
					AF004162, U78525, AL050155, AL096751,
					S76508, AF061573, AB026128, X83508,
					U72620, I89934, I89944, I49625, A32826,
					A32827, X60769, AF148129, AL137560,
					AF026030, AF111849, AL117394,
					AF030513, AF002672, AL137555, X65873,
					AF104032, A18788, AF106945, E02914,
					AF175903, AC018767, AL137478,
					A49139, AL137459, AF094480, AF126488,
					AF124728, AL080140, AL136842, U73682,
					Y08616, AL096728, A27171, AL137259,
					AL133565, E01614, E13364, X06146,
					AF102578, M92439, L24896, Y13350,
					AF118090, AL137271, AF111851, L13297,
					U86379, and X59812.
HUJCT05	164	1165261	1-1632	15-1646	AW268357, AI889091, C15588, AI949350,
					AI056961, AI124874, R39133, AA887911,
					AW023386, AC003962, and AF155116.
HTEGO05	165	932583	1-1086	15-1100	AA059465, AA059211, AA731209,
					AA236961, T86500, T87461, AL024498,
					and M35862.
HRDBH58	166	1226719	1-2731	15-2745	AI863355, AI863364, AI674922,
					AI754389, AI056058, AW295190,
					AI623178, AW131720, AI949042,
					AI056059, AA356949, AI668970,
					AA620354, C14389, C15076, D59467,
					D80164, D59787, D81026, C14331,
					D51423, D81030, D80195, D80391,
					D80166, C14429, D59275, D58283,
					D59859, D59927, D80196, D80022,
					D80253, D59889, D59619, D80210,
					D51799, D80240, D80043, D80227,
					D59502, D59610, D50995, D80212,
					D80038, D80188, D80219, D57483,
					D80366, D80269, D80193, D51022,
					D50979, AW177440, D80251, D80241,
					AW378532, AI557751, AA305409,
					D80024, D80378, D80045, T03269,
					AW178893, AA305578, D80522, D51060,
					C75259, AW179328, D80248, C14014,
					AW352158, T11417, D51250, AA514188,
					D80134, C14407, AW369651, AW178762,
					AW178775, AW177501, AW177511,
					AW176467, AW360811, AA514186,
					D80133, D58253, D80268, F13647,
					AW352117, AW377671, AW375405,
					C05695, AW378540, AI910186,
					AW366296, AW360844, AW360817,
					AW377676, AW375406, AW378534,
					AW179332, AW377672, AW179023,
					AW178905, D80439, AW352170,
					AI905856, D80302, AW177505, D80132,
					AW352171, AW178906, AW177731,
					AW178907, AW179019, AW179024,
					D80247, AW360841, AW179020, C06015,
					D51213, AW178909, AW177456,
					AW179329, AW178980, AW177733,
					AW378528, AW178908, AW178754,
					AW179018, AW360834, C14227, Z21582,
					AA809122, AW179004, AW179012,
					D80014, AW352174, AW178914,
					AW378525, D81111, D51759, D51097,
					T02974, D51103, AW177722, AW177728,
					D80157, AW179009, D80258, AW178774,
					AW178911, AW378543, AA285331,
					AW352163, AW367967, AW178983,
					AW352120, AI557774, AW178781,
					T48593, D59627, D58246, AW177723,
					D59503, D59653, D45260, D58101,
					C03092, D80168, AW367950, AW177508,
					C14344, AI535850, H67854, AW378533,
					D80949, H67866, C14975, AW178986,
					D80064, C14973, AW177497, AI525923,
					AI535686, AW177734, AI525917, D51079,
					T03116, D59317, D51221, AA514184,
					AI525227, D59474, AI535959, AI525920,
					D60010, AI535961, AW378539, D45273,
					D59551, C14046, D60214, AI525235,
					AW378542, AI525242, AI525912,
					AI525925, AI525215, C16955, A84916,
					A62298, AR018138, Y17188, A62300,
					AJ132110, A25909, X67155, AF058696,
					D26022, AR008278, A67220, D89785,
					A78862, D34614, AB028859, X82626,
					D88547, Y12724, A82595, I82448,
					AR025207, X68127, AR008277,
					AR008281, A30438, A94995, AR060385,
					AR008443, AB002449, AB012117, I50126,
					I50132, I50128, I50133, A85396,
					AR066482, A44171, AR066488,
					AR016514, A85477, AR060138, A45456,
					I19525, A86792, Y17187, X93549,
					A26615, AR052274, Y09669, U79457,
					A43192, A43190, AR038669, U87250,
					AR066487, X64588, AR066490, D88507,
					AR054175, D50010, I14842, I18367,
					AF135125, A63261, U46128, AR016691,
					AR016690, AR008408, AR062872,
					A70867, D13509, A64136, A68321,
					AR060133, I79511, AB023656, AF123263,
					AB033111, AR032065, X93535,
					AR008382, AA159456, and AI990060.
HSDGW22	167	934467	1-312	15-326	AF071071, AF170303, AF170304,
					AF077658, and AF071070.
HNTMD79	168	1126594	1-649	15-663	AA305176.
HCE5J51	169	1197900	1-2796	15-2810	AA622725, AI022884, AI003586,
					AI420804, AI682458, H19352, AI808077,
					AA324320, AA855153, W19561,
					AA325225, AA324316, AA853261,
					H18913, H11459, AW014428, AI148776,
					AI659608, AI675556, AW006008, T26639,
					AA853262, and U71294.
HHEFQ42	170	1151482	1-1261	15-1275	N21687, AA447158, W42824, AA046565,
					AI693814, AI092205, AW377670,
					AA443786, AI160460, AI808004,
					AA160291, N34495, R70372, AW008266,
					AA393368, AA769319, AA977890,
					AI332771, AA089858, AA367462,
					AI806021, AA160290, AA164499,
					AA357550, AA909368, AI337806,
					W42734, N31093, AA521439, AA600712,
					AI587601, AI491781, AA047086,
					AA933922, AA078980, N49165, AI623941,
					AW163834, AW020328, AL036705,
					AW151974, AI249946, AI588892,
					AL138406, AW021717, AI648494,
					AW051088, AI345131, AI619820,
					AI500061, AI434731, AA641818,
					AI524654, AI860027, AW020046,
					AL120307, AL038505, AW087987,
					AI919500, AI334893, AW020397,
					AI401697, AA834534, AI538850,
					AI698391, AI659043, AL036901,
					AI440238, AI890907, AW075382,
					AI799313, AI866465, AI696340,
					AW151132, AW083111, AI590043,
					AI627714, AL134840, AW195253,
					AI473536, AI499325, AL138399,
					AL047100, AI884318, AI619525,
					AI249389, AI244249, AL048323,
					AI590755, AW161098, AW129117,
					AL048340, R36271, AI635634, AA765029,
					AA229532, AI491852, AI859991,
					AI690813, AL039730, AA503384,
					AW196720, AI373276, AI741158,
					AI289791, AI699823, AI345745,
					AI431323, AI538764, AI538885,
					AI301710, AA857847, AI244343,
					AI287233, AI241678, AW132034,
					AI277325, AA977968, AA808175,
					AA575874, AI559752, AA001397,
					AL037602, AL045413, AI499986,
					AI923989, AL118781, AL037582,
					AI310575, AI863665, AW188525,
					AI310582, AW020419, AW161579,
					AI879377, AI285439, AI472487,
					AW022093, AW020095, AA648480,
					AI340533, AW170787, AA669025,
					AI685005, AI343325, AL041587,
					AI872104, AI419826, AI345010,
					AI955441, AI581033, AA928539,
					AA127565, AI567971, AI953562, T69241,
					AI784214, AI553645, N33175, AI470717,
					AI499570, AI872423, AI370623,
					AL037454, AI538692, N99092, AL121014,
					AW191844, R32821, AI621341, AI633125,
					AA848053, AW022602, AI287476,
					AI718513, AI538564, AI350489,
					AA502794, AW021464, AI796113,
					AI915291, AA580663, AW152182,
					AL118752, W45039, AL047344,
					AW162189, AI355779, AI312210,
					AI582932, AI688848, AI620864,
					AI634736, AI524179, AI583578,
					AI889189, AI521560, W46378,
					AW089844, N75779, AI539800,
					AW082607, AI800473, AW104141,
					AI309306, AW029457, AI927233,
					AA761557, AA939199, AI805603,
					AI858827, AA470523, AI479292,
					AL043981, AI866469, AA830406,
					AW263569, AI801325, AI500523,
					AI886355, AR000496, U39656, X65873,
					AF126372, AF069506, A65965, A65943,
					AF201468, AF141289, A49139, AJ005690,
					AL136884, X06146, A17115, A18079,
					AR013797, Y16645, AF126247, A77033,
					A77035, AF177401, AL137479,
					AR038854, AL096744, AL110269,
					X66871, AL122106, AL133113,
					AL137627, AF087943, I32738, AR068466,
					A58524, A58523, AF113690, S77771,
					AL137533, AL050277, U02475,
					AL133557, Y07905, I48978, AL080159,
					E12580, A08913, M85165, AF039138,
					AF039137, A08907, E05822, X70685,
					AJ238278, A08912, AL117457, AF125948,
					A08910, A08911, A08909, AL110158,
					AL049276, A08908, AF145233, U70981,
					AL110196, E12579, AL137459, X01775,
					AF151109, S76508, D16301, A48221,
					X76228, AB028451, AF031147, AF061981,
					AL050155, AL080148, E06743, Z97214,
					A48220, I89947, AL122110, X56039,
					AR068753, X59812, AF090903, AF140224,
					D83032, A15345, A23327, AF090934,
					AF067728, AL122100, AL137275,
					AL137488, AL080129, U91329,
					AL133665, A18777, I89931, A08456,
					AF031903, AF017437, AL137478, A76335,
					AL137271, U58996, I52013, AF079763,
					AL117460, AL137529, L04504, AL080074,
					U88966, I08319, I89934, I89944, L24896,
					I49625, AL049465, AL122104, I33392,
					AL137258, U55017, X67688, M27260,
					AL050149, U62807, I18358, I34395,
					AF047443, U42766, E08516, AL049447,
					X97332, AF091084, AF097996, AL117438,
					E02349, AL133081, AF200464, AF183393,
					A91160, I66342, S82852, AF004162,
					AL117435, A91162, M79462, A65341,
					AL137530, AL050172, L13297, AF017152,
					M96857, AL133075, AL023657,
					AL080126, AF061573, AF106862,
					AB026128, AL110280, I68732, AF035161,
					AL133560, AF026816, I79595, AF002985,
					Y13653, S63521, A65340, AL050024,
					AL122050, AL133640, X72624, I36502,
					AF061795, AF151685, AJ010277,
					AL137294, AF139373, AL137267, A18788,
					X57961, AF047716, X72387, AL080118,
					E02152, S61953, AL117648, AF113694,
					S78453, AL049300, A86558, AL137298,
					X83544, AF107847, Z82022, M85164,
					X84990, AL137554, AB007812,
					AF090886, AL050116, AL133016, U37359,
					AL137256, AL117440, AL137722,
					AF112208, AF081571, AL122093,
					AL110222, AF182215, AF061943,
					AF000167, AL080060, AL049339, S36676,
					AL049430, AF131821, I46765, AF111849,
					AL117649, U83172, X99717, AF158248,
					AL122118, AF180525, AF030513, A12297,
					AL137254, AL137521, A23630, AF113013,
					AL137537, AF111112, AR020905, and
					A57389.
HLQDC55	171	1082368	1-691	15-705
HFPHI62	172	1195825	1-3146	15-3160	AA988953, N63548, AA663569, H38453,
					H15532, H41422, AA976078, N94873,
					H46380, N51089, R88023, H41541,
					H48172, H38492, R18083, AI423964,
					AI003013, H11023, AI421373, R90757,
					R88479, H85702, R40487, AI208504,
					R42977, R87980, AA338374, AW207073,
					H15589, AA319224, AA325807, H84794,
					H10745, AA338373, W28283, R13057,
					AA325143, N54215, AB023202, D13613,
					AC004551, D29965, U12571, and
					AC004465.
HE8QH09	173	1152238	1-1439	15-1453	AW451023, F08666, Z41650, AA594745,
					D45858, D28512, and AB000893.
HFAAX29	174	1128791	1-842	15-856	AL119825, AW367632, AA333024,
					AA164770, N53725, AA984472, N44616,
					AF000423, AB026808, and D38522.
HHFOC79	175	1182276	1-2091	15-2105	W37105, W72587, AI417917, N40695,
					N40709, AI750977, AA399093, AA528204,
					AI160861, AI167229, W56631, AA845109,
					AA450162, AA740816, AA708621,
					AA034924, AI610231, AI926222,
					AA600107, AA034932, AI569931,
					W79446, AA450099, AA405199, H99848,
					AI148368, AI755034, H13127, H21360,
					H45102, AI144154, AI022674, R48598,
					N24731, AI750978, H40009, N27945,
					R48134, H44414, M79188, R73380,
					H45412, AA375133, W56545, AI868381,
					H21461, AW015358, AA995764, H14443,
					H28019, R48457, H26214, W15232,
					AA405198, AA852302, AI865401, R11082,
					N27934, AA045985, W76150, R48700,
					H27127, AI082451, N28528, R48133,
					AA046015, AA358230, C17362, H27122,
					AA404366, AA699711, W37806, T30018,
					AA398203, R32099, AI870723, AA483606,
					AA570740, AA568204, AA502532,
					AW057716, AA491767, AA584756,
					AW089016, F11718, AA572813,
					AI755214, AI754567, AI815665,
					AA089756, AW163795, AI915081,
					AI754105, AW022934, AA447247,
					AI249688, AA832145, AI280266,
					AA604904, AI270476, AI080732,
					AA630854, AI432298, H27788, AA772906,
					AI380617, AA846046, AI038304,
					AI679221, AI141130, AW131356,
					AL079734, F16848, AL079894, AI431513,
					F35097, AA491955, AW188742,
					AW192599, AI569100, AW407632,
					AW194077, AI859438, AW157005,
					AI538491, AI623563, AL121657,
					AC007011, AC004655, AL049780,
					AC005015, AC004912, Z97055,
					AL009181, AL034429, Z98949, AC006538,
					AL023575, AL034420, AC007690,
					AC005081, AC002425, AC006449,
					AC004876, AC004797, AC005409,
					AC004491, AC004000, AC005231,
					AL049743, Z99755, U52112, AB023054,
					AC004929, AL035088, AL022727,
					AC006040, AC005578, Z93930,
					AL121754, AC004812, AP000014,
					AC005399, AL049636, AC007193,
					AC006530, AC008072, AC004084,
					AC005197, AL034549, AC005747,
					AC006441, AC004408, AL020997,
					AC003684, AF165926, AC005007,
					AC006211, AC005701, AL031273,
					AC004531, AC004216, L78810,
					AC005695, Z73417, Z82195, AC007637,
					AL049759, AL034417, AC004263,
					AL133445, AC005971, AC000353,
					AF200465, U91321, AL035420,
					AC005102, AC002300, U91318,
					AL096775, AL033524, AC005514, Z83822,
					AC002477, AL133216, AL032821,
					AF207550, Z82203, AL022333, AC005722,
					AL009172, AF109907, AC005940,
					AC005071, AC008044, AC003663,
					AC005920, AC007151, AC005752,
					AC006115, AL133448, AF088219,
					AC002070, AC005666, AP000511,
					AC004895, AC004675, AL050307,
					AL122020, AC003042, AC005815,
					AC006487, AJ003147, AC006965, Z77249,
					AL008718, AL022330, AC004770,
					AC007388, AC004967, AL035457,
					AC005280, AF111168, AC004914,
					AC006241, AP000501, AC003049,
					AC007792, AC004638, AC007263,
					AC005523, AC006946, AC007461,
					AC003009, AB003151, AC000115,
					AL034548, Z99716, AL078477, AC002351,
					AC002301, AL109627, AP000098,
					AC012085, U95739, AC005803,
					AL031291, AC003070, AC002492,
					AC004962, AC002378, AC005366,
					AC008372, AC005808, AC004051,
					U91323, AP000517, AP000697, AC004032,
					AC007225, AC007686, AC005486,
					AL031778, AC005620, AC004938,
					AC005921, AL132712, AC005829,
					AC005740, AC004659, AC005837,
					AC003010, AC005291, AL049539,
					AC004231, AC007298, AC006536,
					AC007425, AL022318, AC002470,
					AC003104, AC004910, AL109865,
					AL049761, AC005207, AL031681, Z98200,
					AL121748, AC005878, AC006120,
					U82668, AC004835, AC007055,
					AC004913, AL008725, AC005476,
					AC007344, AC004020, AL132777,
					AL021977, AC005017, AC002504,
					AC002310, AC005088, AC004844,
					Z85996, AL031680, AC005943, AL133371,
					AC005288, Z98051, AC002347,
					AC006974, AC004745, AC006065,
					Z98941, AL023877, AP000103, AF064858,
					AF015416, Z68869, AL022315, AC007688,
					AC004383, AC007376, AL109628,
					AL031602, AL049814, AF111167,
					AF001549, AP000474, AC002375,
					AL022323, AP000961, U95090,
					AC012384, L44140, AF196972, and
					AL109984.
HOGEQ43	176	1223485	1-3732	15-3746	AW001408, AW025576, AI167306,
					AW183595, AW206547, AA421304,
					AI884557, N53420, AI961482, AI366803,
					AI471722, AI277353, AI208800,
					AI285232, AI923048, AI002657,
					AA905774, AW444453, AW072850,
					AI002663, AA917870, AI420232, Z40060,
					AA995040, Z44009, AA743874, T91698,
					T91710, AA421383, T77085, AI536628,
					AA768502, T92932, F07259, AA465719,
					F13268, AW197122, AI222859, T92460,
					T93049, R13318, AW385033, T92477,
					AI078087, T89796, AA780031, AI680633,
					T89430, AI572783, F03531, AA747975,
					AA465126, AA361777, R57124, AI417757,
					AA808475, AI805839, AA324494, N94713,
					AW384784, AA838146, AA971578,
					AI422164, AA835936, AB033082,
					AF001630, AF038189, AF132479,
					AF132480, and U61167.
HCECQ23	177	938398	1-796	15-810	AI480182, AI500178, AI873131,
					AA322958, AA322718, AI936088, R85125,
					R90888, H05353, AA338672, H51247,
					R35934, AW139057, H05303, R49451,
					R42549, H29245, AI654790, AI638508,
					R51648, AW149807, R44423, AI458144,
					AI419465, F02105, AI499775, Z40525,
					F09051, R85080, H51217, AI569283,
					D29763, D64009, and D64010.
HTGAU79	178	1178621	1-1081	15-1095	AA579641, AI149891, AI028588,
					AA659710, AI889233, AA461487,
					AA460132, AA682750, AA113277,
					AI753378, AA985248, AI421205,
					AI914588, AI493749, AA633392,
					AA936668, AA722409, AI424537,
					AA233726, AW268600, AA516077,
					AA483490, AW082930, AA074311,
					AI752615, AI989665, AA046575, T87841,
					AI087102, and AL031055.
HE9FI33	179	1156432	1-1550	15-1564	AA010320, AA010384, and R01100.
HNHCP79	180	565781	1-288	15-302
HTLIY52	181	1194806	1-1338	15-1352	AI827749, AI580407, AI819667,
					AI025487, AI223109, AI150036,
					AI024234, AW087713, T18864, AI479322,
					AA883975, AW341589, AA860213,
					AI831802, AA913074, AA608857,
					AI050685, AA860223, AA948538, and
					AI075930.
HRAED74	182	942527	1-691	15-705	AC005940, L42810, S83194, AF117384,
					and AB023658.
HFKKN77	183	943757	1-719	15-733
HTEMU66	184	1205381	1-1077	15-1091	AL039924, AL045794, AW013814,
					AL036630, T02921, AL044412, AL044364,
					T24119, T24112, AW450335, AL039476,
					D51250, AL039521, AL045341,
					AL039386, D80043, AL040992,
					AL039109, AL038531, AL037726,
					AL039629, AL039659, AL039625,
					AL039648, AL038837, AL039074,
					AL039566, AL039678, AL039108,
					AL039538, AL039564, AL039509,
					D80253, AL039156, H00069, AL039128,
					AL044407, AL036973, AL042909,
					AL045337, AL037051, AL045353,
					AL039423, D59787, AL039410,
					AL039150, AL038025, AL044530,
					AL039459, AL038821, D80219,
					AL036725, AI535983, AL043422,
					AL043445, D59275, AL043586,
					AL043423, D80240, AL043441,
					AL036650, T23947, D80210, D51423,
					AL036196, D80134, AL037639,
					AW451070, D59619, D80391, D80227,
					AL037615, D80193, AL036767, AI535783,
					D80196, AL039085, AL036117,
					AL042334, AW452756, R47228,
					AL037526, D80366, D59927, AL036238,
					AL036679, AL039504, AL037601,
					AL039842, AL036964, AL036733,
					AL037027, AL036158, AL036924, C14014,
					AL037054, D50995, AL036765, D80045,
					C75259, T23658, AL044413, T23659,
					AL037177, AL036998, AL038851,
					AW293068, AL036227, AL036418,
					AL037047, D59889, AL037643, C15076,
					D81026, AL036133, AL036163, C14227,
					C14389, D50979, AL037082, AL036167,
					AL037124, AL037679, AL036207,
					AL036132, AL037049, AL036191,
					AL037021, D80022, AL037600,
					AL036190, T11417, D59467, AL036139,
					D81030, D80038, T23656, AL036152,
					D58283, D80195, C14429, F13647,
					D80188, AL036900, D52291, T48598,
					T03269, D51799, D80168, D80522,
					AI557751, AL048425, D80378,
					AW451416, AL037178, AL043613,
					C14298, AL039555, D59502, AA514190,
					AL043585, D80164, D80166, D59859,
					D80212, AL037085, Z25782, Z21582,
					D80269, C14331, D59695, D80024,
					D57483, AA285331, AL036953, D59610,
					AL036808, AW450376, D80064, D58253,
					D80241, AL036174, AL037569,
					AL044178, D80949, AL036150, Z99396,
					D80268, D51060, AA305409, AW178893,
					D81111, D51079, H00072, D59627,
					AL036268, AL038043, N47620, D80251,
					D51022, AW177440, C14407, AW179328,
					AI910186, AW178775, AL044447,
					AW378532, AA305578, AW352158,
					D80248, AW377671, AI905856,
					AW369651, D51097, AW178762,
					AA514188, AL043840, AW177501,
					AW177511, D50981, AL037002,
					AW360834, AL037077, AA514186,
					D80133, AL039417, AW360811, C05695,
					AW352117, Z25783, AW135155,
					AW176467, AW375405, AW378540,
					AA809122, AW366296, AW360844,
					AW360817, AW375406, D80132, A85396,
					A25909, A85477, A44171, A86792,
					X68127, AR062871, A84772, A84776,
					A84773, A84775, A84774, AR037157,
					AR017907, AR062872, AR062873,
					AR067731, AR067732, A58522, A91750,
					A20702, A43189, A43188, A20700,
					AR036905, A10361, AR038762, A98767,
					A93963, A93964, A95052, A38214,
					I03343, AR043602, AR043603, AR043601,
					A95117, A95051, A18053, AR022240,
					A18050, AR054109, A23334, A75888,
					I70384, I56772, I95540, AR018924,
					A63067, A51047, A63064, AR031374,
					AR018923, A60111, A48774, A23633,
					A63072, AR007512, A49700, A48775,
					A23998, AR068507, AR068506, A81878,
					AR015960, I60241, I60242, AR000007,
					AR015961, A58521, I63120, A24783,
					A24782, AR020969, E12615, AR035193,
					A92133, E14304, A27396, AR027100,
					I28266, A49045, E16678, A82653, E16636,
					AR031375, A93016, A58524, A58523,
					I25027, I26929, E13740, I44515, I26928,
					I26930, I26927, A58525, I06859,
					AR000006, I49890, I44516, A58526,
					A91753, AJ244003, AR025207, I18371,
					E06034, AF156296, A13038, A29289,
					AR029417, AF156294, AR067733,
					AR029418, AR067734, AR028669,
					AR028668, AR028667, AR028670,
					AR017908, A68112, A68104, A98467,
					I62368, AR031488, I13521, I52048,
					I44531, A84746, A17115, AR028672,
					A18079, AR038066, I50882, I15353,
					A64081, I66495, I66494, I66498, I66497,
					I66496, I66486, I66487, A71440, A71435,
					I13349, A07699, E08322, I74623, A60109,
					A67220, AJ244004, U87250, I00081,
					A70040, AR028564, A83643, A98420,
					A98423, A98432, A98436, A98417,
					A98427, A83151, I01968, A13388, E00974,
					A02228, E00954, E00952, E00953, E00955,
					I08049, I43960, AR021440, E03165,
					E02221, E13364, A10360, E02679, E02104,
					E02098, A92666, E02001, E01718, E02003,
					E02102, E03550, A28163, E02100, E01997,
					A58998, E02291, E02292, E02293, E01999,
					E02396, E02327, E01563, E02431, E01693,
					E01696, A92668, AR005163, AR005154,
					AR005157, AR005160, I09250, AR005153,
					A92667, E01024, AR050583, AR050584,
					E02430, E01148, E12527, E01503,
					AR005165, E12523, E02432, A49701,
					A62009, E01216, I77211, A95096, I70974,
					I31847, I31848, AR060673, AR060676,
					A95106, A95105, A80476, A91965,
					E01324, I08638, A80474, A94048, A94061,
					A80477, AR035224, A80475, A94046,
					A94054, I63560, AR031529, A49428,
					I63561, I63563, and E16036.
HWAGU62	185	1206797	1-2192	15-2206	AI913535, AI762854, AI758705,
					AI677912, AI740876, AI825702,
					AA412665, AI800271, AI525869,
					AA883055, AI823434, R77865,
					AW204604, AA491093, AA134753,
					AA598723, AA845774, R73497,
					AA134752, AA993841, R73498, D62016,
					AI332677, AI535824, AI598069,
					AI535821, N68128, R77771, AA761684,
					W28537, AW370473, AW370408,
					AI758562, AI754802, AA293681,
					AA075272, AI687944, AI916337,
					AI633125, AW198090, AI620056,
					AI608882, AI479292, AI890223,
					AI859932, AW151893, AW152182,
					AW190194, AI802542, AI625079,
					AI677796, AI554821, AI701097,
					AW409867, AA830709, AI687362,
					AI584130, AW073677, AW083572,
					AI819326, AA811202, AI538564,
					AI571439, AW169604, AW020619,
					AI653979, AI702073, AA743430,
					AI673140, AI433157, AW157096,
					AA937566, AI049733, AI636588,
					AW195169, AI241744, AI635032,
					AW166870, AI445025, AI567128,
					AI973152, AW002362, AI637584,
					AI469532, AI635016, AI247293,
					AI619662, AW083374, AI564719,
					AW129722, AI952471, AI811644,
					AI620003, AI357940, AI376425,
					AW104724, AC007785, AF100752,
					X78627, AF124435, AL133049, AF222801,
					X59812, A15345, X60769, AR050959,
					S36676, D44497, AL137550, Z82022,
					AL137476, A60092, A60094, AF031572,
					AC006288, X63162, AF084644, AF084645,
					A27171, A52184, L35261, AR038854,
					AF115410, AL137560, AF124396,
					AL136884, AF111849, U49434, U95114,
					X68497, X52220, X98066, U97675,
					AL023657, A83556, AL133607, AF082324,
					and X68249.
HFPFB39	186	1198036	1-2090	15-2104	AI631883, AI767614, AA018867,
					AA019175, R56792, AI497937, N95592,
					R44001, AW271411, R56793, Z38315, and
					Z42023.
HPMFI38	187	1165993	1-975	15-989	AI765950, N54154, H12876, R93383,
					R56658, R16970, AW205252, R25871,
					AA886432, R93384, R16914, and N58678.
HBXDJ07	188	946830	1-1470	15-1484	H11405, R55569, N27906, H20863,
					N25140, and U27708.
HOFMS43	189	1152417	1-1065	15-1079
HOVCO14	190	1091087	1-592	15-606	AI701529, AA994711, AI192036, and
					AC007198.
HTEPE35	191	1105272	1-825	15-839	AI935040, AA861064, AA933697,
					AA707583, AA872105, AA398866,
					AA609626, AA620685, AA435866,
					AA812556, AA781805, AA993718,
					AF012362, AI217888, and AA824315.
HE8UA52	192	1229490	1-3408	15-3422	AI742521, AW274710, AA723595,
					AW365665, AI141346, AW043776,
					AI469940, AI378321, AI079805,
					AI168469, AI142001, AA772045,
					AI337483, AA478634, AI051463,
					AA912545, AW149092, AI249877,
					AI583065, AI873923, AL040011,
					AI700159, AI805638, AA427373,
					AI560683, AI287793, N42321, AI633125,
					AI499325, AW170635, AW151714,
					AI587114, AI872804, AW087455,
					AI631216, AI669459, N29277, AI921281,
					AI916419, AI538850, AI476478,
					AI242248, AW193231, AW162194,
					AI677646, AA580663, AW192228,
					AI677796, AI434038, AI494201,
					AL039753, AI583308, AW079859,
					AI357599, AI473536, AW152182,
					AW021373, AI884318, AI655841,
					AI241744, N71180, AI468959, AI538564,
					AI564723, AI685798, AI340519,
					AW081311, AW169653, AI863382,
					AI619691, AI432030, AL134830,
					AI620643, AI915291, N36182, AW263804,
					AI590423, AW191844, AA464646,
					AI636457, AI871923, AI631264,
					AI345688, AI933992, AL120526,
					AI690813, AL047422, AI868204,
					AI282307, AW243886, AW149311,
					AI718707, AI554343, AI446373,
					AW265004, AI344817, AI635216,
					AA019328, AW084117, AI687295,
					AI345224, AI679098, AW081322,
					AW104141, AI344935, T99953,
					AA502794, N22406, AI538716, AI539771,
					AI673710, AI624963, AI311892,
					AI579901, AI307736, AI472536,
					AW085673, AI611743, AI491710,
					AI249962, AW189270, AI281867,
					AW059828, N75771, AI635478,
					AA494167, AI684305, AI798456,
					AI554186, AI499131, AW105383,
					AI468930, AW089572, AW084097,
					AI648567, AI610690, AI890954,
					AI627893, AI932794, AL039858,
					AI653979, AW166182, AI890907,
					AW130134, AI951868, AW129916,
					AI670009, AI520862, AI310575,
					AW163554, AI570989, AI445663,
					AA812110, AL042628, AI499947,
					AI702073, AI569579, AI565031,
					AW102864, AA468418, AA835801,
					AI591387, AI340533, AI439527,
					AI890183, AI583085, AI924911,
					AI280732, AA641818, AI249946,
					AW020397, AI537837, AI566003,
					AI690748, AI698391, AI554821,
					AW058233, AI633000, AI623682,
					AI499393, AI801112, AW020693,
					AL037602, H41759, AI433157, AI620859,
					AW079119, AW130681, AI349957,
					AI922707, N29481, AI889189, AL040243,
					AW172723, AI889168, AI440263,
					AI700305, AI340982, AW169527,
					AI345005, AI357316, AI348870, H89138,
					AI340627, AI469505, AI274785,
					AW163834, AL047344, AW023338,
					AL119748, AL046618, AL079963,
					AW129929, AW104724, AI470651,
					AI582912, AI453328, AA833760,
					AL037582, AI679211, AW237857,
					AI445829, AI539707, AI637584,
					AI828705, AI340603, AI889147,
					AI659334, AW105431, AI288285,
					AI564311, AI678496, AI862142,
					AI567612, AW192701, AW083804,
					AI439478, AI096534, AW192042,
					AW152459, AI621362, AA635382,
					AI866465, AI689420, AI918554,
					AI273179, AI815232, AW302924,
					AI251221, AW198090, A21103,
					AL122045, AL122111, AL137529,
					AF183393, AL110225, AF061981,
					AL050149, A18777, I48978, I89947,
					A08913, A08910, AR038854, A08909,
					AL117460, AL049452, A08912, U49434,
					A08908, I26207, S76508, I89931,
					AL080126, I89934, I89944, A15345,
					I49625, A08916, A58524, A58523,
					AF090900, X63410, AF113677, L13297,
					S77771, I68732, A18788, AF026816,
					AF118094, X70685, AF090903, AJ003118,
					D83032, S61953, AL133558, X80340,
					AL137533, AL137488, E01573, E02319,
					A08907, AL049464, L19437, AL049283,
					Y10936, AL137523, A90832, AL137463,
					AL110171, AL137526, AL050277,
					A83556, I46765, AF079763, L31396,
					AL080148, L31397, X57961, E12747,
					AR068751, E05822, AL133640, AL049314,
					AJ242859, AF159615, M96857, AF000301,
					I09499, U80742, AF090901, AB029065,
					AF113694, Y10080, AL122049, AF118064,
					AF118070, AF107847, AL133098, X52128,
					AL133557, AL133016, AL133014,
					Y11587, X83544, AL122106, Z82022,
					AL137648, AF153205, Z37987, AL050116,
					AF146568, A52563, A12297, AL117435,
					AF085809, AJ006417, X98834, AL133568,
					AL122110, AF090943, Y11254, AL080159,
					AL137560, M86826, AF017790,
					AL080127, AL133113, AF125948, I03321,
					U68387, AF090896, AL133606, AL080163,
					AF032666, AF057300, AF057299, A23630,
					AL137550, AF091084, AF100781,
					AB016226, AF100931, Y16645, U00763,
					AF215669, AJ000937, X62580, I33392,
					AF051325, AL137538, X84990, AL122098,
					AB007812, AL117457, AL049466,
					AL137558, AL133565, AL137479,
					AL049347, I00734, AL110159, AL049465,
					AL137276, Y10655, S75997, AL049996,
					AF113019, AL049938, AF067728, X79812,
					A65341, AL122100, AL050108,
					AL137656, AF139986, AF137367,
					AL110222, AL133112, U72620, S68736,
					AL137292, I41145, AL080086, AL133104,
					AF003737, AF017437, X87582, AL122050,
					AL117583, AL117416, U35146,
					AL117585, AL080158, X92070, S69510,
					E08631, U00686, AF113676, AF040751,
					AL122118, U35846, AL137521, AF106862,
					AR054987, AL133665, Z97214,
					AR013797, U68233, AF113690, I92592,
					AL137283, AL049300, AL050024,
					AL110196, AL049430, A76335, AF118090,
					AF106827, A49139, I17767, A93350,
					Y09972, A07647, A45787, AL136842,
					AL050146, AF177401, AL117394,
					AL122093, AF106657, AL050092,
					AL133031, AF079765, X63574, AL137480,
					AF061573, AJ012755, X83508, AL110218,
					A08911, I48979, AL080124, AR020905,
					AF126247, AF162270, U67958, A77033,
					A77035, AF113699, AF158248, AF111849,
					AF026124, I80064, E01314, AL110221,
					AL137712, AL137273, AL050138, and
					AL137641.
HOUBE50	193	1090776	1-1175	15-1189	AL120487, AA578623, N85038,
					AB033086, and AB023168.
HAJAV28	194	1165229	1-1587	15-1601	AA913364, AW027373, AW305275,
					AI799031, AA588138, AA775450,
					AW117480, AW190848, AA411334,
					AA866178, W61038, AA411335,
					AA775769, AA769134, N30274, AI493881,
					AA075643, AA614747, AA627544,
					AI147666, AI025647, N30309, AA075644,
					AA812101, N94919, AW339918,
					AI140386, AI138196, AA868924,
					AA284960, AI554835, AI343592,
					AI128292, AI143201, AI017993,
					AI492556, AI347094, N42630, W72001,
					N20511, AI679099, AI933338, AA040263,
					AI268560, W69402, AI354734, T32745,
					N29505, AA872581, AI017992, N41996,
					AA863176, AA719956, F28362,
					AA448442, AI679673, AI142803,
					AA732322, AA993672, AA444022,
					AI624135, AA846235, AI004213, W44778,
					W44314, AA305351, AI285067, AI304774,
					AA448307, W65308, AW274816, W37097,
					AI475118, N25416, D79265, AI872626,
					AI186604, AA682603, AA285117,
					AI149185, AI339799, AI344717,
					AA996037, AA444000, AI128110,
					AA557809, H13966, AA922743,
					AA515842, F37123, AA732278, W65338,
					N56641, AI239957, AI580506, AA989130,
					R21057, W45686, R96887, AA721150,
					AA034909, F09166, H12989, N26843,
					N57447, W69363, W19542, AW183468,
					AI685763, R96888, C04314, H87003,
					AI719584, R24370, T35889, AA081676,
					T34115, N40568, AW023063, N63592,
					AA010732, T35834, AW089136, Z42311,
					F11505, W76570, T35841, AA913531,
					T30076, AI366940, AA505347, T30517,
					H05630, H27007, Z42248, F09167,
					H87002, W56871, T36163, AA040400,
					W19619, AA721261, AA649338, F34780,
					T35871, H13965, R46237, T35833,
					AA034976, AA863208, AA913094,
					AI274646, N63619, AA890331, AA082031,
					F05477, AI564372, AA603299, AA322616,
					AA603386, R27044, Z38484, R27043,
					R27029, F01840, AI859366, R27028,
					AA748381, F01739, AA355325, H53598,
					AI859362, N46608, AA339209, and
					AF190797.
HAQBZ89	195	1083554	1-1403	15-1417	AI436552, AW071796, AI299053,
					AI334145, AI613263, AI921361,
					AI161282, AI018067, AI984679,
					AI934889, W52097, AI281829, AA236375,
					AA121294, AI342850, W16450,
					AA729045, AA608803, AW135827,
					N78654, AW193167, AI689644, N46334,
					AI159772, AA456075, AA130122, N63941,
					N58535, AL042537, AA367722,
					AA969946, AI432541, AA829498,
					AA781924, AW304842, AI299054,
					T69736, AW194058, AW170746,
					AI382899, AA862441, AA257021,
					AA345125, AI049756, AI983846,
					AI129698, T70395, AA130159, AA455578,
					AA833560, AW351523, AA451639,
					AI205015, and AW512516.
HELHF07	196	949067	1-327	15-341	AC073669, AC074220, AC074220, and
					AC023605.
HE9QQ22	197	1127726	1-748	15-762	N90644, T72234, R83190, AA010242,
					N90655, N90629, N94219, N65959,
					R83191, D50995, D80164, C15076,
					C14014, D59502, D80247, D59275,
					D80195, C14389, D81026, AA305409,
					D59467, D80227, D50979, D80269,
					D51799, D80022, D80166, D58283,
					D80193, D59619, D59859, D80210,
					D80391, D80240, D80045, C14331,
					D59787, AA514188, D51423, D80253,
					D80043, AA305578, D81030, D80188,
					D80439, D51060, D80038, D80212,
					D80196, D80248, D80219, D80366,
					D51022, AA514186, D80522, D59927,
					D80302, D80024, D51103, D57483,
					D59610, D80378, D80133, D59889,
					AW360811, D80268, AW177440, D80251,
					D80241, C14429, AW178893, AW377671,
					AW375405, D80157, T03269, AW178906,
					D51759, AW366296, AW179328,
					AW360844, AW360817, C75259,
					AW375406, AW378534, AW179332,
					AW377672, AW179023, AW178905,
					D59373, C05695, AW378528, AW178762,
					C06015, AW378532, AW176467,
					AW177501, AW177511, T48593, D59695,
					AW352171, AW377676, D59627,
					AW352170, AW177731, D80132,
					AW178907, AW179019, AW179024,
					D51250, AW178983, D80134, AW360841,
					D59653, AW177505, H67854, AW352120,
					AW179020, AW178775, D58253,
					AW178909, AW367967, AW177456,
					AW369651, AW179329, AW178980,
					AW178914, AW178774, AW177733,
					AW178908, AW178754, AW179018,
					AW352158, AW179009, D45260,
					AW352117, AI525923, D81111,
					AA809122, AW360834, C03092, D52291,
					AW179004, AW367950, AW179012,
					D51079, AW378543, AW378525,
					AW378540, AW352163, D59503,
					AW177728, D59551, H67866, T03116,
					D80949, D80258, D80168, T11417,
					AW352174, AW178781, AW178911,
					AI535686, AW177722, F13647, D59317,
					AI910186, AW178986, T74930, AI905856,
					D58246, C14298, AI525917, C14077,
					C14227, D80064, D80014, C14407,
					D51221, C14973, C14344, AW378533,
					AI535850, AW177734, AI525925,
					AI525920, D59474, D60010, AW177508,
					AA514184, D51213, D60214, AI525227,
					AI557774, D58101, AW177723,
					AW177497, C14957, C14046, Z21582,
					AI525242, AI525235, T03048, D45273,
					AI525237, AI525215, AI525912,
					AA285331, AW378542, AI557751,
					AW378539, C16955, D51053, C05763,
					Z33452, T02974, D31458, AI525222,
					C13958, AW360855, D51097, Z30160,
					T02868, H67858, D38100, AB002584,
					AR018138, AB028859, AJ132110, A84916,
					A82595, A62300, A62298, AR008278,
					AF058696, AB002449, AR060385,
					X67155, Y17188, A94995, D26022,
					Y12724, A25909, I50126, I50132, I50128,
					I50133, A67220, D89785, A78862,
					D34614, AR008443, AR066488,
					AR016514, AR060138, A45456, A26615,
					AR052274, D88547, Y09669, A43192,
					A43190, AR038669, I14842, AR066487,
					X82626, A30438, I82448, AR016808,
					AR054175, D50010, Y17187, AR025207,
					A63261, AR008277, AR008281,
					AR066490, AR008408, AR062872,
					A70867, I18367, AR016691, AR016690,
					U46128, I79511, D13509, A64136,
					A68321, AR060133, X68127, AB012117,
					AF123263, AR032065, U79457,
					AR060382, Z82022, A63887, and
					AR008382.
HSDSB06	198	1128280	1-2674	15-2688	AI766068, AW009631, AI817090,
					AI765056, AA127727, AW069132,
					AI372853, AA877550, AI432584,
					AI129942, AA610281, AA102362,
					AA625117, AA948383, AA430522,
					AA447454, AW194550, AI635683,
					AA532394, AA446651, AA724535,
					AI220147, AW263019, AA430607,
					AA019158, AI752984, AI198643,
					AW389353, AA045561, AA516463,
					AW197881, AA186967, R67323, H86071,
					H67029, AA588072, C01179, AI457685,
					H22246, H12434, AW378928, H12433,
					AW050669, H68111, AA768085,
					AA054561, R33871, R66487, AA054621,
					AA478635, N55248, AA359925,
					AA385529, R33870, W68645, AA961423,
					AW002948, AI802284, AA377365,
					D31590, AI742590, AW275740, AI819328,
					AL133047, D89677, AF003234, and
					AW517631.
HACAD35	199	949199	1-1460	15-1474	AI817458, AI810494, AA442536,
					AI271432, AA228126, AA227978,
					AA687616, AW316554, AW351633,
					D62849, AA346825, AW262553,
					AC007363, and AC007363.
HEQAP17	200	949358	1-807	15-821	AI131555, AI769466, AA215577,
					AW190975, AA258335, AA258499,
					AL044652, S63848, Y17793, and A49045.
HMTBB17	201	1128589	1-462	15-476	AA582539, AI963340, AI097093,
					AA286856, AI761614, AI149781,
					AI460219, AI032670, AI636161,
					AI819154, AI089302, H12042, AI811219,
					H05308, T95010, AA836993, AW271462,
					R37000, AI001803, AA904906, AA743196,
					AI015200, AA453607, F05000, AA578803,
					AI241466, AI033193, AA330970, F03322,
					F01968, AA037601, T75492, N47542,
					AW183219, AI288171, AA054759,
					F01965, AA651907, AL122084, and
					AL049611.
HKGDE58	202	1129137	1-1325	15-1339	AW271462, AA582539, AI963340,
					AI097093, AI460219, AA286856,
					AI761614, AI149781, AA448686,
					AI032670, AI819154, AI089302,
					AI636161, H12042, AI811219, AA287162,
					AA836993, T95010, AI001803, AA904906,
					AA743196, AI015200, R37000, H05308,
					AA453607, F05000, AA578803, AI241466,
					AI033193, F03322, AA037601, AA330970,
					F01968, R13858, T75535, H12041, T75492,
					AA053290, Z46111, F07044, T94956,
					H05358, N47542, AW183219, AA454139,
					F05720, AI288171, AA651907, AA054759,
					F01965, F05717, AL122084, and
					AL049611.
HCHMW40	203	1144323	1-941	15-955	AI732539, AI791495, AI791325,
					AA709067, AW082062, AI791964,
					AI732667, AA505923, AW057561,
					AI909857, AI909862, AA601601,
					AI909853, AW082594, AI812032,
					AI310332, AI610362, AI627880,
					AW403717, AA427700, AI687065,
					AW151136, AI783504, AW071417,
					AI446373, AI280670, AI886022,
					AI345253, AI345677, AW189415,
					AI800453, AI284131, AI285826,
					AW051088, AW022682, AL134999,
					AI280732, AI680162, AW168485,
					AI610645, AL079963, AI680498,
					AI805688, AI886181, AL040241,
					AI312428, AW020095, AI537677,
					AI498579, AI400725, AI866741,
					AI251221, AI932915, AI589947,
					AI343059, AI349933, AL119863,
					AL036548, AI345608, AI690410,
					AI571909, AI478123, AI335426,
					AI348777, AL041772, AW274192,
					AI590686, AI869377, AI364788,
					AL036638, AI310606, AW301344,
					AI568765, AI922901, AI345471,
					AI366992, AI863321, AI336575,
					AI950877, AI334450, AL120853,
					AI932794, AL110306, AI929108,
					AA908294, AA225339, AI608936,
					AI345746, AI251205, AW081255,
					AL045266, AW088134, AI824576,
					AI280661, AI659795, AI537617,
					AI520809, AI812015, AI569309,
					AI828568, AW087915, AI434741,
					AI648502, AI919107, AI352497,
					AI678357, AI888944, AI308035,
					AI886123, AW198075, AI174394,
					AI933589, AI686552, AW168709,
					AI587606, AI783861, AI468872,
					AW083778, AW163823, AW084219,
					AW103886, AI952920, AI955866,
					AI628217, AI933785, AI697324, N80094,
					AI633419, AI554218, AW151785,
					AI963216, AI445165, AI590120,
					AI431909, AI866002, AI829327,
					AW268302, AI433976, AW168373,
					AW149227, AL119791, AI282326,
					AI828731, AW302973, AI499463,
					AW079159, AI251830, AI619716,
					AW268060, AI288285, AW072719,
					AI539028, AW023590, AA493923,
					AI702019, AI744256, AI432736,
					AW148716, AW168031, AI648684,
					AI612759, AW152469, AI249962,
					AW089179, AI628316, AW151729,
					AI867042, AI696819, AI566630,
					AI619754, AI623682, AW163834,
					AI699011, AW088903, AW151714,
					AI919345, AW129230, AI698401,
					AI922577, AI249877, AI471361,
					AW088899, AW148356, AI366549,
					AI636719, AI539153, AI073952,
					AL036214, AI539771, AI916419,
					AI439762, AI431424, AI866608,
					AI349645, AI611743, AI800433,
					AW268220, AI689175, AW083804,
					AI590423, AI886192, AI888621,
					AI696626, AI589993, AW059713,
					AI365256, AI271796, AI431408,
					AW167882, AI348897, AI537515,
					AW029611, AI801213, AI863382,
					AI802654, AI783997, AI620639,
					AI310575, AW080135, AI805769,
					AL036396, AI340627, AI791396, F34698,
					AI493559, AI285431, AI340533,
					AI089970, AI564749, AI308032,
					AI800138, AW087445, AI610557,
					AI348854, AW087938, AI343091,
					AI344785, AI889953, AI680457,
					AI921386, AI362580, AW190042,
					AL036718, AI383919, AI886124,
					AI250663, AI824375, AA640779,
					AI285732, Z82022, AF111112, E03348,
					E04233, AL137521, AJ242859, AL133093,
					I89947, I48978, A08913, X87582,
					AL080127, A08916, AL117435, U91329,
					AL080060, I89931, AL133016, A08910,
					I49625, A08909, I26207, AL050024,
					X84990, A45787, X53587, AL050138,
					A03736, AF113690, Y11587, AF090900,
					AF008439, A93016, AL137556, E05822,
					AL080124, AF078844, AL137538, U96683,
					A08912, I00734, U88966, AF162270,
					I42402, E00617, E00717, E00778,
					AL133077, I48979, AR038969, AL137526,
					AF090943, AR059958, AL133557,
					AF113691, AL137463, AL122121,
					AF067790, AR038854, AL110196,
					AL080159, AL049382, AL049314,
					AF183393, AJ238278, AL117585,
					AL133075, AF090903, Y14314, AL050149,
					U80742, X65873, AJ012755, AL110280,
					AL137476, AF090934, AF118094, I09360,
					L19437, AL080074, AL133640, E15569,
					AF153205, AF017152, AL080137,
					AL137527, X96540, AF081197, AL049466,
					AF104032, S68736, A93350, AL050277,
					AL137550, AR000496, AL049430,
					U39656, AL137523, AF026124, AL050393,
					X82434, AF113689, AF113699, AF132676,
					X70685, AL137271, AF061836, AF111851,
					L30117, S78214, AL110221, Y09972,
					AL117440, AL133014, AF146568,
					AL122093, A12297, X93495, AJ006417,
					S61953, AR011880, AF113694, AF113019,
					U67958, AF113676, AL137533, AF158248,
					AL133113, AL133565, U00763, U72620,
					AL122049, AF118064, A90832, A07647,
					AF118070, AL122050, AL133098,
					AL122098, AL096744, AL050146,
					AL133568, AF090896, U42766, AF106862,
					I03321, I33392, E02349, AL050092,
					AL133560, AF097996, AF087943,
					AF061573, AL117460, E07108, AF177401,
					AL137273, AF026816, AL133606,
					AB019565, AL122110, AF091084,
					AL133067, AF067728, A65341, A77033,
					A77035, AL117583, AL049464,
					AL117457, AF125948, AF185576, U78525,
					AF090901, U35846, X72889, AF119337,
					AL133104, AF017437, AF113677, Y16645,
					AL049452, AF113013, AF125949,
					AF079765, AL117432, AF003737,
					AL049300, AL137557, Y11254, AJ000937,
					AL133080, AL137560, Z72491, M30514,
					U58996, AL137648, AL137459,
					AL050116, L31396, U68387, AL050108,
					AL110225, AL133072, L31397, AL117394,
					X63574, AF057300, AF057299, X98834,
					AF061943, AF081195, AL122123, E08263,
					E08264, E07361, A58524, A58523,
					AL137478, AL133645, AF061795,
					AF151685, A18777, AL137480, Z37987,
					E08631, E02221, AL049283, AF079763,
					AF111849, AL023657, AF030513, Y07905,
					E06743, AL050172, AL117649, and
					AL137294.
HE8QZ34	204	1143411	1-1873	15-1887	AI346431, AA600828, AI654068,
					AI627476, AI692275, AI417541,
					AI033899, AA127745, AI634873,
					AI653646, AI564494, AI635599,
					AI434505, AA127671, AI818370,
					AI912908, AI311461, AI914324,
					AI371325, AA622400, AA225468,
					AA811711, AA593299, AA633708,
					AA768315, AW236744, W28575,
					AA210809, AW071534, AA565871,
					AI371817, AA287455, AA210690,
					AA225526, W00592, AA085933, N68915,
					AA908320, AA281938, AA112126,
					R35313, AA225852, AI277214, AA465202,
					AA580581, R86156, W19885, AA455978,
					AA286753, AW020244, AA636108,
					AW405566, AA452896, AI863445,
					AI055868, AA594111, AA772109, T06553,
					AW195517, AA385668, AI673762,
					AA384297, AA730967, Z41832,
					AW338426, R61806, H25863, AA370592,
					R43790, AA361533, AA449099, H50786,
					H89555, AI312685, R25032, AW118452,
					H89367, T35293, Z46079, R20776,
					AA334931, AA490204, R51228, AI874163,
					AI446400, AI475237, AA296796,
					AA249741, C01856, AI630454, AA449535,
					AW073930, AA770110, AW367213,
					AI633501, and AI567975.
HWAFG04	205	1227627	1-1385	15-1399	AW239548, R23870, F07734, D54154,
					AA297059, C14980, AI418298, AA088799,
					C15480, R46685, AA325059, AA974700,
					H42947, AI302185, AI652375, AI394630,
					AA364780, AI936871, AA382960,
					AI559159, AI025217, AI983297,
					AI025310, AW002416, AW206793,
					AA593826, D57560, AW140018,
					AW192088, AI017077, AW401787, and
					AW373232.
HTEKT33	206	1075836	1-2105	15-2119	AL044351, AI817283, AI024728,
					AI744491, AW072402, AW378258,
					AW072368, AL044352, AW192336,
					AI337979, AI627480, AI696944,
					AW369691, AI860188, AW378250,
					AW378255, AI627747, AL042027,
					AI926480, AW378166, AW068812,
					AL047150, AW029453, AA464338,
					AI801683, AI890113, AI745169,
					AI623625, AW069248, AA573520,
					AW378242, AW369645, AA722200,
					AW152579, AI679464, AI754467,
					AW069250, AI863890, AI420021,
					AI754556, AI017236, AA490151,
					AW337220, AI423346, AW385997,
					AW074087, AI015943, AI689287,
					AI587461, AW369622, AA428544,
					AI222770, AI143319, AI720991,
					AI754784, AW152549, AI143344,
					AI589285, AA582432, AA826662,
					AI587096, AI753623, W68196, AI754168,
					AW383083, AW383201, AA045260,
					AA844711, AW378254, AI753721,
					AA595042, AA432225, AI079642,
					AI754630, T63365, AA598475, AI962914,
					AW378175, T51018, AA634355,
					AI752372, AI922832, AI696875,
					AI675948, AI371134, AI598124,
					AI371125, AI143853, AI143041,
					AA779030, AI281593, AI216596,
					AI753783, AI313439, AI571587,
					AA931107, AA598793, W68075,
					AI339836, AW378191, AW351438,
					AA045150, AW169487, AI751039,
					AI051715, AI148583, AI970742,
					AI338164, AW007286, AA541755,
					H12770, AI694286, AI309918, AI358476,
					AI582893, AI304450, AA026628, N78364,
					D53342, AI041911, AW024056,
					AA935545, AW130479, W39177,
					AI354525, AI376810, N34461, AI808534,
					AA778065, AW192368, AW244107,
					AI589361, AI282168, AW028623,
					AA778055, AW150321, C17178,
					AI478760, AI244443, W86793, AI087238,
					W00916, AI446098, AA719311, H24846,
					AI209065, D57494, AA599264, W94304,
					AI083988, AI278860, AI935852,
					AI091878, AI829367, AI751862,
					AI278832, AW382654, AA620910,
					AW262984, W80605, AA834064, N94128,
					N62598, W72648, AW383076, AA026668,
					AW193117, AA084560, AI752585,
					AI624605, H49416, N55278, AI360559,
					AI520753, AW068113, AW370175,
					AL046974, AI815020, AI753242,
					AI963416, AI147036, H42782, AI571697,
					AI751040, AW242018, AI570991, H94334,
					AI953531, N57952, AI141927, AI752371,
					AW242264, D57929, W79127, W01207,
					AL048585, AW068071, AI624798,
					AA564187, W39458, W44950, AA358927,
					W02137, AW239018, AI751675,
					AA485695, AW262921, N67498, H24847,
					AI889395, W01047, AA329561,
					AA777026, N65969, AL048586, H64363,
					AA916595, W32452, AA455154,
					AI539001, AI702017, AA334020,
					AW382258, R77374, AA541671,
					AA505619, R83643, AW024024,
					AA953041, AI636202, R19771, R83636,
					F27591, F07112, F27593, AI751863,
					AW068339, AI920900, F06387, AI014855,
					H63926, H78881, AA953591, D51304,
					AI879452, AA718967, W87292, D56506,
					AW365001, N70195, M14219, AF138300,
					AR012319, AC007115, AF038127,
					U83141, AF125537, S76584, Y00712,
					AF125041, AF140270, U03394, X53929,
					L01131, AF138302, M98262, L75825,
					L01125, AF138304, L01127, L01130,
					L01128, L01126, L01129, A62298,
					A82595, AR050070, and A82593.
HBXDM07	207	1206657	1-2110	15-2124	AI672363, AI589203, AI631066,
					AI810806, AI654696, AA700425,
					AW249815, AI271343, AI127886,
					AI581871, AW044228, AA188637,
					AI769068, AI142895, AA084919,
					AA451876, AA482390, D20750,
					AA463624, AI351007, AI240526,
					AA074549, AW090810, AI143138,
					AI762690, AI752042, AI912224, R56540,
					AI127226, AA626231, R56145, AA190610,
					AA085022, AI336960, AI962785,
					AI690749, AA035626, AI762681,
					AA346622, AA847532, AW139485,
					AA426415, AI625813, AA443041,
					AI940415, AA062842, AA599682,
					AW374890, AI659071, AA953644, and
					U35245.
HFPFA83	208	955614	1-723	15-737	C14389, C15076, D59467, D58283,
					D50979, D80522, D80164, D80166,
					D80195, D80043, D80227, D81030,
					D59275, D59502, D80188, D59859,
					D80022, C14331, D51423, D59619,
					D80210, D51799, D80391, D80240,
					D80253, D80038, D80269, D59787,
					D80193, D59610, D80212, D80196,
					D80219, D81026, D59927, D57483,
					D80378, AW177440, D80366, D80251,
					AA305409, AA305578, D59889, D50995,
					D80024, D80241, D51022, D80045,
					C14429, D51060, C75259, T03269,
					AW178893, AW179328, AA514188,
					AW378532, D80248, C14014, AW377671,
					D51250, AW369651, AW178762,
					AW178775, AW177501, D80134,
					AW177511, AA514186, D80133,
					AW176467, D58253, AW360811,
					AW352117, C05695, AW375405,
					AW352158, D80268, AI910186, D80132,
					AW366296, AW178906, AW360844,
					AW360817, AW375406, AW378534,
					AW179332, AW377672, AW179023,
					AW178905, D80302, D59627, AI905856,
					AW378540, AW352171, D80258, D80439,
					AW377676, AW352170, AW177731,
					AW178907, AW179019, AW179024,
					D59373, D80247, AW177505, AW179020,
					AW360841, AW178909, AW177456,
					AW179329, AW178980, AW177733,
					AW378528, AW178908, AW178754,
					AW179018, AW352174, Z21582,
					AW360834, D51103, AW179004,
					AW179012, C06015, AW178914,
					AW378525, AW367967, D80157,
					AW177722, D51759, AW177728,
					AW179009, AA285331, AW178774,
					AW178911, D51097, AW378543,
					AW352163, D58101, D80064, D58246,
					D80014, D59503, AW178983, AW352120,
					AW178781, T48593, AI535850,
					AW177723, T11417, D59653, AA809122,
					AW177508, D45260, D59317, C14975,
					AW378533, AW367950, F13647, D81111,
					H67854, C03092, C14227, H67866,
					AI557774, AI525923, AW177497, T02974,
					AI557751, AW178986, T03116, C14298,
					D45273, D52291, AW177734, D59474,
					AI525917, AI525227, D59695, D60010,
					C14973, AI535961, C14344, C14407,
					AI535686, C14957, D51221, D59551,
					AI525920, AA514184, AI525242, D60214,
					T03048, C14046, AI525912, AI525235,
					C16955, AI525925, AI525222, D80168,
					AW378542, AW378539, AI525215,
					AI525237, C05763, Z33452, AI525928,
					AW360855, T02868, D51213, D31458,
					H67858, AR018138, AJ132110, A84916,
					A62300, A62298, AR008278, AF058696,
					AB028859, X67155, Y17188, D26022,
					A25909, A67220, D89785, A78862,
					D34614, D88547, I82448, Y12724,
					X82626, AR025207, AR016808, A82595,
					AR060385, A94995, AB002449,
					AR008443, AB012117, I50126, I50132,
					I50128, I50133, AR066488, AR016514,
					AR060138, A45456, A26615, AR052274,
					A85396, AR066482, A44171, A85477,
					I19525, A86792, Y09669, A43192,
					A43190, AR038669, AR066490, U87250,
					AR066487, X93549, I14842, A30438,
					I18367, D88507, AR054175, D50010,
					Y17187, A63261, AR008277, AR008281,
					AR008408, AR062872, A70867,
					AR016691, AR016690, U46128, D13509,
					I79511, A64136, A68321, AR060133,
					X68127, AF135125, U79457, AF123263,
					AB023656, AR032065, AB033111,
					X93535, and AR008382.
HKADO36	209	1189002	1-1364	15-1378	AI886975, AJ011372, AC001644, and
					AC002325.
HFXKG51	210	956596	1-1114	15-1128	R29445, AA585101, AA585476, Z28355,
					Z30131, T11028, D57491, AI546999,
					D57186, AI541365, T18597, AI541374,
					C16300, AI525431, AI546945, R28735,
					R45895, AI525306, AA585098, AI525556,
					AI541523, AI547006, R29218, D55233,
					AI557262, R28892, AA283326, AI526184,
					D61254, AI546875, AA170832, AI540967,
					Z32822, R28895, R28967, R28965,
					AI557734, AI541535, C15406, AI547039,
					AI557763, D60765, C16305, R29177,
					AA585439, AI557787, AI526194,
					AI541205, D61185, AI526140, AI557740,
					AI546891, C16293, C15069, AA585329,
					AI541307, AI526073, AI557731,
					AA585325, AI541514, AI541013,
					AI557727, AI557807, AI541346,
					AI541517, D60844, D59436, AI546996,
					AI547250, AI557864, AI557084,
					AI525316, R29172, AI557408, AA174170,
					AL043444, AL044125, AI541356, T41289,
					AA585453, AI541510, D53472, C15737,
					AI546971, AI556967, AI526176,
					AI525500, AI541345, AI546921,
					AI546828, AI525320, AL041347,
					AL044529, AI540974, R29179, AI526180,
					AI557602, C14723, R29262, AJ239433,
					AL041233, AI557808, AL041296,
					AI526195, AL041086, AL043496,
					AI541390, AL044162, D54897, C15120,
					AI546829, D53161, AI526113, D59751,
					AL040193, C16294, AL041324, AI546855,
					AL043538, AL040621, C16292, AL041098,
					AL041163, AI526187, AL041277,
					AI541508, AL041358, AL041096,
					AL047012, R29657, AL040464, AL041346,
					AI535813, AL040155, T41329, AL041197,
					AI526158, AL043612, AL039915,
					AL040463, AI557155, AL047219,
					AL041227, AL047057, AL047170,
					AL040119, AL047036, AL041292,
					AL041051, AL047183, AL040322,
					AL041131, AL046330, AL041133,
					AL041159, AL041238, AL041142,
					AL045817, AI541534, AA585356,
					AL040625, AL040510, AL043467,
					AL044186, AL040529, AI541383,
					AL044037, AL040091, AL040128,
					AL040168, AL040255, AL040285,
					AL040342, AL040332, AL040617,
					AL045684, AL040745, AL040370,
					AL043677, AL046442, AL040839,
					AL041752, AL041168, AL043775,
					AL044165, AL041140, AL043492,
					AL041602, T23985, AL045920, AL037436,
					AL038838, AL044074, AL041635,
					AL045990, AL040458, AL044199,
					AL044187, AL040090, AL040263,
					AL040294, AL040329, AL040082,
					AL044272, AL040444, AL041186,
					AL040148, AL045725, AL041730,
					AL041523, AL043627, AL079878,
					AL046392, AL041374, D53447,
					AL040052, AL043845, AI525339,
					AL039338, AL042135, AL044064,
					AL038983, AL039316, AL043923,
					AL043814, AA585155, AL043537,
					AL043848, AL037435, AL041459,
					AL043570, AL041577, C15762, AL044201,
					AL044258, AL046850, AL038532,
					AL040768, AL037727, AI557238,
					AL046994, AL040253, AL040414,
					AI541017, AL040571, AL046914,
					AI142134, AL040576, T23957, AL045753,
					AR062871, A25909, AR038855, AJ244005,
					Y16359, AJ244004, D50010, Y09813,
					AF082186, AR062872, AJ244003,
					AR062873, A20702, D78345, AR017907,
					A20700, A43189, A43188, X81969,
					A85395, A85476, D13509, Z32836,
					AJ244007, AR037157, A98420, A98423,
					A98432, A98436, A98417, A98427,
					A98767, AR038762, A93963, A93964,
					I63120, I05558, I44681, X83865, A84772,
					A70872, I08396, I08389, A84776, A84773,
					A84775, A84774, AR054109, AR067731,
					I15718, AR067732, A86792, A58522,
					A91750, AR008429, AB025273, I13349,
					A18053, A60212, A60209, A60210,
					A60211, E03627, I84553, I19525, I84554,
					I48927, I15717, AR031566, A90655,
					D13316, AC005913, A35536, A35537,
					A02135, A02136, A04663, A04664,
					A02712, A77094, A77095, M28262,
					A81878, I00682, A95051, I06859, A18050,
					A23334, A75888, I70384, A64973,
					A60111, A23633, AR007512, A11623,
					A11624, E00609, E13740, A11178,
					E01007, A10361, AF149828, I08395,
					AR043601, A11245, AR054723, I03331,
					A02710, E12615, AR035193, A92133,
					E14304, A07700, A13392, A13393, I62368,
					AR031488, I13521, I52048, A27396,
					AR027100, I49890, I44531, I28266,
					I21869, A91965, I44516, A70040, E16678,
					I01995, A82653, E16636, A95117,
					AJ230935, A93016, A24783, A24782,
					AR051957, I25027, A58524, A58523,
					I26929, I44515, I26928, I26930, I26927,
					AR038066, I08051, X55486, A22738,
					I66498, I66497, I66496, I66486, I60241,
					I60242, A20699, E00696, AJ231028,
					E00697, E03813, I66482, AR009151,
					I66485, E17098, I66483, I66484,
					AR027099, I66487, AJ230902, AJ230972,
					AJ230951, AJ230867, AR051652,
					AR063812, S60422, AR051651, A06631,
					X82786, I66495, I66494, AJ231009,
					Y14219, A22734, X76012, AJ230845,
					I05845, AR035975, AR035977, AJ244006,
					AR022273, AJ243486, AR051865, I03669,
					I03668, A16035, I18895, AJ231011,
					I33632, AR003381, AJ230996, Y09940,
					AR035974, AR035976, AR035978,
					E03654, AR031358, AR031365, I36244,
					AR051864, A22739, AR017826, A05993,
					and A05991.
HFPHR82	211	1187749	1-1597	15-1611	AA913364, AW027373, AW305275,
					AI799031, AW117480, AA588138,
					AA775450, AW190848, AA411334,
					AA866178, W61038, AA411335,
					AA775769, AA769134, AA075643,
					N30274, AA627544, AI493881, AI147666,
					AA075644, AA614747, N30309,
					AA812101, AI025647, AA868924,
					AW339918, AI140386, N94919, AI143201,
					AI347094, AI138196, AA284960,
					AI933338, AI343592, AI128292,
					AI017993, AI492556, N20511, N41996,
					N42630, W72001, W69402, AI554835,
					AI679099, AA040263, T32745, AA872581,
					N29505, AI354734, AI268560, AI017992,
					F28362, AA448442, AI679673, AA863176,
					AA719956, AA444022, AI142803,
					AA732322, AI304774, AI475118,
					AA993672, AI624135, AA846235,
					W44314, W44778, W37097, AA682603,
					W65308, AA448307, AW274816, N25416,
					AI339799, AI128110, D79265, AI004213,
					AA305351, AA285117, AI149185,
					AI285067, AI872626, AI186604,
					AA557809, AA444000, AI344717,
					AA922743, N56641, AA996037, H13966,
					AA515842, F37123, AA732278,
					AA989130, W65338, W76570, R21057,
					N26843, AA721150, AI239957, AI580506,
					R96887, AA034909, W45686, W69363,
					F09166, H12989, W19542, N57447,
					R96888, C04314, AW183468, H87003,
					AI719584, R24370, T35889, AI685763,
					AA081676, T34115, N40568, AA010732,
					AW023063, N63592, T35834, AW089136,
					AA913531, Z42311, F11505, T35841,
					T30076, H05630, AA863208, AA505347,
					T30517, H27007, AI366940, Z42248,
					F09167, H87002, W56871, T36163,
					AA040400, W19619, AA721261,
					AA649338, F34780, T35871, R46237,
					H13965, AA913094, T35833, AA034976,
					AA890331, AI274646, N63619, AA082031,
					F05477, AA603299, AA322616,
					AA603386, R27044, Z38484, AI564372,
					AI859366, F01840, R27043, R27029,
					R27028, AA748381, F01739, AA355325,
					AI859362, H53598, N46608, AA339209,
					and AF190797.
HISAF59	212	959140	1-899	15-913	AW401787, AI394630, AI418298,
					AW375742, T30407, Z44281, F07299,
					R25015, T32685, AA974700, F07734,
					AA297059, AW239548, AA897415,
					R45025, AI807678, AI343378, AW206793,
					AW138409, AW163027, AI815476,
					AA503315, AA047793, AW137324,
					AW140018, AI936871, AI015047,
					AI017077, AI168175, AI302185,
					AI025217, F03423, R46686, AI073417,
					Z40806, AA026054, AW002416,
					AI652375, F03562, T03397, AI983297,
					H42881, T82311, AI025310, AI831833,
					R08769, AI911100, AA471062,
					AW157059, AA382959, H22172,
					AI356604, AI537006, AI825970,
					AW338394, AW192088, AI559159,
					AA593826, AW078709, and Z61277.
HCEHD66	213	1136122	1-926	15-940	AI968437, AI824971, AW104052,
					AI762197, AI598138, AI088543,
					AW135225, AI827280, AW007187,
					AI391466, AA534403, AW028554,
					AI492390, AI369729, AA135928,
					AA507443, AW137272, AW381735,
					AW006062, AW138526, W81153,
					AA918755, AA085774, AA058923,
					C03738, R85039, AI937792, AI867512,
					N62215, AI864402, N62216, D44882,
					H14329, H40979, AI808139, AA463408,
					AI744140, H40980, AI479413, N62166,
					AA319197, W30972, AA460467,
					AA135929, AI400940, N62223, AF186409,
					L27421, and AC006241.
HE8UY74	214	1163590	1-591	15-605	N23547, H06088, Z24919, AA010516,
					R94366, AA004981, AA304780,
					AA343256, and N31310.
HAHIY08	215	962113	1-265	15-279	AA100160, AA307684, AA244505,
					R57782, AA864846, AR044133, and
					AR044123.
H2CBH45	216	1128919	1-983	15-997	AA307462, H86407, AA019170,
					AW351511, AA036880, AA045560,
					D89677, and AL133047.
HMVAM09	217	1194828	1-1835	15-1849	AI685410, AA873182, AI969804, N21495,
					AA708519, AA581446, AA035001,
					AI088511, N20223, AA101798, AA534317,
					AA397365, AA621392, AA397470,
					AI343916, AA035462, AI682643,
					AA397454, AA565111, AI096942, N68558,
					AA101799, AW029215, AI802673,
					AI130817, N73321, AA470951, AA470484,
					AI302901, N29290, AW024919,
					AA358533, AW135812, AI376856,
					AA740383, AA349063, AW051031, and
					AI276887.
HFPEN04	218	1199663	1-2090	15-2104	AI631883, AI767614, AA018867,
					AA019175, R56792, AI497937, N95592,
					R44001, AW271411, R56793, Z38315, and
					Z42023.
HSLJD02	219	1104452	1-965	15-979	AI905856, AW178893, T03269, D80164,
					D58283, D59859, D80022, D80166,
					D80195, D80193, D59927, D51423,
					D59619, D80210, D51799, D80391,
					D59275, D80240, D80253, D80043,
					D59787, D80227, D59502, AW177440,
					D59467, D81030, AW179328, D80212,
					D51060, D80196, D80188, D80219,
					C14014, C14331, D80038, D80269,
					D80366, D57483, C15076, AW178775,
					D50979, D50995, D59889, AW360811,
					D80134, C14389, AW366296, AW375405,
					D80045, AW378532, D51097, AA305409,
					AW177501, AW177511, AW178762,
					AW377671, D51022, AW375406,
					AW378534, AW179332, AW377672,
					AW179023, AW178905, AW352170,
					AW367967, D58253, D81026, AW178980,
					AA305578, AW377676, AW352171,
					AW177731, AW178907, AW178906,
					D80248, D80132, AW179019, AW179024,
					D80522, D80133, AA514186, AA514188,
					AW179329, AW378528, D80247, D80439,
					T48593, D89785, D34614, X67155,
					AR018138, D88547, X82626, A84916,
					A67220, A62300, A62298, Y17188,
					A78862, D26022, AJ132110, A25909,
					AB012117, AR025207, A85396, A44171,
					I19525, A85477, AR066482, A86792,
					Y12724, AF058696, AB028859,
					AR008278, X93549, A94995, I18367,
					AR066490, D88507, AR008443,
					AR066488, D13509, A82595, A26615,
					AR052274, AR016514, D50010,
					AR060138, A45456, Y09669, AR060385,
					AB002449, and AR008408.
HDPFZ30	220	1220164	1-1683	15-1697	AA582196, AI690196, AW207633,
					AI417381, AI494563, H15131, AI220943,
					AI963799, AW055140, AI680222, N54913,
					AW008673, AI000592, H04038,
					AA385773, H03355, AW374840,
					AI014381, H15190, Z41172, AW374989,
					F08100, AA348883, N88565, AI924734,
					T03532, and AA348882.
HPJCR33	221	1217931	1-2404	15-2418	AA630312, AA399309, AI566447,
					W45583, AA148064, AI379707, AI041054,
					AA478756, AI581333, AI745305,
					AA253311, AA947298, AI744665,
					AA545782, AA194036, AA479976,
					R61402, AW297108, AI083947,
					AA398243, AA235081, AI700620,
					AI458557, W45546, AI433426, AI092537,
					AA195635, Z46141, H15959, AA235210,
					AA743383, AI656322, AA015701,
					AA766679, R23558, AI702152, AI370616,
					R61360, AI038624, AA018978, Z41774,
					R60379, AI535639, R14628, R68398,
					R31614, H01672, AA585439, Z28355,
					M85798, R31659, AA585101, R45613,
					Z30131, N87140, AI525556, AI546999,
					AI541365, AI525306, R68600, AI557731,
					AA585453, AI525431, AI535660,
					AI536138, AI547039, AI526194,
					AI540967, AI546855, AI541535,
					AI557807, T11028, AI557262, AI541374,
					AI541514, AI556967, AI526140,
					AI541510, R29445, D61254, AI525316,
					AI541523, H01673, AI546828, R28735,
					AI541013, AI557787, AA585440, D57491,
					AA585434, AL041159, AI541509, R32345,
					AA585476, AL041142, AL041238,
					AL041133, AL047183, AL040322,
					AL041131, AL046330, AL041051,
					AL041292, AL040119, AL047036,
					AL047170, AL047057, AL047219,
					AL041227, AL040463, AL039915,
					AL043612, AL045817, AL041197,
					AL040155, AL041346, AL040529,
					AL041096, AL047012, AL041358,
					AL041277, AL041163, AL041098,
					AL040621, AL043538, AL041324,
					AL040464, AL044162, AL041086,
					AL043496, AL041296, AL041233,
					AL041278, AL045725, AL041140, T23985,
					AL040193, AL040625, AI541534,
					AL040510, C16300, AL043467, AL044186,
					AL040553, AL038761, AL044037,
					AL040091, AL040128, AL040168,
					AL040255, AL040285, AL040342,
					AL040332, AL040617, AL045684,
					AL040149, AL040745, AL040370,
					AL043677, AL046442, AL040839,
					AL041752, AL043775, AL044165,
					AL043492, AL041602, AL045920,
					AL038838, AL044074, AL041635,
					AL045990, AL040458, AL044199,
					AL044187, AL040090, AL040263,
					AL040294, AL040329, AL040082,
					AL044272, AL041186, AL040148,
					AL041730, AL041523, AL043627,
					AL040253, AL046392, AL041374,
					AI535813, AL040052, AL043845,
					AL043537, AL039338, AL042135,
					AL044064, AL038983, AL039316,
					AL043923, AL043814, AL043848,
					AL041459, AL043570, AL041577,
					AL044201, AL044258, AL046850,
					AL038532, AL040768, AL037727,
					AI546891, AL046994, AL040414,
					AL040571, AL046914, AI142134,
					AL040576, AL045753, AL044274,
					AL079878, AL049018, AL040444,
					AL045857, AL041168, AI541205,
					AL039744, AL038822, AL045671,
					AI541508, T41289, AI525320, AL046327,
					AI557796, AL040238, C16305, AL049069,
					AL043444, AL041246, AL040472,
					AL040075, AL041347, AL041955,
					AI557799, T23957, AL080031, AR038855,
					AR062871, A25909, A85395, A85476,
					AR008429, AR062872, AF082186,
					AR062873, AR017907, AJ244004,
					AJ244005, A20702, A20700, A43189,
					A43188, AJ244003, AR037157, A98420,
					A98423, A98432, A98436, A98417,
					A98427, I63120, A98767, I18895, A93963,
					A93964, A58522, Y16359, I44681,
					AR038762, A84772, A84774, A84776,
					A84773, A84775, AR054109, AR067731,
					AR067732, A91750, X83865, D78345,
					A86792, AI8053, M28262, I06859, I13349,
					I15717, I15718, E03627, U94592,
					AJ244007, I48927, I19525, A02712,
					A77094, A77095, I84553, A81878,
					A95051, I84554, A18050, A23334,
					A75888, I70384, A64973, A60111,
					A23633, AR007512, I08396, A60212,
					A60209, A60210, A60211, I00682,
					A11624, A11623, E00609, E13740,
					A11178, E01007, A10361, A91965, I49890,
					A93016, A35537, A35536, A02136,
					A04664, A02135, A04663, I08395,
					AR043601, A11245, I03331, E12615,
					A02710, AR035193, E14304, A07700,
					AI3393, AI3392, I62368, AR031488,
					I13521, I52048, A27396, AR027100,
					I44531, I28266, I21869, A70040, E16678,
					A82653, E16636, A24783, A24782,
					A92133, A95117, A58524, A58523,
					A90655, I44516, AF149828, I01995,
					I08051, AR031566, I25027, I26929,
					I44515, I26928, I26930, I26927, I60241,
					I60242, AR038066, A20699, E00696,
					E00697, E03813, I66482, AR009151,
					I66485, I66483, I66484, I66497, I66496,
					AR027099, I66486, I66487, Y09813,
					I66498, AR051652, AR051651, Z32836,
					A62298, X81969, AJ230935, D50010,
					AJ230902, I05558, AJ230972, A62300,
					A70872, A82595, AJ230951, U87250,
					A84916, I08389, A22738, D13316,
					X07299, A70869, D13509, AR035975,
					AR035977, AB025273, AR051957,
					E12584, I18302, AR018138, AC005332,
					Y17188, AR035974, AR035976,
					AR035978, AR016808, I66495, I66494,
					AJ132110, E17098, I66481, A83642,
					A83643, I66488, I66489, I66490, I66491,
					I66492, I66493, A83151, AR008278,
					X55486, A22734, AR022273, AJ231028,
					AB028859, AF058696, AC005913,
					AR054723, AR064707, Y17187, AJ230867,
					AJ230845, AI231009, A94995, X67155,
					D26022, A67220, D89785, A78862,
					D34614, I36244, AF006072, AR051864,
					D88547, Y12724, A06631, X82786,
					S60422, AR051865, R32371, and
					AI191037.
HTOAK34	222	1081321	1-827	15-841	AA491322, AA505126, and AW408167.
HE8N124	223	971296	1-737	15-751	AA883367, AA332611, AA732890,
					AI283442, AI673342, AI631153,
					AI200800, AI910962, T11417, D80258,
					D59503, D80014, D81111, C14227,
					D80064, AI557751, D58246, C06015,
					AA514184, AI535959, AW178893,
					AW178907, AW375405, AW177440,
					AI535686, AW360834, AW178908,
					AW360811, D80314, AA809122, D80251,
					D80253, C03092, D80247, D80043,
					AA285331, AW176467, C14389,
					AW179328, T48593, AW375406, D80439,
					AW378534, AW179332, D58283,
					AW377672, AW179023, AW178905,
					D59859, D80022, C14331, D80166,
					AW177731, D80195, AA305578, D80193,
					D59927, T03269, D59467, D51423,
					D59619, AW378528, D80210, AW178906,
					D51799, D80391, D80164, D59275,
					AW178762, D80240, D80038, AW179019,
					D59787, D80227, AW378533, D59502,
					AA305409, AW378532, F13647, D45260,
					AW178914, AW378542, AW360855,
					AW377676, I50126, I50132, I50128,
					I50133, AF123263, A70867, D88547,
					AR062872, AR066488, AR016514,
					A62300, D50010, X82626, AR066487,
					Y17187, AR060138, A84916, A45456,
					A67220, D89785, A62298, Y09669,
					Y17188, AB028859, A82595, A78862,
					D34614, A94995, D26022, AR060385,
					A30438, AJ132110, AR018138, A26615,
					AR052274, A43192, AR008278, X67155,
					Y12724, A63261, A43190, AR038669,
					AF058696, A25909, X68127, AR008443,
					AB002449, AR025207, AR016691,
					AR016690, and U46128.
HAMFM39	224	1055532	1-4620	15-4634	AI660231, AI304355, AI745391,
					AI951619, AI814592, AI467782,
					AI274105, AA426190, AW301083,
					AI375593, AI922346, AI829867,
					AW136366, AA227834, AW105735,
					AI304726, AW194167, AW297557,
					AI971865, AA151872, AI985643,
					AA757072, AW028756, AI202419,
					AI346603, AW295401, AW176248,
					AI659079, AA149658, AA425159,
					AI870033, AW194075, AA233413,
					AW102818, AI765117, R61588,
					AA365664, AA365663, AA601170,
					R61532, AA357346, and AA551861
HBGMG39	225	1126283	1-343	15-357	AI497641, AW069135, AI623708,
					AW084071, AW339039, AI569972,
					AL036585, AW192429, AI458409,
					AI379125, AI066465, AW003414,
					AI742565, AI740930, AI743686,
					AI168481, AI991329, AI061450,
					AW007899, AW102701, AI342244,
					AI609020, AI453165, AI248142,
					AW044270, AI761292, AI693756,
					AI870883, AI129686, AI992036,
					AW057507, AW151858, AI362058,
					AI475537, AI864435, AI479128,
					AI378430, AW008808, AI080156,
					AW191953, AW080685, AI627434,
					AI369151, AI926062, AI963067,
					AI923881, AI740972, AL045227,
					AI351617, AI334039, AI452903,
					AI700412, AI469546, AI187911,
					AI066744, AA551905, AW132118,
					AI190677, AI812069, AI081231,
					AI050026, AA577674, AI890929,
					AI096904, AI554840, AW073739,
					AW190499, AW250073, AI524714,
					AI884727, AW168902, AI858574,
					AI422058, AA304774, AI890721,
					AI052823, AI683215, AA682804,
					AI087154, AW004991, AI640737,
					AA461453, AI668789, AA532435,
					AA912478, AW079985, AA054275,
					AA970861, AI819302, AW085591,
					AA010790, AI017023, AI217784,
					AI584163, AI581899, AI569968,
					AA984939, AI469425, AA709077,
					AA744639, AA779825, AI000961,
					AI095374, AA864689, AI564659,
					AA969103, AA827905, AA918799,
					AA862362, AA446048, AA024454,
					AW087352, N53410, AI672825, W48745,
					N20167, AA931463, AI587533, AI193638,
					AA612750, AW150032, AI961508,
					AA024670, AI619904, AA429899,
					W02113, AA969104, AW190663,
					AA765028, AA780072, N50640,
					AA533847, AW182184, W32574,
					AW073566, AI933617, AL041483,
					AI952283, AA937508, AI095341,
					AI917215, N48059, T23065, AI869852,
					N78603, AW444850, AA877348,
					AA010101, AA252354, AW297832,
					AA011219, AW204879, AA506948,
					AI167689, N53257, AI917614, AI937775,
					AW168023, AI858564, AW043696,
					AA450098, AI263865, AI885655,
					AW139189, AA883859, AI801558,
					AI859652, AI554186, AA151875,
					AA187616, AI828806, AI095024,
					AI628324, AI678623, AW161202,
					AI560004, AI393038, AI584130,
					AI687568, H89138, AA835947, AI673140,
					AI521005, AI287476, AI678324, E12258,
					AF153686, E12259, E12260, D44497,
					AC007559, A15345, X99971, AL080159,
					AL133062, AF061981, AF111849, A21103,
					and S36676.
HSXBV89	226	1128699	1-2233	15-2247	Z99410, AW373793, AA553665,
					AI190674, AI366341, AI184600,
					AW004692, H10539, AA482462, R45646,
					AI521134, AA973962, R42556, AA720003,
					H11452, AA211375, R22747, AW009222,
					AA417872, AA632195, W39346, R52677,
					R61178, AA720022, R61892, T80548,
					R20364, H46470, F07364, R86859,
					R55930, Z41453, AI360146, R87776,
					H08592, AA483558, W38313, R55720,
					R43749, T30657, AA426408, H95699,
					AA363950, R18352, R15260, R18538,
					R87830, F05821, R87766, R10214,
					R90750, T15918, F03602, T34747, H95698,
					W84692, R87845, T78493, F08462,
					T16643, AA210976, R13935, R25677,
					H50912, AA349344, AI302317, Z99411,
					F07877, AA643729, R52724, R43750,
					AA522619, F02068, R43495, R41527,
					H52035, AI092517, AI291295, AI570476,
					AI951902, AI906668, AI906666, H38986,
					AI553790, AW268395, AI312547,
					AW450243, AI681390, AI344432,
					AI343814, N44903, W84640, AA614791,
					AJ245820, AJ245821, AJ245822, and
					AF131749.
HBIOZ10	227	1143756	1-559	15-573
HTLEJ11	228	1085651	1-956	15-970	M62294.
HAWAM69	229	1207835	1-2944	15-2958	AW385785, AA430300, AA541688,
					AA776700, AA679037, AA573270,
					AA126614, AL045796, AI268236,
					AA682186, AI963606, AI926591,
					AW192904, AI924827, AI922590,
					AI032288, AI375804, AA705172,
					AW081541, AA694514, AI130883,
					AI800450, AA931725, N25288, AI270687,
					AI366906, AW058362, AI683319,
					AA436891, R59176, AI597744, AI446542,
					W69578, AW453004, AI911821,
					AI095665, AA687634, AI130013, W69579,
					R59232, AA722782, AI587015, AI191864,
					AA398533, AA676733, AI476374,
					AA115447, AA554327, AA759328,
					AW242281, AI139766, AA042956,
					AA886732, AA664356, AA358590,
					AA135916, AI565897, AW304844,
					AA618576, AA916086, R66162, H71919,
					AA363371, AA430199, AI370031, Z44808,
					AA320329, AI934183, AA393105,
					AI004140, AA135927, AA042816,
					AW452852, AA135926, H44791,
					AA813424, AI865731, T35731, R42647,
					R27785, T32691, AI857286, AW008428,
					AI631988, AA115446, AA678468,
					AW075384, AI569918, H44790, AI918635,
					AA601518, AA603858, H42641, AI745618,
					AI445766, R27874, AI939990, AA677131,
					AW364938, AI569374, AW029062,
					AL042382, AL119511, AL119457,
					AL042544, AL119399, AL079794, C01947,
					AL043152, AI863382, AL043168,
					AL119324, AI670009, AI698391,
					AL036403, AI358701, AI909661,
					AL046944, AL037454, N42321,
					AW082113, AI886124, AI590120,
					AI978703, AI525669, AW167228,
					AI525653, AI254727, AI637584,
					AI783504, AL079963, AI557808,
					AL119863, AI609409, AA127565,
					AW020397, AI247193, AI889189,
					AL039086, AI866608, AI590686,
					AL045500, AL121306, AI612885,
					AI364788, AI433157, AI702073,
					AI888661, AW238730, AL043975,
					AI541027, AI633125, AI610357,
					AI673278, AL079741, AL121328,
					AW022682, AL045997, AI859991,
					AI686906, AI923989, AI621341,
					AI269862, AL042745, AI620284,
					AI915291, AW020419, AI340519,
					AW023338, AI522052, AI874166,
					AI866770, AI679550, AI284509,
					AI541056, AI801793, AW163464,
					AI280637, AI744243, AW104641,
					AA640779, AI537677, AL045163,
					AL041150, AI571439, AI538885,
					AI557238, AL121365, AW411235,
					AA493647, AI491842, AL080011,
					AI627988, AI340603, AL121270,
					AI623941, AI583578, AA420758,
					AI538850, AA420722, AI624693,
					AI499285, AL047100, AI590601,
					AI669864, AL110306, AW020592,
					AW051088, AW021717, AI554821,
					AI866573, AW161579, AI801325,
					AI539771, AI929108, AW162189,
					AW198090, AI521560, AI500662,
					AI619502, AI500659, AI285448,
					AI541048, AI538008, AW160916, D50977,
					AI500523, AW079654, AW162194,
					AI284517, AI500706, AI445237,
					AI491776, AW151138, AL036548,
					AW409775, AI922707, AI633493,
					AI620003, AI434256, AI591228,
					AL138386, AI284513, AI888118,
					AI859464, AW104056, AI582932,
					AW303089, AI582558, U77594, Y11587,
					S68736, AL050277, AF118094, I48978,
					AL133072, AR011880, AL122110,
					AL137550, Z97214, AF182215, I89947,
					AL122093, AF126247, AL133640, A91160,
					AF146568, AL133080, A93016, AL049382,
					AR029490, A08916, A08913, I48979,
					AF100781, Y10655, AF113694, AF177401,
					AL137479, AF207750, X56039, AL050393,
					AR034821, S61953, X82434, Y11254,
					AF079763, AF159615, AL050149,
					AL096744, A08910, A08909, A77033,
					A77035, Z82022, AL137294, AL117460,
					U35846, AF113019, AF114170, AL050024,
					AL137459, AL080126, A65341, I03321,
					AJ005690, AF090934, I33392, AL133075,
					I68732, X63410, I89931, X79812, M27260,
					I00734, I49625, E00617, E00717, E00778,
					E01614, E13364, A76335, AB007812,
					AL117435, A03736, AF057300, AF057299,
					X72889, AF139986, A57389, AL122049,
					A07588, AF067728, AF111851, AF183393,
					AF091084, AL110221, AF090900,
					AL137548, A18777, AL049283,
					AL137560, X70685, AL133557, Z37987,
					AF090903, S78214, D83032, AF017437,
					Y16645, AF090886, I66342, AF104032,
					AR068751, U88966, AR038854,
					AF065135, AF087943, AL110197,
					AL133016, I09499, AL133113, A58524,
					A58523, AL122050, AL049430, AF113699,
					AL137271, E02349, I92592, AF026124,
					A08912, X65873, AL122121, AJ012755,
					AL137463, X81464, AF028823, A08908,
					AF069506, AL122100, AL137533,
					AF079765, AL137521, AF008439,
					AL117457, AL133558, AF017152,
					M96857, U80742, AF090901, U75932,
					E03348, X66862, AL137478, I17544,
					X63574, AF061943, AL080074, AL049300,
					AL049466, X84990, A93350, I30339,
					I30334, AL117394, AF106657, AL050138,
					AL122123, AL133560, AL133637,
					AF113689, X72387, U00763, AL137523,
					AJ003118, AL137557, AL137300,
					AL110225, AF081571, AL137705, L04504,
					X96540, I89934, AR013797, AF113690,
					AL137283, AF118070, AL110196,
					AL049314, AL049452, AR059958,
					AL137538, AJ238278, AL122098,
					AL050146, U78525, AR068753,
					AL137526, AJ000937, AL080158, E07108,
					AL133606, AF106862, AB019565,
					AF113677, I09360, AF097996, E06743,
					AL137648, AF031147, AL117585,
					AL137558, AL050108, AF090896,
					AL133010, U42766, X83508, AL137476,
					AF111112, AF111849, AL133665,
					AL133568, E15569, S76508, AF113691,
					AL137539, AL080124, L04849, A65340,
					AL137530, I42402, AL080159, AL117583,
					M86826, X92070, Y14314, AL050116,
					AF125948, AL137660, A23630, AL137488,
					AL050155, AF113013, AL049464,
					AF078844, X06146, AF100931, A86558,
					AF090943, X87582, U67958, AL122106,
					U87620, AF125949, L31396, AL080148,
					and AW664335.
HSCKD11	230	1056288	1-3714	15-3728	AL037558, AA417129, AW021717,
					AL042365, AI440238, AI885989,
					AA641818, AI378123, AW088560,
					AI648699, AI673278, AI572717,
					AI559752, AW023338, AI280732,
					AW238730, AI538885, AI866608,
					AA805434, AI923989, AI249877,
					AW022636, AI697324, AL118781,
					AL120995, AA514684, AI349226,
					AL048323, AL079963, AI929108,
					AL048340, AI697420, AI784252,
					AI318280, AW151714, AI811192,
					AW022102, AW161098, AI565031,
					AW029457, AI471429, AI862880,
					AW163834, AI536836, AI950729,
					AI582932, AI521594, AW088903,
					AI862144, AI954183, AI288285,
					AL037592, AW118448, AI348777,
					AI335426, AW082532, AI537677,
					AI611743, AW166742, AW161579,
					AI567971, AI954422, AI633125,
					AI925404, AI809062, AI860027,
					AI815232, AW152182, N22276,
					AW162194, AI538716, AI345688,
					AW366372, AI334893, AI440260,
					AI241678, AI335214, AI493836,
					AI499285, AL041220, AI432644,
					AI798456, AI702091, AW021189,
					AW073697, AW083573, AI537261,
					AW089840, AI252023, AI586931,
					AW151132, F26535, AW020480,
					AL047344, AI340603, AI963668,
					AW161402, AI589004, AI473208,
					AI524654, AI621341, AW104141,
					AI338427, AI287233, AI349246,
					AA908294, AA420722, AI886123,
					AI623941, AI340519, AI690813,
					AW170787, AI254042, AI627714,
					AW051088, AW020381, AI680165,
					AI473536, AW020397, AI240978,
					AW079432, AI365256, AL036923,
					AI269862, AI635016, AL038605,
					AI368579, AI623736, AI500061,
					AI699020, AW129456, AW087336,
					AI289791, AI138480, AI567351,
					AW029216, AI927233, AW059828,
					AI866465, R39624, AI969641, AI589428,
					AW022699, AI915291, AW020419,
					AI470651, AL048496, AW169234,
					AI421328, AI587606, AI439452,
					AI539771, AW169604, AI540674,
					AI745329, AI282652, AW054931,
					AW020561, AI538829, AI887163,
					AI525653, AW129202, AI969655,
					AI610086, AI348854, AL121270,
					AI523806, AI432532, AI282930,
					AA602414, AW090768, H89138,
					AI873644, AW189473, AW162189,
					AI536601, AW079706, AW148356,
					AI345415, AI355779, AW074605,
					AI254420, AL110306, AI625467,
					AL045349, AA806719, AA833760,
					AI620056, AI591101, AW118237,
					AA736984, AI680280, AI538764, F27788,
					AA503384, AI623396, AW078895,
					AI868831, AL135024, AI758924,
					AA829061, W45039, AI472487, AI434223,
					AI289436, AI962858, AI673363,
					AW129230, AW194014, AW022300,
					AL039086, AL043981, AW090103,
					AI890907, AW025464, AW103628,
					AI554821, H43387, AW029186, AI499325,
					AW080766, AA808175, AL046942,
					AW090492, AI698391, AI863479,
					AI612885, AW087200, AI921244,
					AI804531, AA001397, AI340627,
					AL036705, AI677796, AW079572,
					AI696358, AI247293, AI452560,
					AW019985, AI620287, AI246319,
					AA764968, AJ243342, I72363, U12336,
					S53987, M30514, AL050116, AL137256,
					AL133080, I89934, AC005291, A65340,
					AF017437, AF200464, AF058921,
					AL133560, AF047716, AL122110,
					AF026008, AL050280, AF113676, A08910,
					A08909, M79462, U78525, I48978,
					Y16645, AL137258, AF124728, AL080148,
					AL137276, S36676, AJ005690, AL133113,
					I00734, AC004987, AL050393, U72620,
					E01356, AL080118, AF008439, AL133557,
					AF113690, AF090896, AF002672,
					AL133010, AF102578, AR038854, I89947,
					AF000167, AF082526, AF118094, L40363,
					A08913, AL137459, AL117460,
					AR034821, AL137550, AL137463,
					AF100931, A86558, AL133070, AL080159,
					U73682, X80340, U58996, X89102,
					X59812, AF043493, AF090934, Y13350,
					AF145233, AL110158, AF090901, E00617,
					E00717, E00778, AL122104, X62580,
					AF069506, AF183393, AF185614, I66342,
					AL050172, L13297, Y10936, A08912,
					Y07905, M92439, A08911, A08907,
					AF038847, I18358, I34395, AL080074,
					AL110228, AR068466, U88966,
					AL080057, S54890, I89931, AL133067,
					AL133084, X76228, AF097996, AF051325,
					S76508, X72387, U51587, AL137558,
					AL133623, I49625, AF106862, AF090923,
					I33391, AR029490, M85164, AF080622,
					AL122093, AL137479, AL122123, I79595,
					AF002985, AL137657, AF175903, E12580,
					AL137648, AL117629, AF158248,
					AF180525, I32738, AB008792, AL122118,
					U75604, AB008791, U42766, AF182215,
					Y13653, A91160, I28326, A77033,
					A77035, U68233, I92592, Z37987, A03736,
					A18777, A08916, AL117463, AL137478,
					AL122050, AL133081, AL117416, S77771,
					AF118558, AL133568, AR050959,
					AF111112, AF067790, M19658,
					AR020905, AL133104, AL137429,
					A08908, Y10823, AF065135, E12579,
					AF090900, U37359, X99717, AL080150,
					AR022283, S78214, AL049347, AF026816,
					AL136884, and X82397.
HDPLT62	231	1027241	1-2693	15-2707	AI279417, AL079734, AA502991,
					AA410788, AI755214, AA643770,
					AW023111, AI754105, AI754567,
					AI805363, AW328331, AA632765,
					AL042373, AI254779, AA704393,
					AI962030, AA659832, AA507042,
					AI253376, AI380617, AI923052,
					AA524229, AA904275, AI460050,
					AA714110, AI345695, AL119247, N23913,
					AA572813, AW008169, AA470933,
					H45698, AA169245, AA477503,
					AA829036, AA535216, AA452887,
					AA809546, T71936, AI311647, AI278972,
					AI783911, AI674840, AW409710,
					AA581247, AI620585, AI754767,
					AA524616, AI114733, AI677655,
					AW265688, AI133552, AA618316,
					AI627614, AI491765, AW419389,
					AI053696, AA632993, AA601394,
					AI056046, T07225, AI270602, AA837686,
					AL120343, AW083934, AL135108,
					AW193493, AA714288, T74524,
					AI912401, AA228778, AI921765, R99034,
					AL041894, AI242011, Y18994, D50671,
					AP000031, AF053356, AC006333,
					AP000252, AL008718, AC004858,
					AC004999, AL049757, AL121653,
					AC006538, AC006449, Z82172,
					AC005751, AC005480, AB023049,
					U80017, U62293, AL049759, AL049830,
					Z81369, AC020663, AL034548,
					AC005057, AL096701, AC000004,
					Z95114, AL079295, U91326, AL035086,
					AL021977, AC002350, AC010582,
					U63721, AL023655, AL023553,
					AC005821, AP000134, AP000212,
					AP000116, AC004991, AC000353,
					AB003151, AC005031, AL031295,
					AC010205, AC005736, AL139054,
					AL133245, AC006480, AC005288,
					AF130343, AL022238, AC006057,
					AC004895, AC005363, AC007637,
					AP000304, AC005274, L11910, Z95118,
					AC005725, AF111168, AC007707,
					AC007041, AL031662, AC007216,
					AC004148, AF064858, AL031311,
					AC003042, AC005695, AC007688,
					Z97205, AC007283, AL031005,
					AC005104, AC005678, AF109907,
					AC005777, AC003007, AC007371,
					AP000688, AC006088, AC007450,
					AC003957, AL034420, AC006537,
					AL096791, AC009516, AL031276, Z99716,
					AC004905, AL049713, AL022723,
					U91318, AF001550, AC004859,
					AC004598, AC007774, AL021154,
					AC005037, AC007899, AC005067,
					AC005046, AC000118, AL132712,
					AL031770, AC005332, Z86061, Z98946,
					AL049776, AC005779, AP000044,
					AP000112, AL031779, AP000513,
					AC005365, AC004655, AC005291,
					AL135744, AL008582, AC004755,
					AC006344, AL022316, AP000344,
					AC006084, AC004408, AL080317,
					AC007686, AC006285, AL078638,
					AC004025, Z83840, AF196969, AC007731,
					AC005619, AC006199, AC004771,
					AL031281, AC004797, AC016025,
					AC006046, AF001549, AC007014,
					AC000026, AL121652, AC002352,
					AC000062, AC002431, AL020997,
					AC005041, AL132994, AJ246003,
					AC004526, Z84483, AC004890,
					AC005231, AC004883, Z84487, AP000065,
					AC004821, AC002558, AL009179,
					AC002059, AC007193, AC002544,
					AF196779, AC005081, AC004878,
					AL133163, AC008115, Z99755,
					AC005565, AC005899, Z95115,
					AC004834, AF190465, AL031768,
					AL035697, AL022336, AC005632,
					AL078581, AL022311, AC005409,
					AJ003147, AP000545, AC005005,
					AL035495, D84394, AC005911,
					AC000003, Z86090, AL121658, AL049869,
					AC007766, AC002364, AL035691,
					AL031230, AC002565, AC004129,
					AC008126, AL031123, AC005839,
					AC005207, L78810, AC005089,
					AC006160, AC005902, AC002477,
					AF124730, AC004650, AC005944,
					AC005519, AL031848, AC002351,
					AC002429, AC004832, AL023281,
					AC006012, AC005783, AL009173,
					AC004765, AC004601, AC005378,
					AL021453, Z98941, U95742, AL033376,
					AL121825, AL024498, AC006241, Z85996,
					AC006120, and AL021391.
HTPFX16	232	974296	1-470	15-484
HE9NO66	233	1079624	1-976	15-990	AI732997, AA865818, AA977633, Z69734,
					AB035267, AB020741, and Z68339.
HSDJI44	234	1154068	1-2093	15-2107	A38246, A11524, AR029497, E05333, and
					E00893.
HFXDP53	235	1126294	1-1567	15-1581	AR001481.
HWADY66	236	734565	1-490	15-504	AA923698, AI673803, AI302688,
					AF191838, AR016417, AF145705,
					AF191839, and AC000025.
HLDBC63	237	1144557	1-859	15-873	AW374344, AI424750, H12370, R32561,
					H12318, R28631, AI638545, AI760745,
					L39211, L07736, U88294, and Z56143.
HFIVB68	238	978211	1-823	15-837	AA332003, AB033033, AF182316,
					AF182317, and AL096713.
HTLAC56	239	1181355	1-836	15-850	AA614273, AA149526, AA722818,
					AA151569, AI299133, AI150935,
					AA542982, AI360422, AI079938,
					AA603610, AA716009, AI751611,
					W79786, AI083848, M78943, H40867,
					T31238, AA662256, AA298393,
					AA297499, AA541718, W79587, and
					AI074815.
HSSAD41	240	753094	1-566	15-580	AA149526, AA151569, AA722818,
					AA614273, AI299133, AI150935,
					AA542982, AI360422, AI079938,
					AA716009, AI751611, W79786, AI083848,
					H40867, M78943, AA603610, T31238,
					AA662256, W79587, AA541718, and
					AA298393.
HCFMT57	241	1218436	1-2155	15-2169	AI452994, AW370315, AI333235,
					AI983346, AI811889, AA598963,
					AW370305, D81728, D81129, AA344996,
					R14748, AI699873, AC004687, AB014512,
					and AF039571.
HDAAV61	242	1188787	1-1319	15-1333	AA314786, AA160847, AA158845,
					AA157440, AA083972, AA159380,
					AI762433, AW404501, AI191825,
					AW105372, AW386309, AA157878,
					AI140935, AI922109, AW386330,
					AA442139, AA159268, AA083866,
					AW390887, AA100183, AW390888,
					AA262414, AA041219, AA488548,
					AA158846, AA158270, AI187149,
					AW076076, AI167533, AA743207,
					AA837990, AA442140, AA488413,
					AF125532, Y11092, AL137565,
					AC007136, and Z25424.
HDPKD75	243	1096253	1-623	15-637	AA923698, AL040000, Z21326,
					AR016417, AF191838, AF191839, and
					AF145705.
HTEON29	244	1126312	1-538	15-552	AW004028, AA432290, AI968030,
					AW237673, AW138422, AA428635, and
					AA861634.
HSKAC24	245	1121800	1-497	15-511	AF170301, AF170302, AF077659, and
					AF144573.
HTJAA71	246	1216498	1-1721	15-1735	AW238721, AW265324, AW238371,
					AW238695, AW238323, AW084388,
					AF077831, and AF185276.
HTEKS20	247	1124378	1-1061	15-1075	AI936596, AA868353, AI797296,
					AA725553, AI221970, AI073397,
					AA428462, AA429551, AA431190,
					AA629305, AA629047, AW235895,
					AI123443, AI808267, AA609412,
					AI914363, AA953895, AI214385,
					AA431516, AA911681, AA781953,
					AI825106, AA298758, AI215028,
					AA909534, AA723768, D10393, and
					S63991.
HE9TK49	248	1125192	1-1353	15-1367	AA086273, AF126965, AF126966,
					AC004590, AF124351, AB012043,
					AF134985, AF134986, AF125161,
					AF027984, and AJ012569.
HCHAT01	249	1202275	1-2977	15-2991	AL079756, W80383, AA570709,
					AA746031, AA316540, N24219, W78982,
					AA740804, M78765, AA985314,
					AW337818, AA348323, H23489, W01009,
					AW273022, F10250, AW050885, H30484,
					AI494441, AA732761, N41828, Z41805,
					D51145, AL041943, AW079303, Z46179,
					H20834, H12176, H90615, AA641974,
					N28433, N45481, T31584, F12634,
					AA342119, R43266, AW365055,
					AA459071, AA464017, AA464078,
					R43775, T78049, T31949, AA046221,
					AA477480, AW139948, AW372243,
					AA143521, AW372245, R17167,
					AI655751, AA496370, R43146, T31978,
					AA496647, R25017, AA348324, H46223,
					T35092, AW071171, AA150812,
					AI085437, N99421, AA342120, AA131786,
					R08999, R09622, AW020710, and
					AB014576.
HCEEN06	250	1150867	1-752	15-766	AW249673, AI568057, AI762163,
					AW300914, AI760528, AI341537,
					AI685427, AI572091, AI560209,
					AI453713, AI025000, AI761048,
					AI972204, AW170258, AW009963,
					AA864405, AI343959, AI912498,
					AI079913, AI559574, AI418784,
					AI438969, AI559101, AI973222,
					AI660152, AW016547, AI986363,
					AA806938, AI656111, AW003957,
					AI018296, AW028203, AI652597, R52151,
					H27175, D20315, H27174, and H77974.
HDPKI83	251	883382	1-781	15-795	AA287508, W15561, N80792, AA922507,
					and AF159356.
HSPBQ12	252	1152258	1-1130	15-1144	W02910, AA282287, N72351, AA829957,
					AW205583, AW408526, AA282483,
					W86878, AA249705, R97467, AI090365,
					AB014536, and AF077226.
HPCID78	253	886915	1-793	15-807
HDTKQ14	254	886936	1-541	15-555	AL023653, AL049683, AL359542,
					AL359542, and AL359542.
HRACK83	255	888037	1-566	15-580	AC005832.
HSIAO78	256	1156438	1-1990	15-2004	AA527435, AW195324, AI653000,
					AW051613, AA514619, AI652532,
					AI675204, AA435717, AI796596,
					AI273289, AI659333, AI880669,
					AI826786, AA889355, AI174916,
					AW004627, AA377072, AA255838,
					AA397980, AA430523, AI565825,
					AI435476, AW001866, N52904,
					AA430608, AI760594, AA298640,
					W69756, AA594479, AI149418, AI911011,
					AI871818, N71537, AI089421, AA400874,
					AI038591, AA854839, AW044396,
					AI565867, AI131012, AI144119, H65663,
					N47230, AI732273, AW079534,
					AA847967, AW027678, AL044698,
					AA224892, T36269, AA009702, AI668849,
					AW182206, AA011130, N78511,
					AI676028, AA968449, AI984040,
					AA207018, AA658246, N73670, AI937659,
					R53598, AA453038, AA904224,
					AW293549, R48261, AA775033, H52314,
					R38289, H48428, AW083969, AA588654,
					F10880, AA578060, AW298073, W25831,
					AA889378, AA483944, AC002302,
					X62260, AC002288, AL035588,
					AC007425, AC004216, AF181896,
					AP000280, AP000038, AP000107,
					AF003528, AL033525, AC009498,
					AC007676, AC006080, AC005704,
					AL022328, AL118497, AC005332,
					AC007221, AL132987, AC005011,
					AC004874, U69570, Z48484, AB020858,
					AC004382, AC005213, AL049753,
					AC005771, AC004894, AC006023,
					AC003976, AL035668, D83402,
					AL139165, K03021, AC005046,
					AL035671, AC005184, AC005235,
					AC005183, AC005004, AC002541,
					AC005161, AL117338, AC004100,
					AF042484, AL117436, AC006354,
					AC004671, AC002546, AC007637,
					AC004129, AC004875, AL021877,
					AC006599, Z83822, AP000030, U61375,
					AC003693, AL009183, AC005922,
					AC004098, AC004982, Z75741, AJ006345,
					AL049821, AL035663, Z95114, AL080286,
					AL021395, AC008012, AC007529,
					Z84484, AF095703, AC006973, AL035696,
					AL078638, AP000252, AC007392,
					AC004061, AL117375, AL133162,
					AL031123, AP000466, AC007680,
					AC006952, Z82246, Z86062, AL035427,
					AF001550, AP000134, AP000212,
					AC011605, AL035106, AC006360,
					AC012088, AC000378, AC004984,
					AC005060, AL022159, AF001548,
					AC011594, AL135746, AB014079,
					AC004616, Z96074, AC007543,
					AC004015, AC004530, AL024508,
					AL031390, AC008069, AC005533,
					AC009263, AC000119, Z97876,
					AC004838, Z68324, AL031737, AP000088,
					AC006398, AC006139, AP000140,
					AP000146, AC005086, AP000228,
					AL132718, AC007198, AC007450,
					AP000299, AC004889, AC004055,
					AL035633, AC009275, AC004882,
					AL021707, AC007314, AC007156,
					AC006511, AC002563, AF152365,
					AP000514, AC005553, AC005690,
					AF047825, AC006367, AL034425,
					AL117347, AB020865, AL020989, Z84480,
					AC004888, AC005562, AP000113,
					AP000045, AC005529, AC005393,
					AC005538, AL021407, AL049839,
					U95740, AL031120, AC005701, Z75957,
					AC007617, AC000072, AC012083,
					AL008635, AC004381, L77569, AL031056,
					AC009464, Z84488, AC011700,
					AL110120, AL109914, AL035072,
					AC007262, AC007455, AL022162,
					U91319, AL118512, AL022329,
					AL121866, AL034555, AC005587,
					AL023806, AJ006995, AC006196,
					AC006213, AP000536, AC004968,
					AC006998, AC006064, AC007628, and
					AC002132.
HWAGS73	257	894404	1-587	15-601	AF156884, AL096870, and AL096870.
HCMSL08	258	898203	1-1740	15-1754	AI141895, AI201842, AI351867,
					AA251985, AA197256, F20444,
					AA194198, AI800873, F36894, F26457,
					AA482914, AA197255, AA482932,
					F30374, F32249, F27719, F32998, F01019,
					F01208, F31596, F34858, F00856, F29622,
					AA194227, F29621, F36047, AA016148,
					F00201, AA178901, F34860, AA176342,
					F35465, AA252091, F21999, AA192776,
					AI023647, F34620, S73775, U93291,
					M15747, M22717, M22712, M20142,
					M22714, and M22713.
HLWFN63	259	1101533	1-3089	15-3103	AA707313, AI880426, AI684827,
					AI744551, AI307796, AA101249,
					AI284152, AA007399, N98643, AI375268,
					N66095, R71685, R02817, AA085724,
					AI221876, AI061056, AW207571,
					AA111956, AI460369, AI333887,
					AA594062, R18624, R62793, W22434,
					AW007868, AA776586, T70023, R71720,
					H70803, AA101290, AA323135,
					AA029721, AA320669, AI193496, R07828,
					AA007478, AI915644, AI932703, T69946,
					R62792, AA029660, AI859215, AA205667,
					AI625446, AI273982, AB018333, and
					AC006599.
HPWAY10	260	1128033	1-1154	15-1168	AI027613, AA332875, AW367440,
					AW376896, AA330257, AL042522,
					AW367550, AW304212, H80390,
					AA447076, AI923485, AW316546,
					R08512, AB023178, Z30174, AC007676,
					AC007842, AC004696, AC005498,
					AB021641, and X78933.
HOUDH19	261	1153909	1-392	15-406	AW207457, AI084622, AI392839,
					AA628082, AA534387, AW243188,
					AW129204, AI695812, AI572814,
					AI948743, AA651748, AA301865,
					AW371758, AC007842, and AC005614.
HDPFF24	262	1194719	1-1774	15-1788	AI279875, AW369718, AI800428,
					AI566117, AA446945, AI246362,
					AA565728, AI436697, AA443369,
					AI761945, AW237445, AI889318, N66534,
					AW103788, N52334, AW302153,
					AW131719, AA588564, AA261806,
					H56725, AA199832, AA287107,
					AW419044, AI015242, AI807571, T80574,
					AI929099, N75104, AI269178, AA207149,
					AA912487, AA086082, AA780112,
					AI928828, R38930, AW450464,
					AA766626, AI904377, AA086081,
					AA365879, N88094, R68759, AA662606,
					AA281290, AA577126, R58834, H67457,
					D58175, N87549, H56648, T03486,
					AA261992, N28632, and AI913676.
HWLFH94	263	1152278	1-1268	15-1282	AI339104, AA861042, AA134985,
					AA868144, AA134946, AI626100,
					AA922724, AA535447, AA308766,
					AA056635, D25742, AA916634,
					AA551763, AA873574, AW192836, and
					AR044148.
HWMBM13	264	1152283	1-879	15-893	AI339104, AA861042, AA134985,
					AA868144, AA134946, AI626100,
					AA922724, AA535447, AA056635,
					AA308766, D25742, AA916634,
					AA551763, AA873574, AW192836, and
					AR044148.
HFIUE75	265	1172525	1-1596	15-1610	AA745592, AW408392, AA780791,
					AI680317, AA205127, R06019,
					AW074511, T76970, T86065, AI709216,
					T77135, R05922, T85884, R77022,
					AA730855, C14389, C15076, R65976,
					D81026, D59467, D80164, D81030,
					D59787, D80166, D59619, D59502,
					D80210, D80240, D80212, D80219,
					D80188, D80022, D59859, D51423,
					C14331, D51799, D80253, D80043,
					D59610, D58283, D80195, D80391,
					D59275, D80227, D57483, D80366,
					D80193, D80196, D59889, D59927,
					AA305409, D80241, D50995, D80251,
					D80269, D80038, D50979, D80522,
					C14429, D80024, AW177440, D51022,
					D80045, AA305578, D51060, D80378,
					C14014, AW378532, T03269, C75259,
					AW178893, D80248, T11417, D80133,
					AW179328, AA514188, AA514186,
					AW377671, D80134, D80268, AW177501,
					D51250, AW177511, C05695, AW360811,
					AW178762, D58253, AW369651, C14077,
					AW352158, AW178775, D59373,
					AW176467, AW375405, AW352117,
					AI910186, F13647, D80439, D80132,
					D80247, AW366296, AW360844,
					AW360817, AW375406, AW378534,
					AW179332, AW377672, AW179023,
					AW178905, D81111, AW378540, C06015,
					D51213, D80302, AW352171, AW377676,
					AW178906, AW352170, AW177731,
					AW178907, AW179019, AW179024,
					AW360834, AI905856, AW177505,
					AW360841, Z21582, AW179020,
					AW178909, D80157, AW177456,
					AW179329, AW178980, AW177733,
					AW378528, AW178908, AW178754,
					AW179018, D80014, AW352174, C14227,
					AW179004, AW179012, AW178914,
					AW378525, D59627, D51103, D51759,
					AW177722, AW177728, T02974,
					AW179009, AW367967, D59503,
					AW178774, AW178911, AW378543,
					D58246, AW352163, D51097, D80258,
					D59653, AW352120, AA285331,
					AW178983, D58101, AW178781, T48593,
					D80064, AW177723, D45260, D80168,
					H67854, C03092, AI557774, AW177508,
					C14975, AI535850, D80949, AW367950,
					D51079, H67866, AW378533, C14407,
					AA809122, AI525917, C14344, AI525923,
					AW178986, AW177497, D51221,
					AI535961, T03116, D80228, AW177734,
					D59317, D59474, C14973, AI525920,
					AA514184, D59551, C14298, C14957,
					D45273, AI525215, D60010, AI535686,
					D50981, AI525235, D60214, AW378539,
					AI525227, C14046, AI525912, D51053,
					AI557751, T03048, AI525242, AW378542,
					AR018138, A62298, A84916, A62300,
					AJ132110, AF058696, AR008278, A25909,
					X67155, D26022, Y17188, AB028859,
					A67220, D89785, A78862, D34614,
					D88547, Y12724, X82626, A82595,
					AR025207, AB002449, A94995,
					AR060385, AR008443, AB012117, I50126,
					I50132, I50128, I50133, AR066488,
					AR016514, X68127, AR060138, A45456,
					A26615, AR052274, A85396, AR066482,
					A44171, A85477, A30438, Y09669,
					I19525, A43192, A43190, AR038669,
					A86792, I18367, AR066487, I14842,
					X93549, AR066490, AR008277,
					AR008281, U87250, D88507, AR054175,
					D50010, Y17187, A63261, AR008408,
					AR062872, A70867, AR016691,
					AR016690, U46128, U79457, D13509,
					AR060133, A64136, A68321, I79511,
					AF135125, AF123263, AR032065, and
					AR008382.
HNTCP13	266	1182313	1-2243	15-2257	AA463847, AI479379, AW273740,
					AI740675, AI922082, AW009462,
					AI014722, AA463334, AI073540, N95224,
					AA007373, AI190238, AI798079,
					AA476563, AA670286, H02882, N92851,
					AA652716, H45475, W25554, AA774170,
					AW016339, H45576, AI370125, H03781,
					AW119159, AI811794, H20952,
					AA853882, AA853883, AI471060,
					AW382128, AW371996, W21053, H20991,
					AA368628, AW138258, AA476448,
					AA876335, AA788825, AF037447, and
					AC004486.
HB1BQ89	267	1175111	1-2849	15-2863	AA496424, AW296705, AA292435,
					AA768388, AI359369, AA136659,
					AA435941, AW192609, AI361569,
					N62073, AA136739, AA411140, AI940074,
					AA101178, H09588, AA419044, AI358988,
					AA399613, AA323662, AL118665,
					AI268044, AA436039, H09587, AA627787,
					N55651, AA325534, T15506, AA082253,
					AA423798, AA904377, Z41610, R19206,
					F01655, F11248, R44468, C00466, Z42117,
					N77119, F08911, AA767800, AI418714,
					F05395, T35421, and AB007925.
HWBEG18	268	1169125	1-448	15-462	AI114866, AI500518, AW327796,
					AW328350, AI755116, AW328609,
					AW410322, AW409642, AI754439,
					AW409590, AI754460, AI287514,
					AA551550, AA483482, AW205951,
					AA535393, AI201181, AI699829,
					AW409683, AW328376, AW328614,
					AW087373, AI827247, AW328444,
					AW327862, AW328440, AW328380,
					AW007896, AI971783, AW328007,
					AI628924, AI610070, AW080272,
					AW134985, AI440000, AA603360,
					AA501684, AI560651, AI559540,
					AA574413, AI818460, AA854768,
					AI754142, AA283266, AI497632,
					AA772414, AA496883, AA679713,
					AI050044, AI619744, AI339813,
					AW250421, AI274211, AW020501,
					F32918, AA579416, AA652660, AI567937,
					AA632536, AI831479, AI186976,
					AI151481, AW328320, AA877933,
					AI185119, AA513486, AI620681,
					AI690593, AA558105, AA610650,
					AA632560, AI922235, AA843775,
					AI924171, AI961721, AW250755,
					AW090148, AA491636, AI338728,
					AI123375, AW081336, AW090155,
					AI539209, AI890302, AW137738,
					AA847963, AA632723, AW007719,
					AA757769, AI573062, AA886011,
					AW245791, AI028444, AI863898,
					AI439763, AA886913, AA508174,
					AI749978, AA863478, AW261931,
					AA714364, AI634383, AI191638,
					AI198771, AI719450, AI344453,
					AI718439, AI268677, AI253560,
					AW250772, AI796657, AI347293,
					AI619835, AA569292, AW169077,
					AI570813, AI697471, AI149358,
					AI355377, AA610275, AI565047,
					AI193415, AI571454, AW262848,
					AA954603, AA600356, AI674831,
					AW316876, AA536172, AI185211,
					AI660181, AW273029, AI818029,
					AW192285, AA580796, AI719806,
					AI813549, AW242012, AI620986,
					AI830017, AI478688, AI925379,
					AI683998, R02544, AI745129, AI491901,
					AW338471, AI582160, N91538,
					AW090784, AI610180, AI697356,
					AI660159, AI925537, AI224078,
					AI859783, AW028278, AA598891,
					AI281231, AI289421, AW105711,
					AW305195, AA908802, AW073669,
					AI800405, AI342580, AI432916,
					AW170472, AA513180, AA653476,
					AI272858, AI963461, W73177, AI620289,
					AI523503, AI891159, AI475307, F24388,
					N32326, AW008147, AI270199, AI924530,
					AA448266, N64026, AW118551,
					AI560707, F20364, AA776791, AI206373,
					AI189997, AI510744, AA723534,
					AI631303, AA991428, AI979037,
					AI689023, AA505910, AA304640,
					AI962912, AA879052, AW073952,
					AI673755, AI951247, AA737215, F21939,
					AW005146, AI624705, AA879000,
					AA662258, AW023162, AA609197,
					AA984855, AI983037, AI734902,
					AI921779, N32870, AI718498, AW170473,
					AI924173, N34014, AI860956, AI523495,
					AW166489, AI818256, N31753, AI583997,
					AI000938, AI749136, AI333494,
					AA580751, W85708, AW328378,
					AA580635, AW328608, AI439940,
					AI830217, AI924195, AA491865,
					AI986358, AA312014, AW440520,
					AI860497, AI557538, AI185035, W37825,
					AI160628, AW148607, H73192,
					AA888879, AW273989, M36072,
					AC000089, AJ224080, AC004217, X06705,
					X61923, X52138, AC002107, AB023058,
					AP000521, AF055066, AL022723,
					AC004192, AL034417, AJ224082,
					AC004172, AJ224081, X15013, AC000399,
					Z84469, D63790, AC005042, AL031736,
					AC004129, AL078595, AC007110,
					AB020653, AC002452, and Y17212.
HTAHB43	269	1221956	1-2344	15-2358	R53155, AW374891, AA029227,
					AA010232, AA149376, AA077657,
					AA077229, AA077669, AA076731,
					AW405369, AW386712, AW386708,
					AA077893, AF139794, AA077980,
					AA077825, AA078429, AI768799,
					AI912020, AA077544, AI738591,
					AA076983, AA076893, AI125178, F01048,
					AW373785, AI963990, AB011110,
					AC004084, and AC004985.
HSYBX32	270	909846	1-216	15-230	AA078429, AC004084, AB011110,
					AC004951, AC004951, AC004951,
					AC004084, AC004084, and AC004084.
HCEHE35	271	1124531	1-537	15-551	AB019692.
HFCBB56	272	1204971	1-2144	15-2158	AA547979, AI696793, AA847499,
					AI889995, AI279417, AA669155,
					AA833875, AA833896, AL036909,
					AW162288, AW237905, AA862183,
					AA019542, AW408767, AA491955,
					AA904211, AW265688, AI366555,
					AI620992, AI251034, AI250552,
					AI284543, AW303098, AI251203, F13749,
					AW407889, AW026305, AI251284,
					AI421950, AI628922, AA831426,
					AA916430, AA828834, AA339423,
					AI493583, AL038606, AA614214,
					AI223626, AI224619, AW005974,
					AI492579, AA572983, AL047247,
					AA864271, AA053463, AL042667,
					AL042670, T57767, AI254770, AW316599,
					AA600202, AA832016, AA565232,
					AI278372, AI791185, AI753969,
					AL022316, Z84469, AC007934,
					AC000025, AL122020, AF015262,
					AL049869, AJ229043, AL021977,
					AC009516, AC005800, AC004821,
					Z83844, Z83822, AL031681, AL033392,
					AC005726, AC007298, AL133163,
					AC002549, AC006001, AL034429,
					AC006530, AL031311, AP000558,
					AL034400, AP000310, AC002395,
					AL022067, AC006441, AC002565,
					Y07848, AC005531, AC005527,
					AC004991, AP000155, AC005871,
					AL049758, AL049761, AC005736, Z95114,
					AC005529, AL008631, AL031680,
					AL133353, AC002472, AC009509,
					AP000116, AC012384, AC007325,
					AL022322, AL139054, AP000501,
					AC000035, AP000704, AC005972,
					AP000210, AC004815, AC002477,
					AC005484, AC012085, AC011311,
					AL031659, AC002430, AC005300,
					AC005229, AL050318, AC004895,
					AL008731, AC006241, AC005089,
					Z95115, AC005243, AC007384,
					AC007242, AC005520, AC002492,
					AC016831, AC002312, AC003664,
					AC020663, AC002091, AC005088,
					AL049712, Z73359, AC002381,
					AC005876, AC005480, AC005837,
					AF165926, AL135744, AC005952,
					AC004263, AC005829, AC004494,
					AC005412, AL031657, AL022238,
					AP000030, AC005697, AL049872,
					AC004699, AC002300, Z94056,
					AL022315, AC005755, AP000132,
					AC008040, AC004883, AL020997,
					AC005670, AL022163, AC003684,
					Z98047, AC007546, AC007065,
					AC005231, AC005220, AL049874,
					AC004859, Z85986, AC016025, AF196969,
					Z86090, AL096768, AP000014, AL031587,
					AC004552, AC000026, AC005874,
					AF134471, AC005901, AF111168,
					AL031282, AC004921, AC005399,
					AL121658, AL049709, AL031848,
					AC004167, AL030996, AF064861,
					AL034420, AL035086, AL023877,
					AF111167, AC004659, AL132777,
					AC006160, AC003962, Z98884,
					AL022165, AC002350, AL031431,
					AC004884, AC006974, AL133243,
					AC005037, Z95331, AC005859,
					AL031295, AC007055, U91322,
					AC000003, AL096791, Z82189,
					AC004149, AC005667, AF001550,
					AF207550, AL035423, AL031591,
					AC008928, AC009946, AL121603,
					AC004383, AL009172, U91321,
					AC006065, AC008018, AC006285,
					AL096701, AC004812, AC007130,
					AC004231, AL133448, AF117829,
					AC007435, AC007227, AL121655,
					AC003043, AL022476, AC005011,
					AC005031, AC005722, AC005808,
					AL035555, AC006275, AL049829,
					AL078477, AL049538, AC005703,
					AC006958, AC007406, AC007631,
					Z95113, AC008179, AC005592,
					AC005295, U52112, AC002310,
					AC004675, AC005996, AC006013,
					AF205588, AF003626, AC002369,
					AC007308, AL031585, AC006377,
					AC007880, AP000694, AC007948,
					AC007563, AC007216, U52111,
					AC004865, AC004150, AC004084,
					AC005216, AL135783, AF088219,
					AC012330, Z83826, AL031588,
					AC004020, AC005377, AC005206,
					AP000088, AC002059, AC005358,
					AL031280, AL050341, Z97056, AC005754,
					AC004773, AL034406, AP000065, and
					AC000379.
HAMFL82	273	910074	1-489	15-503	T78839, and AB029015.
HBXCM38	274	1174533	1-2161	15-2175	AI752485, AI804792, AI439106,
					AI971133, AI991958, AI752484,
					AI432296, AI478420, AW082819,
					AI912373, R89026, AI554161, AA894797,
					AI752414, H13307, AI249165, R61527,
					N62403, R89727, N47856, AI689339,
					R61583, AI368569, AI984780, H44175,
					AA219502, T32963, AI802627, AI752415,
					AW295386, AA985168, H06745, R40750,
					M79099, AA203312, R00511, A91842,
					A91846, A91844, and A91848.
HLHCR16	275	910123	1-3790	15-3804	AA402528, AI379350, AA716107,
					AI123557, AI127175, AA234106,
					AA234698, AI039768, N77999, AI580137,
					AA424560, AA419490, AI334141, R71349,
					AI224976, AI417798, AI080508, N58410,
					AI818475, AA424657, N91089, AA399612,
					AI144265, AA399137, AI498363,
					AA410986, AA235306, AA399148,
					AW292497, AI249102, W86869,
					AA115407, H81257, AI077499, H00194,
					H45499, R01206, AW104245, AA234880,
					AA367417, AA852175, F05822,
					AA853077, AA852176, R82875, H81245,
					AA298421, R71350, R22096, H81585,
					AI985171, T49265, H81591, AA115408,
					R64037, T54283, AI492930, AI492932,
					R82876, R81695, R33935, R34138,
					R25630, H81595, R32025, R81696,
					T49264, R95688, R01319, R22040,
					Z21579, R33043, Z38741, AA514393,
					T97662, T34993, AA705441, D79105,
					R32078, H45500, AA707178, R30943,
					H81576, H81250, AI032721, AL079279,
					and I76197.
HE6GF02	276	1153883	1-599	15-613
HOUFT36	277	1162680	1-1842	15-1856	AI190165, AI979249, AI917302,
					AI806483, AI633819, AI624750,
					AI147946, AI471728, AW196791,
					AI471611, AI985423, AA609421,
					AA256164, AA705338, N22327,
					AA811162, N75202, AW236751,
					AI922484, H79904, AA057615, H79810,
					AW362445, AW407702, AA542823,
					AF162130, AF161181, and AC005084.
HAGGF84	278	1197460	1-4064	15-4078	Z99408, AI829910, AI004608, AI263188,
					AI262955, AA777512, AI625727, Z99409,
					AI436555, AI494561, AI085959,
					AI540110, AA481595, AA521313,
					AA283109, AL135568, AA988090,
					AA810697, AA233122, AI933149,
					AI754128, AA010623, AA806759,
					AI818869, AA809487, AA766911,
					AA316038, AA010624, AI750702,
					AA235130, W88865, AW296786,
					AI537382, AI432148, AA837093,
					AW385431, AW190812, AI033124,
					AI002712, W88760, AA283596,
					AA234956, AW295662, AA788729,
					N44843, AA777583, AA554176,
					AA889979, AA446963, AA448956,
					N55182, AI374973, AA447669, AI690467,
					AA283023, AA233206, AI073663, N33311,
					W27009, AA490727, R44959, AW135448,
					H12918, AA683306, AW021785, N93004,
					AA491218, W05278, AI393402, R37684,
					W30935, H54295, W45465, AA865595,
					AA765107, AA614573, AA767313,
					AA009487, H17018, AA767430,
					AW022593, R13824, AA736921,
					AA282705, H54372, AL120285, H67974,
					F00924, W56321, AA447819, W02795,
					AI124777, AA665370, AA687964, F00219,
					R20172, AW239099, N77241, H17017,
					AW262494, AA449684, AA481529,
					T39306, AI810957, W05327, AI750703,
					H87993, AW263323, F02227, F05900,
					Z33528, N75469, AA782796, AW262536,
					N75534, H05503, N37017, W56241,
					H54503, F02057, F05985, T40514,
					AA009901, F05811, AA322373,
					AA476641, R00735, R58669, H67654,
					AA732599, R00734, AA766461, AI381341,
					AW130224, R08857, AA330053,
					AA400645, AA730271, R08964, N88052,
					T19108, AI432714, AA424457, AI051190,
					W21355, AW148465, AF071569, D14906,
					U73504, AJ252239, J05072, X63615,
					L07044, AC004168, AC004056, U66064,
					X77192, X75774, X77193, X77195,
					X77194, L13406, L13407, L13408,
					AF059029, U50361, U73738, AF067728,
					AC006115, AC006112, AF107018,
					Y00093, AF179633, AC005156,
					AL133088, AW627616, AND AW630893.
HTTKP07	279	1119031	1-598	15-612	AI640500, AA035703, AF130247, and
					AF165138.
HE9SE62	280	1171014	1-706	15-720	AI765247, AW021430, AI822051,
					AI822104, AA010459, N70537, AL133567,
					and AB018312.
HUJAD24	281	1162674	1-1732	15-1746	AI923935, AI336906, AI333385,
					AI312076, AW204515, and AI203953.
HWLFG75	282	1228123	1-2024	15-2038	AI356559, AW163067, AI937030,
					AI652337, AW028706, AW157098,
					AW028808, AA004795, AA443325,
					AW005140, AW173645, R60229,
					AA442531, AI274924, AI810652,
					AI924004, AI572794, AI336556,
					AI672253, AI147260, AI872258,
					AI347103, AA467751, AA724594,
					AI280850, R52646, AA536110, H16834,
					AW450707, AW444512, AI376913,
					AA468349, AI807962, AA927875, R42625,
					AA609873, W28566, AI918962,
					AA578362, AA578062, R17389, C18386,
					R15375, AI016851, R60462, H16941,
					AI423739, AA467933, AA740299,
					AA025666, R42116, AA978110, AI423740,
					AW117517, AI886594, AA443338,
					AI857296, AW071349, AL048871,
					AL047763, AI702406, AI250293,
					AW117882, AI702433, AW195957,
					AI439087, AL119791, AI568870,
					AI433976, AI499463, AI538716,
					AI633419, AI349933, AI678302,
					AW274192, AI868831, AI498579,
					AI613017, AW162071, AI699857,
					AW071417, AW235035, AI540832,
					AI863014, AI628205, AW169653,
					AI249257, AW238730, AI349004,
					AI690835, AI224992, AI349772,
					AW301409, AW103371, AI866608,
					AL120736, AI564719, AL135661,
					AI866002, AI440426, AI590128,
					AI620284, AI275175, AI281779,
					AI433157, AL036146, AL036396,
					AI340582, AI521012, AI500077,
					AL040243, AI567351, AW074993,
					AI349645, AI500553, AW268253,
					AL045500, AI312152, AI345735,
					AI349937, AW089572, AI366549,
					AW068845, AI568854, AI597918,
					AI673256, AL038605, AI497733,
					AL047042, AI969601, AW148320,
					AI800453, AI800433, AI636456,
					AI635461, AL121270, AL036802,
					AI800411, AI682841, AL119049,
					AI610645, AI282655, AI597750,
					AI921379, AI758437, AI866887,
					AI432229, AI625079, AI690751,
					AI343112, AL036274, AI349256,
					AI567632, AI349614, AI570384,
					AI281773, AI434281, AI686926,
					AI687728, AI282903, AW303152,
					AL043326, AI207510, AI697137,
					AA640779, AI445432, AL121365,
					AA613907, AA572758, AL036759,
					AI679724, AI499393, AL038779,
					AI539771, AI811863, AL036980,
					AW074869, AW085799, AI475371,
					AI620868, AI815383, AL119748,
					AI569616, AI610307, AI436456,
					AI064830, AI631107, AI969567,
					AI608667, AI818683, AI687376,
					AI285735, AI439745, AI348897,
					AL046849, AL040169, AW002342,
					AL038778, AI920968, AI475134,
					AI469532, AI872711, AW301300,
					AI889203, AW168384, AI580984,
					AL047041, AI580190, AI873731,
					AI269696, AI680113, AI889839,
					AI671679, AI874109, AI753683,
					AI610756, AL120854, AI934036,
					AI609592, AI583316, AW166645,
					AW167776, AW080838, AI343059,
					AI446606, AI799199, AI499131,
					AW196141, AI255071, AI866780,
					AI919058, AI539153, AI687415,
					AI818206, AI345860, AI952114,
					AI687375, AL042753, AW087445,
					AI149592, AI906328, AI907070,
					AI804585, AI492540, AI469811,
					AI636445, AI345111, AI500659,
					AA508692, AI349226, AL080060, I48979,
					AL133016, Y11587, I89947, S68736,
					AR059958, AF090901, AF113691,
					AL110221, AL137527, AF113689, A93016,
					AF113676, S78214, AL049452, AL050393,
					AF090934, AF104032, AL133640,
					AF113013, AF118064, AF118070,
					AF078844, AF090900, AF090903,
					AF125949, AF113694, AF090943,
					AL049938, L31396, AJ242859, AL050146,
					AL133606, L31397, AL117460, AF113690,
					AL050149, AF106862, AL110196, X84990,
					AL117457, I89931, AF090896, A08916,
					AL050116, AL050108, AL050138,
					U42766, AL049466, AL133075,
					AB019565, AL049314, E03348, AL122050,
					AF113677, AF113019, AL080137, A08913,
					AF017152, AL080124, AL137283,
					AL133557, AL122093, AL050277,
					AL096744, I48978, U91329, AR011880,
					AL133093, AL122121, AF158248, X63574,
					AL049430, AF113699, AL137557,
					AL133565, Y11254, AL133080, X82434,
					Y16645, AJ000937, E07361, AL122123,
					AF091084, AF111851, AL137459,
					AF177401, AL117394, AC002467,
					AF146568, AL117583, AF125948,
					AF097996, AL110225, AL021393,
					AF079765, I49625, S61953, I33392,
					AF017437, A08912, U80742, U00763,
					AL050024, AL117585, AL049382, E07108,
					AL133560, AL137550, A65341, AF000145,
					A08910, AF095901, AL049464, AJ238278,
					E02349, AL049300, AL117435, AF067728,
					X70685, X72889, Z82022, AL122098,
					AF183393, AC006222, AC006371,
					AC007390, AF118094, U62317, A58524,
					A58523, AL137271, U72620, A08909,
					I03321, AC002464, AL137463, AL096776,
					I09360, AL137538, AL022147, AL133113,
					AC004200, AL122110, AL049283,
					A03736, AL080127, AC007172, A77033,
					A77035, E05822, A12297, AP000344,
					U35846, AF087943, AL137648, AL031281,
					X96540, AC010077, AF061943, A08911,
					X65873, U95738, AC004690, AC009233,
					AL110197, AC005291, X93495,
					AC007458, AC005057, AC006336,
					AF177767, L13297, AC004093, U67958,
					AL080159, AJ012755, U95739, AC005048,
					I42402, X98834, AL022723, AL049557,
					AF111112, A21622, AL031732, AL078630,
					AC006112, AC004686, U66059, A21625,
					Y09972, AL133072, AL137521, AF132341,
					AC007298, AL080154, M30514,
					AC003977, AF093117, and I17767.
HT3BG12	283	1092417	1-1050	15-1064	AI028599, AA774434, AA905685,
					AI393349, AA991810, D80022, D80268,
					D58283, D80043, D80166, C14389,
					D50995, AW360811, AW178893, C14331,
					T03269, AW177440, D59927, D50979,
					D57483, D59859, D80195, D51423,
					D59619, D80210, D51799, D80391,
					D59275, D80240, D80253, D59787,
					D80227, D80522, D59502, AA305409,
					D80164, D59467, AW178906, D81030,
					D81026, D51060, AW377671, AW375405,
					C14429, D80188, D80212, D80193,
					D80196, D80219, AW179328, D80247,
					D80038, D80269, D80366, D59889,
					C15076, D80024, D80439, D80248,
					AA514186, D80045, AW366296, D59610,
					AW360844, AW360817, D80378,
					AW375406, AW378534, AW352158,
					AW179332, AW377672, AW179023,
					AW178905, AW378532, D51022,
					AW378528, AW178762, C14014,
					AA305578, T48593, D80133, AW176467,
					D80302, AW369651, AW178775,
					AW177501, D80241, AW177511,
					AW177731, AW352120, AA514188,
					AW352171, AW377676, D51759,
					AW352170, AW178907, AW179019,
					AW179024, D51250, AW178983,
					AW179020, D80251, AW360834,
					AW360841, D51103, AW178908,
					AW177505, C75259, AW352117,
					AW178909, AW177456, AW179329,
					D80157, AW178980, AW178914,
					AW178774, AW367967, AW177733,
					AW178754, AW179018, AW367950,
					AW179004, AW178986, AI905856,
					AW378543, AI910186, AW378540,
					AW177728, AW378525, AW352163,
					D80134, AW178911, D80132, AW178781,
					C06015, C05695, AW177734, AW378533,
					D51097, D45260, D58253, T11417,
					C03092, AW177723, H67866, H67854,
					D80064, AA809122, F13647, AA285331,
					C14227, AW378542, D59317, AW378539,
					AI525923, D80014, AA514184, AI525917,
					D59474, T03116, AI535686, AW360855,
					D58246, D81111, D80258, D59503,
					C14973, D80314, AI525920, AI525913,
					AI525227, D58101, AI525242, D59551,
					AI557751, AI557774, AI525912,
					AI525235, AI535959, AI525925,
					AB028951, AL122055, A78862, A62300,
					AJ132110, AR018138, X67155, A67220,
					D89785, D34614, A84916, A62298,
					AF058696, Y17188, D26022, A25909,
					AB028859, AR008278, I50126, I50132,
					I50128, I50133, A94995, Y12724,
					AR066488, A82595, D88547, AR008443,
					AR016514, AR060138, A45456, Y09669,
					A26615, AR052274, AR060385,
					AR066487, X82626, AB002449, A30438,
					A43192, A43190, AR038669, AR025207,
					D50010, Y17187, A70867, A63261,
					AR016691, AR016690, U46128,
					AR008408, AR062872, AR066490,
					D13509, AR060133, AR054175, I18367,
					A64136, A68321, I14842, AB012117,
					X68127, AR008277, AR008281,
					AR050680, AF123263, AR032065,
					U79457, and AR008382.
HTLJC71	284	922923	1-1738	15-1752	AL039539, AL045443, AI336919,
					AA406128, AA405229, AL042307,
					AA431504, AA311249, AW086440,
					AA813520, AI240644, AA897733,
					AW268487, AA782009, AW172455,
					AI301209, AI014598, AA969918,
					AL041043, AA431178, AL039540,
					AA973051, AI221826, AL133030,
					AC009516, AP000552, AP000556,
					AP000557, AL117509, AC023490,
					AC023490, AC009516, AC009516,
					AC009516, AC018751, AC018751,
					AC018751, AC007957, and AC007957.
HCOMM05	285	1194701	1-1624	15-1638	AI681802, AA534542, AL044632,
					AI912061, AI912050, AI298280,
					AI271683, AA587766, AA143726,
					AA565889, AI052230, AI983603,
					AI148467, AI028441, AI369272,
					AA079779, N93876, AI950520,
					AW024410, AI933105, AW138648,
					AI244430, AA583571, AA436795,
					AA158795, AA079751, AA595313,
					AA947417, R27340, AI373637, AI869920,
					AI244362, AW182724, AW381284,
					AI991003, AI250467, AI252203,
					AI252717, AW086414, AI252210,
					AI611516, AI345868, AI348932,
					AI308005, AI345138, AI310659,
					AI250541, AI311504, AW303046,
					AW301779, AI311180, AI250964,
					AI335365, AI250009, AI348928,
					AW086115, AI862506, AI305732,
					AI335130, AI311179, AI269522,
					AI305978, AI371584, AW301495,
					AI251162, AI254155, AI310038,
					AI311043, AI251045, AI335320,
					AI590436, AA158794, AW301422,
					AI224292, AI310178, AI284537,
					AI252538, D31472, AI053635, AI540612,
					AI685886, AI862262, AW268255,
					AW371409, W40369, AW071370,
					AI886550, AW371414, AI955911,
					AI024888, AA143739, AI254135,
					AI246935, AW177721, T35070, C00345,
					AW371416, AA902858, AW369434,
					AA581215, R34522, AA835966,
					AA083230, AW078797, AI475833, and
					R35706.
HSLJE54	286	1229928	1-2015	15-2029	AA224020, AI906305, AA325180,
					AI282479, AW237905, AL038842,
					AW410354, AW069227, AW327624,
					AW340905, AA904211, AI634187,
					AW162288, AW023111, AI696793,
					AA584489, AI278972, AA558404,
					AI340641, AW275432, T05834,
					AA640430, AI635028, AI457313,
					AW272294, AA225406, AI076236,
					AA916430, AI340832, AI284640,
					AI358712, AL046409, AA640410,
					AI891080, AI280266, AL039041,
					AL039042, AW276827, AI753365,
					AI609972, H73550, AW021917, F13749,
					AA742815, AI192440, H71738,
					AW264901, AA829065, AA557982,
					AW271917, AW243793, AI362442,
					AA704393, AW303196, AA133472,
					AW274349, AI560085, AI755057,
					AA503018, AL079869, AI587583,
					AA747757, AW243831, AI587565,
					AI890324, AA832175, T47138, AI694784,
					AI246796, AI628859, AI570261,
					AW105346, AI250552, AA557945,
					AW301350, AI284543, AW408767,
					AW157731, AW193265, AA828619,
					AI620992, AW341903, AI859438,
					W63553, AA565911, AA182731,
					AW084445, AW068596, AA639155,
					AW029038, AI254770, AI245693,
					AI909199, AI570943, AA169245,
					AW328446, AI457597, AI251284,
					AI251034, AI251203, AI223626,
					AA502532, AI310464, AI431303,
					AA659832, AA772906, AA604831,
					AI251104, AI635196, H71678, AA653823,
					AA469327, AW078909, AF116548,
					AF116546, AF116547, X94152, AJ132661,
					E13557, M64755, AF116545, AF115343,
					AF115344, AL049779, AC005722,
					AP000692, AC007363, AL035462,
					AC007899, AC007707, AL049760,
					AL023553, AP000228, AP000140,
					AC007546, AC007201, AF129756,
					AP000555, AP000088, AC004552,
					AP001052, AC005529, AC006441, Z84487,
					AC005740, AC006285, AF107045,
					AC000118, AF031076, AL022718,
					AC009044, AC005233, AL031984,
					AL049548, AC005015, AL133485,
					AC005081, AC006130, X96421,
					AC007285, AC005837, AL008726,
					AC005881, AL031311, AC010205,
					AL049869, AC005409, AC005921,
					AC004778, AC005284, AF031078,
					AC003104, AF134726, Z85996, AC006965,
					AC005261, AC005363, AC009247,
					AF003626, AL109799, Z93023, Z95115,
					Z94056, AC005274, AC005527,
					AC005520, AC004534, AC002037,
					AC005049, AC005300, AF047825, Z93244,
					AC005899, AL049776, AC007253,
					AC005200, AL049576, AL035361,
					AL031432, AC003957, AC005598,
					AL031427, AC005620, AC004841,
					AC006312, AP000553, AF190465,
					AL031767, AC005004, Y18000,
					AC000068, AL096701, AL031286, Z93930,
					AC005775, AC005666, AC004922,
					AL122020, AC005288, AC005345,
					AL022320, M87889, AC004859,
					AL031681, AC009516, AF001549,
					AC006125, AC007327, Z93096,
					AC005011, AC005839, AC004525,
					AC007868, AL080243, AC004776,
					AL031774, Z98051, AL121658, L35532,
					AL031729, AF077058, AC005763,
					AC006040, AF030876, AC005694,
					AC004819, L78810, AL022336, Z82201,
					AL035461, X53550, AC005874,
					AF134471, AC006241, AC002070,
					U96629, AL109798, AF196969,
					AC007541, AL049743, AC003683,
					AC004598, AP001053, AC007649,
					AL031587, AC004743, AJ246003,
					AL031230, Z81314, AC005988,
					AC005189, AC007510, AC003665,
					AC003070, AF015160, AC008064,
					AC002394, AC007386, AP000065, Z97053,
					AC006101, AL009181, AC000353,
					AL022165, AC007406, AL080317,
					AC005962, AL021397, AC006064,
					AL049748, AL035530, AL109753,
					AC004659, AC005544, AC006468,
					AC006006, D83989, AC007435,
					AL049766, AC005229, AC005378,
					AL021918, AL023582, AC003035,
					AP000213, AL049823, AC005476,
					AC004211, AP000313, AP000135, X75335,
					AC004757, Z83846, I34294, AC002306,
					AC002477, AC002347, U57008,
					AP000303, AL035413, AL024508,
					AC002350, AC002365, AL008725,
					AC004760, AP000031, AC003080,
					AC004752, AB001523, AP000117,
					AC006372, AC004884, AC004668,
					Z95152, AL121603, and AC003010.
HTGED07	287	927411	1-489	15-503	AA565765, AA565751, AI765474,
					AA085796, AA988365, AI380028,
					AI243840, AA976164, F05393, H13329,
					Z78407, T78216, D82559, AI868591,
					AL121852, AL117355, AB020724,
					AF092139, and AF110646.
HOFNH30	288	928365	1-362	15-376	AF186380, and AF127138.
HWNCY05	289	1179767	1-968	15-982	W40569, AW025860, D63226, AA334307,
					and AC006928.
HDPDA47	290	929193	1-1036	15-1050	AW402583, AL049683, and AL023653.
HWMEV63	291	931154	1-440	15-454	D13626, and AC078816.
HCFAT25	292	1052857	1-626	15-640	AI287912, AI349658, AI792640,
					AF096300, AB014587, AC005035,
					AL137755, and U88984.
HHEQV39	293	1165420	1-873	15-887	AA355773, and AA355926.
HHFJH79	294	1228195	1-2303	15-2317	AW370568, AI684034, AI567533,
					AW361753, R17150, AA554360,
					AW245518, AW245843, AL046054,
					AI185853, AI814502, AI830917,
					AW027953, AI423947, AI761370, R77851,
					AW028779, AA338439, R59685, R25627,
					AI244276, AA587224, AI342419,
					AI377795, AW188290, AI361824,
					AI249713, AW008444, AW173497,
					Z45900, AA339575, AA232181, AI206821,
					AA142987, H11878, AA470821, AI933390,
					AI636179, AA317977, AA363355,
					AA373480, U79287, AC006942, and
					AL050131.
HUCOW17	295	1155190	1-1693	15-1707	AI245305, AA307147, AW139688,
					W52616, AA416742, AA102287, R60274,
					AI085546, AI167698, R60782, H17001,
					AI400152, H15571, D78731, AI264789,
					H17000, H15631, AA192581, C03464,
					AI571949, AA872017, AI694004,
					AA486536, AA112946, AA533831,
					AA872016, and AI357709.
HFKIT06	296	1078092	1-1554	15-1568	AA747315, AI392901, AI697980,
					AW295170, AA148983, AI283647,
					AA148982, AI393927, AA687243, R70140,
					H44117, H44044, AI783873, AI918219,
					R70141, AI741034, D80164, D80227,
					D51799, C14331, D80022, D59467,
					D80195, D59275, D59787, D59502,
					D80269, D59610, D58283, C15076,
					D59859, D81030, D80166, D51423,
					D59619, D80210, D80391, D80240,
					D80253, D80043, D80378, C14429,
					D80038, D80212, D50979, D80193,
					D80196, D80188, D80024, D80219,
					D59927, D80241, D57483, D50995,
					D80366, D59889, D51060, AA305409,
					AA305578, C14389, D80045, C14014,
					T03269, AW178893, C75259, AW177440,
					D51022, AW378532, D81026, D52291,
					AW352158, AA514188, D80134,
					AW179328, AW178775, D51250, D80251,
					D59695, AA514186, AW369651, C14407,
					D80522, F13647, D80248, D80133,
					D58253, D80168, AW178762, AW177501,
					AW177511, C14227, AW360811,
					AW378540, D81111, C14298, AI557751,
					AI910186, D80268, D80064, AW176467,
					C05695, AI905856, AW352117,
					AW375405, D80439, AW377671, D80247,
					D80302, Z21582, AW360834, AW366296,
					AW360844, AW360817, AW375406,
					AW378534, AW179332, AW377672,
					AW179023, AW178905, AW178906,
					D80132, D51103, AW352171, D51097,
					AW377676, AW352170, AW177731,
					AW178907, AW179019, AW179024,
					D59373, AA285331, D80157, AW177505,
					AW360841, AW179020, AW178909,
					AW177456, AW352120, AW179329,
					D51759, AW178980, AW177733,
					AW378528, AW178908, AW178754,
					AW179018, T11417, AA809122, C06015,
					AW177728, AW179004, AW179012,
					AW367967, AW178914, AW178774,
					AW378543, AW378525, T48593,
					AW178983, AW177722, AW352163,
					AW352174, AW179009, AW178781,
					AW178911, D59653, AI535686, D45260,
					D59503, AW177508, D58246, AI525923,
					AW367950, D59627, H67854, C03092,
					H67866, D58101, C14344, AW177723,
					AI557774, T03116, AW177497, D59317,
					AW178986, D80258, AI525920, D45273,
					AI525917, AI535850, D80014, C14973,
					AW378533, D51213, AI525227, D80228,
					D60214, D51221, D59551, D59474,
					AW177734, D60010, AA514184, N66429,
					C14957, C14046, AI525242, AI525235,
					Z33452, T03048, AI525925, AI525912,
					AI525237, AW378542, AW378539,
					AI525215, C16955, AF075060, A62300,
					A62298, A84916, AJ132110, AR018138,
					Y17188, A78862, X67155, A25909,
					D26022, A67220, D89785, D34614,
					AF058696, AB028859, D88547, X82626,
					AR008278, AR025207, I82448, A82595,
					Y12724, AR060385, AR008443,
					AB002449, AB012117, A94995, X68127,
					AR016808, I50126, I50132, I50128,
					I50133, A85396, AR066482, A45456,
					A44171, A85477, AR066488, I19525,
					AR016514, A86792, AR060138, A26615,
					AR052274, X93549, I14842, A30438,
					Y09669, A43192, A43190, AR038669,
					AR054175, AR066487, AR062872,
					Y17187, U46128, D50010, AR066490,
					AR008277, AR008281, A63261, I18367,
					Z82022, AR016691, AR016690,
					AR008408, D88507, A70867, U79457,
					I79511, D13509, A64136, A68321,
					AR060133, AF135125, AF123263,
					AR032065, AR060382, and AR008382.
HDTBY88	297	1104159	1-523	15-537	AA868305, AI700890, AA789239,
					AI803004, AI694352, AA043382, F08474,
					R21498, AF112183, AF112184, and
					AC005354.
HWLHS82	298	1082268	1-1335	15-1349	AI939391, AW401390, AI202873,
					AI869600, AW411117, AI142585, Z99396,
					H50446, AL119457, AL119324,
					AL036418, AL038837, AL037051,
					AL036725, AW392670, AA631969,
					AL119443, AL039074, AW384394,
					AL036924, AW372827, AW363220,
					AL036858, AL119497, AL119355,
					AL037094, AL038509, AL039564,
					AL119483, AL039085, AL119335,
					U46351, AL119319, AL036196,
					AL039156, AL039108, AL039109,
					AL039128, AL036190, U46349,
					AL119341, AL119484, AL119363,
					AL119391, AL042544, AL119399,
					AL036767, AL039659, U46350,
					AL119418, AL037082, AL119522,
					AL037526, U46341, AL134902,
					AL037639, AL119396, AL038531,
					AL042984, AL119496, U46347,
					AL037085, AL119444, AL036268,
					AL134533, AL039625, AL039648,
					AL037077, AL045337, AL119401,
					AL036238, AL037205, AL119439,
					U46346, AL134536, AL038447,
					AL042450, AL042909, AL043033,
					AL039386, AL039678, AL039629,
					AL119464, AL134538, AL042614,
					AL036733, AL039423, AL038520,
					AL042965, AL042975, AL039150,
					AL134525, U46345, AL040992,
					AL043029, AL042551, AL037027,
					AL036998, AL037615, AL038851,
					AL043019, AL037178, AL134542,
					AL043011, AL042542, AL036765,
					AL037726, AL036719, AL036191,
					AL039410, AL043003, AL036679,
					AL036774, AC005581, AC005781,
					AR060234, AR066494, A81671,
					AR023813, AR069079, AR064707,
					AB026436, and AR054110.
HDPNC96	299	1081629	1-720	15-734	AA256100, and AB023182.
HCE5I78	300	1197899	1-3149	15-3163	AA988953, N63548, AA663569, H15532,
					H38453, AA976078, N94873, H41422,
					H46380, R88023, N51089, H41541,
					H48172, AI423964, H38492, AI421373,
					R18083, AI208504, AI003013, R90757,
					R88479, H11023, R40487, R42977,
					H85702, AW207073, R87980, AA338374,
					H84794, H15589, AA325807, H10745,
					AA319224, AA338373, W28283, R13057,
					AA325143, N54215, AB023202, D13613,
					AC004551, D29965, U12571, and
					AC004465.
HISDS62	301	1159625	1-888	15-902	AA126105, AA306119, W27339, D80253,
					D80366, D80043, D58283, D80188,
					D59502, D80166, D80195, D51423,
					D59619, D57483, D80210, D51799,
					D80240, D59859, D80391, D80212,
					D80219, D80227, D59889, D80196,
					D51060, D81030, D59927, D59610,
					D80269, D80038, D80022, D80024,
					D80193, D59275, C14389, D50979,
					D59787, D50995, D80241, C14014,
					C75259, D80045, C14429, D80164,
					D80378, D59467, T03269, C14331,
					C15076, AA305409, D80251, AW178893,
					D80134, AW177440, D51022, D80949,
					D51079, D58253, AW178775, AW179328,
					AA305578, AI905856, AW378532,
					D80248, D51097, D80522, AW352158,
					D81026, D59695, AA514186, AA514188,
					AW177501, AW177511, AW178762,
					D80268, AW360811, D80133, R58551,
					AW352117, AW375405, AW366296,
					AW377671, AW360844, AW360817,
					AW375406, AW378534, AW179332,
					AW377672, AW179023, AW178905,
					D80302, D80439, D80247, D80132,
					AW352171, AW377676, AW352172,
					AW178906, AW352170, AW177731,
					AW178907, W27700, AW179019,
					AW179024, AW177505, AW179020,
					AW178909, AW177456, AW179220,
					AW179329, AW178980, AW177733,
					AW378528, AW178908, AW178754,
					AW179018, AW179004, AW178914,
					AW367967, C14975, AW352174,
					AA033512, AI535850, AB007884,
					AJ250425, AJ132110, A62298, A84916,
					A62300, AR018138, Y17188, X67155,
					A67220, D89785, A78862, D26022,
					A25909, D34614, D88547, AR008278,
					AR025207, AF058696, X82626,
					AB028859, AB012117, A85396,
					AR066482, A44171, A85477, I19525,
					A86792, X93549, Y12724, AF135125,
					A94995, D88507, AR008443, U87250,
					AB033111, AR064240, I18367, AR066490,
					U87247, U79457, and X93535.
HDQDV69	302	1212566	1-2558	15-2572	N63562, AI905612, N75655, N94726,
					AA297704, N64807, AI919048, AI567676,
					AI884404, AI797998, AI570067,
					AA765899, W27084, AW162314,
					AA632355, AI174827, AI281622,
					AW021674, AW085626, H86399,
					AA196994, AI745666, AI888050,
					AW029626, AA527633, AI150934,
					AW303052, AI065031, AI003391,
					AI049845, AW410844, AL121039,
					AW192930, AL138262, AI702049,
					AI307563, AI445699, AW162332, H47461,
					AI434103, T03928, AA015948,
					AW265468, AW328185, AA828840,
					AI538404, AA610644, W02419, AI547110,
					AI828721, AI370470, AI890857,
					AI744259, AI302350, AA847341,
					AI268465, AI003086, AI733523,
					AI064968, AW020612, AL118628,
					AW148821, H81270, AA568433,
					AI889177, AI857834, AI312614,
					AI280566, AA557945, AW149241,
					AI624191, AW327673, N49298, M77888,
					AA846046, AI744963, AW239465,
					AI311796, AI003068, AL044966,
					AA748071, AI791659, AI590404, N55076,
					H53109, AA947352, AA814719, AI801563,
					AA525953, AA199582, AA598608,
					AA280886, AI926656, AW439224,
					AI167715, AI207534, AA152398,
					AA167656, AW070901, AA133568,
					AI446574, AI905408, AI815770,
					AI934664, AA969564, AA846014,
					AI344906, AI318548, AA601712,
					AI819419, H48017, AW028376,
					AW419201, AI683079, AI376687,
					AA676462, AA313025, AA935827,
					AI969090, AI342863, AA715848,
					AA604149, AI754926, AA112864,
					AA018258, AA315052, AI350189,
					AI049999, AW152451, AI076729,
					AA774223, AA487053, AI800706, H62123,
					AI221027, AA669165, AA668727,
					AI039257, AI860423, AA601718,
					AA421536, AA602458, AA084439,
					AI620666, AI038990, AW131394,
					AA493245, AA526542, AL044701,
					T10218, AI872229, W45215, AW023975,
					AA525753, AL133768, AI921744,
					AI282488, AW275432, N53783, AI274480,
					AA729004, AI679759, AF169035,
					AF085233, Z98752, AL050338, AC005701,
					AC002375, AL133448, AC007537,
					AF196779, AC005519, AC004808,
					AC005822, AC004685, AC006079,
					AC004765, AC008044, U85195,
					AF176815, AE000658, AC006581,
					AC003665, AL049694, AP000076,
					AF207550, AC005089, AF001549,
					AC004033, AC002036, AC007731,
					AC005500, AC004263, AC004531,
					AC002558, AF109907, AF165926,
					AC006006, Z75744, U91327, AC003982,
					AP000692, AC005175, AC006511,
					AP001068, AL050321, AC005412,
					AC002310, AC005696, Z83844, AF024533,
					AJ003147, AC004019, AC004890, Z98941,
					AC002996, AC005632, Z84474,
					AL033527, AC005484, AL049538,
					AL049776, AC002472, AL022238,
					AF107885, AL021707, AC005399,
					AC006539, AL031680, AL109852,
					AC004997, AF104670, AP000030,
					AC012627, AC009247, AC009784,
					AC004233, AC004643, AC005920,
					AC002094, U93163, AL021579,
					AC005585, AC006597, AC006455,
					AC000353, AR036572, U91328,
					AC007036, AC005261, AC004771,
					AC005821, AC002477, AC005003,
					Z92542, AC004491, AP000555, AC007664,
					AL008712, AC007050, AL035445,
					AC006509, AL022323, AF064861,
					AL031864, Z80232, AL035420, AC005529,
					AC002351, AL022313, AC005914,
					AC004673, AP000251, AL121603, Z73979,
					AP000503, AC006071, U73636,
					AC007243, AC003108, AC004950,
					AC004703, AC004891, AC005393,
					AC000070, AL022241, AL121825,
					AL035079, AC007934, AC000082,
					AC004552, AC005859, AL035551,
					AL030996, Z83838, AC005598, AL031311,
					AC005365, AL080317, AC006277,
					AC002991, AP000365, AP000547,
					AF134726, AD000092, AL022334,
					AC005212, AL049839, AL109952, L78810,
					AC007227, AC005071, AC003037,
					AP000141, AC007993, AC005057,
					AC005355, AC003957, AC001052,
					AL136130, AP001046, AL049562,
					AC004099, Z84469, AL050318, M89651,
					AC005736, Z84719, AC010205, AJ011930,
					AL096701, AC000040, AP000116,
					AC005535, AC006013, AC004973,
					AC002306, AC005409, AP000049,
					AL024507, AC005081, AC000025,
					Z82201, AL022315, AC004751, D16583,
					AC007911, AC004500, AF043945,
					AL109627, AC005527, Z84480, AL021453,
					AP000309, AC005755, AC004783,
					AC004006, AP000694, AC002476,
					AL034417, AP000689, AF038458,
					AP000311, AF045555, Z94721, AL022333,
					AC005064, AP000038, AP000106,
					AC006211, AC007066, Z79997,
					AC004659, AB003151, Z84492, Z84486,
					U95739, AL135744, AC005220,
					AC004821, AL008582, AC005303,
					AP000211, AP000133, Z81364, AC006116,
					AC005512, AL050348, AC006274,
					U22376, AC003682, AL109802,
					AL133355, AC002544, AC006953,
					AC006968, U78027, AL031281, M27835,
					Z93241, AP000048, and AA887783.
HEMBT61	303	939957	1-449	15-463	N86549, AW369713, and AB002301.
HRODZ70	304	1088554	1-927	15-941	AA167766, AA167655, AA292911,
					H97685, AA635138, Z41812, AA507096,
					R40592, T17069, and AB007941.
HHERQ79	305	1184003	1-689	15-703	AW340333, AW407893, AI806295,
					AW268810, AA827664, AA829237,
					AA909185, AA919008, AA604425,
					AI539428, AA011359, D63485, AB016590,
					and AB016589.
HCECM90	306	1031741	1-1379	15-1393	AA463356, AA453500, AA322899,
					AA340682, H24259, AA603868,
					AA330182, R19782, and AB023227.
HWHGW72	307	1199614	1-1625	15-1639	AA961509, AF190823, AF109388,
					AF190822, AF109387, AF190825,
					AF053328, AF053327, AF190824, U14414,
					AF053329, Y10473, Y10475, Y10474,
					AF020759, AF064549, AF190826,
					AF020756, and Y09910.
HPCRV84	308	1219890	1-863	15-877	AA307070, D79997, L76158, and X95351.
HNSAA28	309	946988	1-1544	15-1558	AA713959, AI564093, AA768779,
					AA825697, AA808021, AA808149,
					AI401490, AW181992, AW444640,
					AI018159, AF146277, and AF077003.
HLWAR77	310	947484	1-1275	15-1289	AA449919, AA449920, and AF119815.
HTTJW49	311	1127477	1-1486	15-1500	AW268880, AA199865, AW444872,
					AI769428, AI061340, AA707168,
					AI970984, AW236544, AI884812,
					AI479954, AI356088, AI701720,
					AA722812, AI989992, AA410516,
					AI765045, AI267987, AI298592,
					AA005114, AI865503, AW389168,
					AA360112, AI633370, AI498423, T55265,
					AA878382, AF118838, Y17571,
					AF164632, AC002450, AF164529,
					AF164526, AF164530, AF164528,
					AF164527, AC004458, AC002540, and
					AF164525.
HWAFS18	312	1155193	1-1873	15-1887	AW009940, AI394293, AI082857,
					AW207417, AA227673, N99896,
					AA227560, AA491391, AA361942,
					AI000839, W25237, AA491389, and
					AF156884.
HFCBA44	313	1082762	1-769	15-783	R85476, AW293022, AA339398, D80166,
					D80193, D81030, D59502, C14389,
					D80195, C15076, D80164, D59619,
					D80210, D80240, D80045, D80022,
					D59467, D59275, D80219, D80227,
					D80212, D80269, D58283, D59859,
					D80391, C14331, D59787, D51423,
					D51799, D80253, D80038, D80043,
					D80196, D81026, D50979, D80366,
					D80188, D59927, AA305409, D57483,
					D80378, D59889, D50995, D80024,
					D59610, D80133, D51060, C14014,
					AA305578, C14429, AW178893, D80248,
					D80522, D80241, AA514188, D51022,
					T03269, AW360811, AW177440, D80302,
					D80251, C75259, AA514186, D80439,
					AW377671, AW375405, AW179328,
					D80268, D80247, AW378532, AW352158,
					AW366296, AW360844, AW360817,
					AW375406, AW378534, AW179332,
					AW377672, AW179023, AW178905,
					AW178775, AW178762, D59373, D80134,
					AW369651, AW377676, D80157,
					AW177501, AW177511, C05695, D51250,
					D51103, AW352171, AW352170, D59695,
					AW178906, AW177731, AW178907,
					AW378528, AW179019, AW179024,
					D80132, D51759, D52291, AW176467,
					D80949, AW360841, AW177505, D80168,
					AW179020, C06015, D80064, AW178909,
					AW177456, AW179329, AW178980,
					AW177733, AW178908, AW178754,
					AW179018, C14298, AW352117,
					AW378540, D59653, D58253, C14227,
					D59503, AW179004, AI905856,
					AW179012, AI910186, AW178914,
					AW378525, AW352163, C14407, T48593,
					AI525923, D80258, AW360834,
					AW178983, C03092, AW179009, D45260,
					AW178774, AW178911, AW378543,
					AW177722, AW177728, AW352120,
					D58246, D59627, AA809122, H67854,
					H67866, AW178781, AI525917, D59317,
					T03116, D58101, C14077, T11417,
					AW367950, D51097, F13647, AW178986,
					AI525925, AW177723, AI535686, D81111,
					AI525920, D80014, D59551, C14973,
					AI525227, C14344, AW378533, AI557774,
					D51221, AA514184, D59474, D60010,
					D51213, D60214, AI525242, AI525235,
					AW177734, C14957, C14046, T03048,
					AI525912, AI525215, AI525222, D45273,
					AI525237, AA285331, AW378542,
					AI557751, AW378539, C13958, C16955,
					AI525928, C05763, Z33452, T02974,
					Z21582, AW360855, T02868, D51053,
					A84916, AJ132110, A62300, A62298,
					AR018138, AB028859, AR008278,
					AF058696, AR060385, X67155, Y17188,
					D26022, A25909, A82595, A67220,
					D89785, A78862, D34614, AB002449,
					Y12724, D88547, A45456, A94995,
					I82448, X82626, I50126, I50132, I50128,
					I50133, AR025207, AR008443, AR016808,
					AR016514, AR060138, I14842, AR066488,
					A26615, AR052274, Y09669, A43192,
					A43190, AR038669, AR066487, A30438,
					AB012117, AR054175, Y17187, D50010,
					A63261, AR008408, X64588, AR008277,
					AR008281, A85396, AR066482, A44171,
					I18367, AR062872, A70867, A85477,
					I19525, A86792, AR016691, AR016690,
					U46128, X93549, I79511, A64136,
					A68321, D88507, I50121, I50125, D13509,
					AR060133, X68127, AF123263,
					AR032065, and AW512144.
HVADT77	314	1180374	1-236	15-250	AI217375, AI554767, AI948424,
					AI693185, AL134259, and AC006356.
HUFCN91	315	1189013	1-2534	15-2548	AW401749, AW451778, AW450685,
					AW268855, AW152133, AI983406,
					AI656119, AI961994, AW448985,
					AI831678, AW403024, AW296492,
					AA195250, H09181, AI433189, AA258743,
					AA258380, AA866028, AI982819,
					AI919443, H09127, C01544, AA262275,
					and Z85996.
HAGBX32	316	951351	1-624	15-638	W29095, H04905, H11833, AF100346, and
					AC004125.
HWMIB81	317	1092933	1-1604	15-1618	AW380440, AW299858, AW391525,
					H78769, H78659, H53674, AA628987,
					AA447173, AW204470, AA343468,
					AA480342, AA114131, and AF155118.
HCEMU86	318	1156430	1-2145	15-2159	W28902, AI694781, AA780441, W26632,
					AA861408, AI598157, R87939, AI360413,
					AA206559, H06785, AA496386, H14668,
					AA443069, AA437394, AW007070,
					AA351204, AI499867, AI982847, H14395,
					AW007079, T08889, AI933154,
					AA082863, AA085216, F07213, T33930,
					AA324000, AI366734, AI683546, R35601,
					T08328, R85233, AA325921, H09089,
					F07449, AA931914, T09198, AA297096,
					T07392, H14346, R40510, F02224,
					R13080, AA975823, R24819, H09438,
					H06678, F05981, F09630, F11982,
					AA551277, T83837, T30652, H21015,
					T65199, F08411, F08469, T33716, F13035,
					T08309, D54295, R58912, T05132,
					R51804, AI567931, F10628, T33189,
					T03545, H06677, R41862, Z19847, F04626,
					AI468068, AI803000, AA987266, R16332,
					AA365773, AI275574, AI092574, T65130,
					AI254357, AW183676, AA496337,
					R38256, H06605, AB018279, S47919,
					L05435, L01788, and A75140.
HRDAF83	319	1153911	1-1211	15-1225	AI825217, AA316377, AW302711,
					AI144081, AA488067, AI587537,
					AI253519, AI953573, AW339743,
					AW302753, AA828046, AA292719,
					F35011, R70326, AA601230, T96582,
					AI053560, AW301906, AI133727,
					AI973207, AA205743, AW292981,
					H80463, AW085744, AA297496,
					AA502223, AA730601, H73438,
					AW438539, AA262086, AW301854,
					AA654849, AA491864, AA640495,
					AA363225, AI435248, AL041325, R21949,
					AA904231, AI696343, AA159046,
					AI745457, AI754567, AI754105,
					AI755214, AA669132, AA652267,
					AA984920, N25819, AA479930, AI734052,
					AI625693, AF109681, AF137378,
					AL135747, AL035251, AL049553, Z99128,
					AC002431, AC003046, AP000704,
					AC005993, AL020993, AC005844,
					Z95113, L44140, AC004068, AF002223,
					AP000500, AC004910, AL133163, Z84489,
					AC003012, Y10196, AC003664, L40817,
					X92763, Z73359, AC004757, AL035458,
					AF051976, AC003044, AF196971,
					AL109758, AC007298, AC006559,
					AC000026, AL031985, AC004150,
					AC005668, AL022326, AC007707,
					AL049653, AC002059, AP000212,
					AP000134, Z83855, AL023285, AC005193,
					AP000030, AL035106, Z49250, AP000251,
					AC003007, AC004675, AC003084,
					AC007934, AC005083, Z83845, AP000402,
					L42103, AL049778, AL117592, AC005189,
					AC002457, AP000013, L48038, AL121577,
					AL049709, AC005608, AC005304,
					AL109865, Z23091, AF190465, AC005212,
					Z97053, AL023653, AL049538, Z93244,
					AL133245, AC006312, AC002470,
					AC010205, AC005632, AC005773,
					AC005409, AL109627, AF054589,
					AL034548, AL121655, AC002430,
					AC006145, AL139054, AL109977,
					AC007878, AC005871, AP000459,
					AL031602, AL078477, AL080243,
					AC007384, Z68756, AC006965,
					AC004966, AL031657, AL035089,
					AL035249, AF020503, AC009294,
					AL034429, AC001231, AC018633,
					AC005696, AL022721, AL031289,
					AC005730, AC005011, AP000155,
					AC004094, AC005949, AC005969,
					AC004673, AP000565, U95739,
					AL049733, AC005484, AC005015,
					AC002094, AL050307, AL049557,
					AC000003, AF087970, AC010170,
					AC005821, Z94801, AF088219, AC004629,
					AB001523, AC005393, AC004386,
					AC002300, U73168, AL132777,
					AC002418, AL022313, AL022333,
					AC007226, AC002407, AC006237,
					AC007510, Z98750, AP000355, AC010209,
					AP000511, Z95116, AC004953, AC007639,
					AC007388, AL022165, AC020663,
					AL022163, AL049694, AL109946,
					AC005138, Z84481, AL117340,
					AC003956, AC005105, AC005952,
					U73166, AB023048, and AL121652.
HUVGZ88	320	1204719	1-2072	15-2086	AI302185, AI652375, AI418298,
					AI936871, AI394630, AW206793,
					AI025217, AI983297, AI025310,
					AW002416, AI559159, AA593826,
					AW140018, AW401787, AI017077,
					AW239548, D54154, T03397, H42947,
					D57560, AW192088, R23870, AA026054,
					AA503315, Z40806, AW375742, F07734,
					AI807678, C14980, AA297059,
					AW338394, AI073417, AW138409,
					AA088799, AI356604, C15480, AI825970,
					AI537006, AI168175, R46685, AW078709,
					AA364780, AI343378, R46686,
					AW137324, AI015047, AA974700,
					H42881, AA325059, AI831833, H22172,
					T30407, AA897415, Z44281, F03562,
					R45025, F03423, F07299, R25015,
					AA382960, T32685, AW163027,
					AI815476, AA471062, T82311, AI911100,
					AW157059, R08769, AA047793,
					AA382959, and AW373232.
HSCKS55	321	1197921	1-2278	15-2292	AW183030, AA535809, AI885834,
					AI831611, AA534906, T15603, AI364740,
					H29399, N27334, AI689402, H17545,
					AA353936, AA903747, R81708, D31451,
					R33400, AI707698, N75704, AI735097,
					R31870, AI608711, AI357830, R87560,
					AA954380, AI904965, AI289077, Z78378,
					AL046356, AL045891, AL041862,
					AI432666, AI434223, AL047675,
					AW172723, AL119748, AW151138,
					AL042787, AI366900, AI815232,
					AI805769, AI433157, AW151136,
					AI539771, AL042551, AI537677,
					AI494201, AI866786, AI500659,
					AI801325, AI500523, AI436429,
					AI582932, AI284517, AI923989,
					AI500706, AI445237, AI491776,
					AI521560, AI889189, AI500662,
					AI284509, AI860003, AI889168,
					AI866573, AI633493, AI434256,
					AI888661, AI284513, AI888118,
					AI889147, AI371228, AI440252,
					AI610557, AI887499, AI433976,
					AI554821, AL045163, AI440263,
					AL042488, AI432656, AL045500,
					AI866465, AA483831, AL047092,
					AI890907, AW172745, AL040207,
					AI866510, AI872423, AI923046,
					AL045620, AW191003, AI859991,
					AL047163, AI275175, AI934147,
					AL039276, AL047422, AL079977,
					AL042745, AL043089, AI371251,
					AI499463, AI610362, AL046990,
					AI440239, AI628850, AI620284,
					AW197139, AI537273, AI371265,
					AI436456, AI433968, AL046926,
					AI963846, AI567940, AI817244,
					AI612913, AI285826, AI863014,
					AI521594, AI499512, AI889133,
					AI866469, AI537515, AI610429,
					AI539632, AI889148, AW118237,
					AI539847, AI828583, AL042538,
					AI872300, AI354998, AI567935,
					AI805762, AL042365, AL135012, N80094,
					AI400725, AI582483, AI434242,
					AI608936, AI866608, AL042572,
					AI251205, AI800138, AI610402,
					AI242736, AI857724, AI866820,
					AI627880, AI274759, AI866741,
					AL042440, AL042557, AI538850,
					AI623682, AI818578, AI696378,
					AI866457, AI499381, AW082113,
					AI636268, AI049851, AI343091,
					AI567993, AL135025, F27438, AL042628,
					AW087938, AI654276, AI269862,
					AL048323, AW168485, AI431909,
					AL041772, AL048375, AI364788,
					AI922577, AI886022, AI538878,
					AI689175, AI445165, AW082594,
					AI919107, AW149227, AI873644,
					AI687065, AL047037, AI250663,
					AI824557, AI560023, AI812015,
					AW083804, AL043321, AL038445,
					AI697243, AL040243, AI916419,
					AI499986, AI590423, AA715307,
					AL036214, AI801561, AI355779,
					AI307210, AI823670, AL042377,
					AI343059, AL121270, AI538885,
					AI612885, AA420758, AI280670,
					AI349933, AI432644, AI097410,
					AL048312, AW078680, AI521596,
					AL048496, AI282326, AI439995,
					AW023590, AI888953, AW088899,
					AL042744, AA911767, AI919345,
					AI829327, AI349598, AL048377,
					AI619716, AI648567, AW269097,
					AI345347, AI686073, AI824375,
					AI334930, AI950664, AL118781,
					AI345608, AL038565, AI554218,
					AA427700, AI866002, AI471361,
					AW079159, AL122049, I48978, AL133565,
					AL133077, AL137550, A08916,
					AL133049, AL050277, AL117432, I89947,
					A08913, A08910, A08909, I89931, E15569,
					AL096744, I49625, AF125949, I48979,
					AL133093, AF162270, X70685, AL117585,
					AL122098, AL050108, AL133104,
					AL050116, L30117, AL137527, AF079765,
					E03348, AL110196, AF113013, AF090896,
					AL137459, AR059958, AF017152,
					A08912, S61953, AL122110, AR038854,
					AF113689, AL050024, Y11587, AL133080,
					AL122050, AR000496, U39656, M30514,
					AL117440, X93495, E07361, AF090943,
					AL122101, U80742, AL080137,
					AL117583, AF111112, AL137521,
					AF026816, Y16645, AL133072, I33392,
					Z72491, AL050172, AJ242859, AL049464,
					AL080127, U96683, AL137273,
					AL133606, AJ012755, AL080060,
					AL137523, AF153205, AL133557, X65873,
					E02221, AF003737, AL049466, AC002467,
					AL137526, AL049300, AL080159,
					AL133640, AL137271, Y14314,
					AL133016, AF146568, AL133113,
					AL122121, AL137476, AL122123, S68736,
					X72889, AF113694, AL049430, AL080074,
					AL049314, S78214, AF113676, AL050146,
					AL122118, U35846, U42766, AB019565,
					AF113699, I42402, AR011880, AF158248,
					AF104032, AF119337, A93016, AF091084,
					A65341, AF118070, A93350, AL110221,
					AL110225, AL122093, AL117435,
					U72620, AF078844, I26207, AR038969,
					AF113690, AF113019, AL137556,
					AF090934, AF118064, AF067728, E04233,
					AL049382, AF111851, Z82022, AF183393,
					AL137538, AL117460, Z37987, Y09972,
					U78525, AF090901, AL050393, X63574,
					AL137463, AF061943, U00763, AF113677,
					L19437, I09360, A90832, X87582, E05822,
					Y11254, U67958, E02349, AL133098,
					X84990, AL133075, AF090900, AL117457,
					A45787, L31396, AL133568, AL133014,
					AL050138, AL133560, L31397, AF106862,
					A58524, A58523, AL133067, AF118094,
					E08631, X98834, AF097996, AL137557,
					AJ000937, AL137648, E07108, AF090903,
					A12297, Y07905, U91329, AF057300,
					AF057299, X96540, I03321, AL049452,
					AJ238278, AF177401, AL080124, X82434,
					AF017437, A77033, A77035, AF087943,
					AL137560, U58996, AF111849, AF026124,
					AF113691, AL050149, AF125948,
					AL137533, I00734, AF185576, A03736,
					AF008439, AL110280, AF067790,
					AL049283, AL137478, AF079763, A07647,
					E00617, E00717, E00778, U68387,
					AL137480, E08263, E08264, AL117394,
					AL080086, X62580, AF081197, AL049938,
					AF132676, AL133081, AF061836,
					AJ006417, AL137292, AF081195,
					AF100931, AF210052, AL133053, X92070,
					AF061795, AF151685, X83508, AL137283,
					AF051325, AL137300, X53587, E06743,
					AL137294, AF061573, AF032666, I68732,
					and AL122111.
HOEET48	322	963290	1-1466	15-1480	AI797684, AW239200, AA456267,
					AI478733, AI751749, AI990902,
					AA427646, AI379565, AI970534, W95460,
					AA788855, AA405402, AW068453,
					AW294114, AI751750, AA594137,
					AA947297, AW177719, AI057073,
					AA427487, AI341112, AA232452,
					AA041304, AW068711, H73236,
					AA041328, W95567, AW167569,
					AA853047, AI652166, W02069, H74164,
					R34003, AI341381, AW176526,
					AA580289, D30965, D31176, AA367502,
					and AR035969.
HBODE51	323	1193149	1-2774	15-2788	AW411466, AW137475, AA922772,
					AA974304, AW204679, H05447,
					AI357778, AL044000, AL138265,
					AI038990, AW131249, D63198,
					AL120269, AI951863, AI732911,
					AI471543, AA601355, AL048969,
					AW102811, AA722372, AW248523,
					N66012, AW055226, F28204, AI457389,
					AA837677, AI952885, N49425,
					AW188427, AI863046, AW080062,
					AW070703, AA618412, AL079869,
					AL137984, AW167374, AL046746,
					AI791227, AL135698, AA610271,
					AA631507, AA604395, AA593752,
					AA706495, AL119123, N80210,
					AW204532, AW085751, AL046457,
					AA603421, AL042539, AA130901,
					AI313166, AA223932, AW008089,
					AA515250, AI859742, AL038705,
					AA634991, AI821044, AA577719,
					AI028148, AI569982, AI583978,
					AA744826, AA121815, AA679794,
					Y16610, AC004491, AF134726,
					AC005529, AC005015, AL022316,
					AC005081, AC009247, AC004383,
					AC002310, AC004967, AC005694,
					AC006312, AC007225, AF111169,
					U47924, AP000553, AC005484,
					AC004821, AC005531, AC005011,
					AL109984, AC004638, AL009181,
					AC006211, AC004851, AL096791,
					AP000688, AC004678, AC006285,
					AL031311, AC004263, AC007216,
					AC002316, AC006120, AC005837,
					AC005037, AC004019, AB023049,
					AC000025, AC007055, AL031681,
					AF001548, AL049795, AC002300,
					AC004814, AL031005, AL031848,
					AL024498, AL139054, AL034549,
					AC005225, AL109628, AC003101,
					AL135744, AC003070, AC006071,
					AP000557, AL133448, AC007686,
					AC007193, AC002301, AL035249,
					U91326, AC006538, AC007227,
					AF030876, AF030453, AC004812,
					AC007666, AF080517, AC006111,
					AC005527, AF080518, AP000512,
					AC004765, AC005972, AF196971,
					AL121603, AC007993, AL096701,
					AC016025, AC005088, AC005488,
					AC005480, AC005180, AL035683,
					AL049569, AL121653, AF196969,
					AC005620, AC007371, AC005089,
					AF053356, Z95114, AF001549, Z98941,
					AC007226, AC006064, AC004707,
					AC005049, AC003982, AL022476,
					AC007057, AL035659, AC000353,
					AC020663, AC002365, AL031602,
					AL033527, AL049776, AC002126,
					AC016830, AF196779, AC000026, Z93241,
					AF031078, AC005846, AF045555,
					AC005500, AP000350, AC006160,
					AC007731, AC004150, AC005755,
					AC009516, AL050318, AC005736,
					AL031670, AC007688, AL133355,
					AP000117, AC004887, AC004953,
					AC004832, AC007707, AC006088,
					AL021155, AC005899, AC006441,
					AC005071, AL049780, AC008040,
					AP000555, Z99128, AC000159, AL035684,
					AC002059, AC005921, AL022315,
					AC007536, AL020997, AL034420,
					U95742, AC004895, AL033392,
					AL034379, AC002400, AC006511,
					Z85996, AL109839, AL080242, AC005821,
					Z85987, AL022165, AL049830, AL008718,
					AC004217, AL035413, AP000503,
					AC005839, AC005516, Z97054, U62317,
					AC002425, AC005971, AC007917,
					AC006241, AC005746, AC006449,
					AP000356, AL021154, AC002470,
					AC002477, Z95115, AL049843, AL031667,
					U78027, AC004386, AC005520,
					AL031276, AC005519, U80017,
					AL117258, AL031295, AL031283,
					AC005004, AC004167, AC007308,
					U96629, AC004883, AC005914,
					AL022323, AC006013, AC005778,
					AC005696, AL022163, Z94044,
					AC007676, AF111168, AC000052,
					AF088219, AL031577, AC006057,
					AC004675, AC003029, Z84466,
					AC005328, U95740, AC002350,
					AC007842, AL031427, AL031733,
					AL021453, AL109759, AL035086,
					AC002544, AC006581, AC002288,
					AC005800, AL022328, Z82190,
					AC003043, AP000692, AL132987,
					AL049759, AF196972, AC006121,
					AC004882, AL133245, AC005231,
					AP000045, AL049761, AC004922,
					AL023807, Y14768, AL034429,
					AL022238, AL031255, AC000003, and
					W26963.
HHFCK09	324	965304	1-2789	15-2803	AI218626, AI076006, AW162820,
					AI797880, AI922744, AI872391,
					AI559566, AL045117, AW161046,
					AW162613, AI565503, AW183962,
					AI857802, AA460810, AI884907,
					AI371131, AW248493, AI081779,
					AA460372, AA679085, N27884,
					AA581796, AA074070, AA971563,
					AI292006, AI922373, W76538, N93245,
					AI609183, AW172513, AI904299,
					AI682939, AA075764, AI885613,
					AA747871, AA449042, AA928020,
					AW401847, AA449757, AW268637,
					AW073851, AW304978, AI683858,
					AA568598, W74167, AI367698,
					AW191998, N62781, AW016535,
					AI902503, AA347639, AA297591,
					AA379280, AA568887, AA649970,
					AW264577, AI221886, H20460,
					AW387087, AW000860, AI275195,
					AA341002, T32918, AW162711, W25103,
					AI699657, R42681, AW243790,
					AA768740, T78554, AI279653, AI560482,
					AI696251, AI951374, Z45830, AA147203,
					AI499410, R43259, AI350354, AA732831,
					AW079129, AA375228, F08622,
					AI475009, R56337, AA379846, R17163,
					AW380349, AA783050, AW247402,
					N47545, R35508, R51077, AI474934,
					N79729, D61534, Z41466, AI678630,
					AA339343, AW367003, AA160401,
					Z41592, AW079321, N47546, AI252528,
					R58857, T16943, H55297, AL022238,
					AL137499, and AJ236700.
HCOOZ11	325	1110364	1-1321	15-1335	AI218626, AI076006, AI797880,
					AI872391, AI922744, AA449042,
					AI559566, AW162613, AI565503,
					AI857802, AW248493, AI922373,
					AI292006, AA679085, AI904299,
					AA074070, W76538, AI682939,
					AA928020, AI609183, AW172513,
					N79729, AA747871, AI885613, AA449757,
					AW268637, AW183962, AW304978,
					AA568598, AI683858, AA379280,
					AI371131, AI884907, N62781, H20460,
					AI367698, N93245, AW073851,
					AW191998, AA581796, AA568887,
					AW016535, T78554, AI081779, AI221886,
					AW264577, AA649970, AI350354,
					AI275195, AI902503, AW000860,
					AW162711, AI699657, AA460372,
					AA379846, AA147203, AI951374,
					AI560482, AW243790, R42681,
					AA375228, AI499410, AI279653,
					AA732831, AI475009, N47545, AI696251,
					R43259, D61534, AA783050, AW079129,
					AI474934, R51077, AA160401, Z41466,
					W74167, AI678630, Z41592, AW079321,
					N47546, AL022238, and AL137499.
HDPPO35	326	1119032	1-1889	15-1903	AI640500, AW439548, AI823872,
					AW297416, AA831672, AI815031,
					AA994323, AA741162, AA471280,
					AW339548, AI223999, AW235171,
					AI635436, AA035703, AA747998,
					AI371399, N67227, AA361754, AI536057,
					AA063573, AI357169, R33401, C01451,
					R33402, AA825399, AF165138, and
					AF130247.
HLWDZ53	327	1157542	1-2001	15-2015	AA772242, AI309977, AI268079,
					AW152237, AI923556, AI968056,
					AA394106, AI985775, AI124863, T66217,
					AA700659, AA398135, AA927679,
					W68401, AW105606, AA989587, Y08708,
					AA559050, W68288, H11047, R23506,
					AI277174, F09831, H08254, R37378,
					AA339671, H11135, Y08709, H08154,
					H46511, R50952, H47050, F12201,
					R13468, AA320227, W31952, Y08714,
					R44639, R35282, H58759, H11255,
					T66150, W31329, AI910241, AA772192,
					AA662681, N84315, Y08707, T08656,
					AP000546, and AC002038.
HEOPL36	328	1197910	1-2122	15-2136	AI061632, AW316850, AW367730,
					AA814516, AW367737, AI754746,
					AA777525, AW367804, AI097103,
					AW367782, AW367735, AW367773,
					N30303, AA847688, AW404639, N31888,
					AA779663, AW367809, AW367777,
					AW367785, AI923024, AA953814,
					AW367237, AI305265, AI624406,
					AA582843, N20267, AI827125, AI093328,
					AA911743, AI292227, AI684334,
					AI554543, AA290888, AW367806,
					AA503789, AW367741, H29119,
					AW338358, AW342022, R55898,
					AI401634, W79584, N45284, H25738,
					AA626619, AI024861, N31823, N42550,
					N33984, H17043, H41983, H99343,
					AI002168, AI979180, AI311586, N78814,
					AA564287, AA351508, AA968656,
					W20290, N31566, R75948, AI372938,
					AI277345, Z44878, AW367805, H29018,
					H60714, H17044, H71114, AI567783,
					H53271, AA599764, R60811, AI673673,
					T35639, AA158814, AI129803, H60713,
					H25974, AI423976, R61308, T30051,
					AA582155, AI174537, AI186537,
					AA705042, M85360, W79783, N29173,
					AA161097, R00089, N26452, Z17839,
					F01057, T34112, N54731, AI471185,
					AI023664, AW130265, W31954, H41935,
					T33806, R59766, AA826327, AI244584,
					AI202016, AI077600, N90670, AW009848,
					AA987544, N24540, AI432312, R09698,
					AA777544, R76786, AW081089, T31022,
					AW089365, AI468541, Z40650, AI217229,
					AI371184, T77157, Z28806, AA069041,
					AA505841, N42027, N42580, AI220752,
					AA346958, AI497869, AA160430, T32679,
					R09699, R55813, AI400851, AA298583,
					AI919072, T33966, AA159592,
					AW196132, AA743892, AI689177,
					W31331, T34006, AA911196, AW371882,
					AA301187, AW367265, AI217099,
					AA856916, AA879055, N29277, AI285514,
					H89138, AI819663, AA830044, AI687568,
					AW411043, AI583578, N49165,
					AW020381, AW151132, AW080076,
					AI954721, AI610426, AW198112,
					AI306705, AI306613, AI656270,
					AI628875, AI811373, AA737649,
					AI612885, AW189196, AA838230,
					AI274527, T66952, AI421662, AI249946,
					AL039011, AI470717, AI624529,
					AI318603, AW059828, AW303152,
					AI380329, AI225000, AI345778,
					AL037626, AI702527, AI627714,
					AI796743, AI056328, AI473652,
					AI280561, AW090550, AL045983,
					AI491904, AI799273, AI886355,
					AI933992, AI114703, AI678446,
					AW409775, AI479292, AI648699,
					AI250282, AI868204, AW022907, F37409,
					AI590043, AI500061, AW188388,
					AI553926, AI524654, AA579232,
					AI401697, AW080157, AW083484,
					AI815232, F26535, AA420722, AI471909,
					AA514684, AI370623, AI538885,
					AA761557, AW150762, AI540382,
					AW021189, AI682968, U69181,
					AL036980, AI860027, AW166870,
					AI452857, AW149849, AI628325,
					AI537187, AA746607, AI349957,
					AI804505, AF128536, AL049758,
					AF128535, AF139495, AF139493,
					AF139494, AF139492, AR030257,
					AL133624, AL133047, AF185614, U70981,
					AL137271, AL137555, U72621,
					AL049276, AR060156, AL133014,
					AJ010277, U57352, Y14634, I48978,
					AL080234, A07647, AF036941, AF115392,
					AR029580, L13297, AL122050, AL110222,
					AF102578, AF124728, AL137298, A58524,
					A58523, AF090943, AF038847, AF210052,
					AL050116, AF115410, AF113013,
					AF030165, AF111851, E12580, X53587,
					A07588, AJ238278, S61953, AF091084,
					AF120268, U42031, AF090886, AL110225,
					E02221, I89947, AF167995, S36676,
					AF097996, AL117457, I66342, AL137548,
					A08913, AF159148, AF044221, AL110221,
					AF015958, AR068466, I89931, AF090934,
					Y16645, AF118094, AL110224, A08910,
					AF081195, I49625, AR016469, A08909,
					AR012379, U02475, S77771, AL137665,
					AR050959, A18777, AR020905,
					AL049464, U89906, Y13350, U95114,
					AF125948, S68736, AL133010, AJ012755,
					AL133665, A70386, AF161699, U77594,
					U87620, AL080140, AL117394, X59414,
					AF043642, AF032666, I68732, AL137550,
					AF035161, AL137539, AF013214, A65340,
					AJ000937, AF118090, A93914, S82852,
					AF106657, AF061573, AF019298, X83508,
					X72889, AF113691, I00734, AF113690,
					AB016226, AF119336, AF176651, E00617,
					E00717, E00778, AL133049, AR011880,
					S78214, AL137463, A26498, AF067790,
					U92992, X82434, AF100931, AF017437,
					E03671, E12579, AF200464, AF183393,
					X52128, A91160, AL137711, AF090903,
					AF118558, AL050149, L31396, AL136842,
					AL080147, U42766, L31397, AF124435,
					A91162, Z97214, AL110280, U72620,
					I48979, AF118070, A77033, A77035,
					X62580, AL117460, AL122093,
					AL049452, X98834, AF067728, Y11254,
					AL050277, X80340, E07108, AL137716,
					AL133560, AF078844, AF031903,
					AL137557, Y18680, U92068, AL137560,
					X70685, AL110296, AJ242859, M96857,
					AL137281, U80919, U91329, AF057300,
					U88966, L24896, AL122110, AL136884,
					AF205861, AL035458, AL080159, Z82022,
					U77351, AL133557, U00763, U80742,
					AJ012582, X93495, S69510, A08916,
					E12747, AL080124, AL096728, X66862,
					AF070632, AL137478, AL117587,
					AL049382, AL133640, AL137459,
					AF111849, AL137554, AB007812,
					A93350, I09499, U73682, AL137658,
					AF146568, AL117435, AL133031, A03736,
					AF026816, A32826, A30330, A32827,
					A30331, and U01145.
HMCFS02	329	1152252	1-1432	15-1446	AL119990, AI459232, AI990971,
					AW274849, AA524531, AI703399,
					AW295852, AI086621, AI582316,
					AI887899, AI198620, AW444954,
					AI201159, AI761662, AA769116,
					AI678189, AI769819, AA908833,
					AW001104, AI797112, AW339272,
					AW151222, AI025272, AI638810,
					AA291544, AW083242, AA781447,
					AW003604, AW015232, N30310,
					AA831760, AI624665, AI027612,
					AW276610, AW168171, AA442455,
					AW170708, AI807572, AW080508,
					T62956, AI052790, AA827853, AA737447,
					AI969056, AA465529, H03505, R78862,
					AW378235, AA465115, AW205495,
					AA515398, AI972735, AA805386,
					AA436647, H03615, N56642, AI825714,
					AA293351, AI473377, AA404571,
					AI349471, AW292091, T63206,
					AA252574, R79349, Z38283, AA399447,
					AI582475, AI870404, AA252529,
					AA708728, AI670981, AA429843, C06324,
					C06235, T88738, AA429867, AA748807,
					T10782, AW392315, AI650622, and
					D20600.
HDPSR15	330	1194752	1-1682	15-1696	AW195239, AW149418, AA461376,
					AW005579, AI392913, AI378013,
					AA461199, AI860240, AA779830,
					AI436586, AA147800, AA576717,
					AI276889, AW337924, AI264931,
					AI203549, AA459985, AW104319,
					AA460078, AI377235, AI925811,
					AI094031, AI291778, AI612894,
					AA147758, AA639492, AA767986,
					AA037273, R61563, AA463275, H59980,
					AA832298, AA417605, AA628790,
					AW166255, AA768536, R35919,
					AI289261, AA157070, AA731955,
					AI273576, AA508841, AI360737, N47107,
					AI301339, AI682196, AA463188, H59937,
					AI208175, D20738, AI391726, W42645,
					R14353, AI271983, AI073411, N30324,
					N56657, T53535, H57854, AW001677,
					R35723, AI242094, AA969269, N50317,
					AI808646, AA514325, AI280324,
					AA360254, AI699261, AA551384, T77863,
					AA263061, AA906804, AA741518,
					T11446, AI091790, AA505982, AI208678,
					AA031793, AA214523, AA428834,
					T12550, T11445, AB026289, and
					AR044150.
HNTAV78	331	1217231	1-3733	15-3747	AI417713, AW235714, AI537274,
					AL042544, AL119457, AL119511,
					AL119399, AL043152, AL042382,
					AL119324, AL134524, AL079794,
					AI431323, AL043168, AI889189,
					AI521560, AI433157, AI539771,
					AI537677, AI500659, AI801325,
					AI500523, AI284517, AI500706,
					AI445237, AI491776, AW151138,
					AI500662, AI284509, AI633493,
					AI538885, AI866573, AI434256,
					AI888661, AI284513, AI888118,
					AI582932, AL045500, AI537273,
					AI815232, AI433976, AI567935,
					AI554821, AI889376, AI371251,
					AI889168, AI620284, AI275175,
					AW151136, AL042551, AI866510,
					AL042365, AI923989, AI440252,
					AL110306, AI499463, AI929108,
					AI610362, AI440239, AI927233,
					AI436456, AI432656, AI567940,
					AI817244, AL042787, AL119863,
					AI612913, AL041862, AI285826,
					AI863014, AI499512, AI889133,
					AI610402, AI434223, AI610429,
					AI963846, AL042538, AI432666,
					AI805769, AI889148, AI628850,
					AI633125, AW161579, AI866608,
					AI859991, AI567993, AI860003,
					AI364788, AL036980, AI922901,
					AI491710, AL042866, AL134259,
					AW022682, AI889147, AL047422,
					AW083804, AL045163, AI866457,
					AA572758, AI446373, AI654276,
					AI866786, AI612885, AA420758,
					AI874166, AI494201, AW089272,
					AW021717, AI805762, AL048496,
					AI866469, AL037454, AI872423,
					AW301300, AI349598, AW172723,
					AI702073, AI440263, AW269097,
					AI434242, AW051258, AW191003,
					AI436429, AI371228, AI872300,
					AI610557, AI242736, AI887499,
					AI539632, AI539847, AL045620,
					AL042627, AL042557, AI433037,
					AI500714, AI567961, AW081255,
					AL079741, AI538850, AI955441,
					AI345010, AW129106, AL042745,
					AI312428, AL036705, AL039086,
					AW020693, AI289791, AI890907,
					AI521594, AW087445, AA613907,
					AI348897, AI635492, AI670009,
					AI673278, AW023072, AL119836,
					AI269862, AI637584, AL119828,
					AI432644, AI340603, AL036631,
					AI582926, AA635382, AA259207,
					AI567953, AI537515, AI318280,
					AI537191, AA420722, AW082113,
					AI499131, AL119791, AL040241,
					AI866465, AL119748, AI274759,
					AI916419, AL047387, AI811344,
					AL046926, AW268220, AL041573,
					AI431307, AW073865, AI049851,
					AI648567, AI690946, AL022726,
					AC006296, AL031295, AL030998,
					AC007392, AC005224, AL096709,
					AC005723, AC008394, AC010175,
					AC006115, AC004062, AL009029,
					AL031123, AC004808, and Z83840.
HFKDR14	332	1145842	1-1308	15-1322	AI761729, AW104395, AW298361,
					AI073443, N40162, AW162515, AI827518,
					AW297353, R52045, AI342317, R71958,
					AF128625, AF021936, and AW517595.
HDPBI30	333	974711	1-2911	15-2925	AA714520, N78665, W15172, AL134531,
					AA074818, AI251157, AI311635,
					AA079403, AW130754, AI935943,
					AF083955, AC005015, AL034423,
					AP000030, AC002992, AC004216,
					AC003013, U91321, AC003684,
					AC002528, AL117258, AL021155,
					AP000045, AF053356, AL033521,
					AC004598, U91326, AL035072,
					AD000091, U82668, AC012384, L44140,
					AF006752, AL034350, AC006039,
					AC005756, AC005072, AL034429,
					AC002352, AC005682, AC003663,
					AC005049, AC007298, AC005620,
					AC004887, AL117694, AC005911,
					AC007688, AC006014, AC004797,
					AL031186, AL031283, AC004963, L47234,
					Z84466, AC004125, AC005529,
					AL031293, AC006276, AL034400,
					AC004099, AC005089, AL049871,
					AC004893, AL080243, AC007021,
					AL049712, AC007993, AC006581,
					AC005837, AF139813, M13792,
					AC005086, AL096791, AJ251973,
					AC002301, AC006139, AC005488,
					L78810, AC006115, AC004966,
					AC006538, Z93244, AC004834,
					AL049570, AC004084, AP000113,
					AP000251, and AC005696.
HODFF88	334	1094875	1-1843	15-1857	D80164, D59502, D80193, D80195,
					D59275, C15076, D80227, D58283,
					D80022, D80166, D81030, D59859,
					D51799, D59619, D80210, D80391,
					D80240, D59787, D51423, D80253,
					D80043, D80269, D50979, D80212,
					D80038, D80196, D80024, D80219,
					D80188, C14331, D59467, D57483,
					D59927, D80378, D80366, C14389,
					D59889, D50995, D80045, D59610,
					AA305409, C14429, D80241, D51060,
					T03269, C14014, AW178893, C75259,
					AA305578, D81026, D59695, D51022,
					AW179328, D81111, AW178775, D80134,
					AW378532, AW177440, D51250,
					AW352158, D80268, F13647, AA514188,
					AW369651, D80251, D80522, D51079,
					D80248, D80949, D58253, AW178762,
					D80168, D52291, C14227, AA514186,
					AI905856, AW177501, AW177511,
					D80133, Z21582, AW360811, C05695,
					C14298, AW352117, D80064, AW176467,
					AW375405, AW378540, C14407,
					AW377671, D51097, AW366296, D80302,
					AW360844, AW360817, AW375406,
					AW378534, AW179332, AW377672,
					AW179023, AW178905, D80132,
					AW360834, AA285331, D80439,
					AW352171, AW377676, AW178906,
					AW352170, AW177731, D80247,
					AW178907, AW179019, AW179024,
					D51103, AW177505, AW360841,
					AW179020, AW178909, AW177456,
					AW179329, AW178980, AW177733,
					AW378528, AW178908, AW178754,
					AW179018, AW179220, AI557751,
					AW179004, AW178914, AW378525,
					AW352174, T11417, D80157, AW177728,
					D59627, D51759, AW367967, AW178774,
					AW178911, AW378543, AW352163,
					D59503, D80258, D80014, C06015,
					AI557774, AW178983, AW352120,
					T03116, AW178781, T48593, D58246,
					C14077, D59653, AW177723, D58101,
					D45260, AI525923, AW178986,
					AW367950, C03092, AA809122, H67854,
					D59551, H67866, C14975, T02974,
					AW378533, AW378539, D51213,
					AW177734, AI535686, D59317, D51221,
					AI525917, C14973, AA514184, C14344,
					D45273, AI525925, AI525920, D59474,
					AI525227, D31458, C14046, AI525242,
					AI525235, T03048, AI525912, AW378542,
					AI525215, AI525237, C16955, C05763,
					Z33452, AI535850, AI535961, A84916,
					AJ132110, A62300, A62298, AR018138,
					X67155, Y17188, D26022, A25909,
					A67220, D89785, A78862, D34614,
					D88547, AF058696, X82626, AR008278,
					AB028859, AR025207, I82448, Y12724,
					A82595, AB012117, AR060385,
					AB002449, A85396, AR066482, A44171,
					A85477, A94995, X68127, I19525,
					A86792, X93549, AR008443, AR016808,
					U87250, I50133, I50126, I50132, I50128,
					AR066488, AR016514, AR060138,
					A45456, A26615, AR052274, I14842,
					Y09669, A43192, A43190, AR038669,
					AR066487, A30438, AF135125, D88507,
					AR066490, D50010, AR054175, I18367,
					Y17187, A63261, AR008277, AR008281,
					AR008408, AR062872, A70867,
					AB033111, AR016691, AR016690,
					U46128, D13509, AR060133, I79511,
					AR064240, A64136, A68321, U87247,
					AB023656, U79457, AF123263, X93535,
					and AR008382.

[0089]

TABLE 4
Code	Description	Tissue	Organ	Cell Line	Disease	Vector
AR022	a_Heart	a_Heart
AR023	a_Liver	a_Liver
AR024	a_mammary gland	a_mammary gland
AR025	a_Prostate	a_Prostate
AR026	a_small intestine	a_small intestine
AR027	a_Stomach	a_Stomach
AR028	Blood B cells	Blood B cells
AR029	Blood B cells activated	Blood B cells
		activated
AR030	Blood B cells resting	Blood B cells
		resting
AR031	Blood T cells activated	Blood T cells
		activated
AR032	Blood T cells resting	Blood T cells resting
AR033	brain	brain
AR034	breast	breast
AR035	breast cancer	breast cancer
AR036	Cell Line CAOV3	Cell Line CAOV3
AR037	cell line PA-1	cell line PA-1
AR038	cell line transformed	cell line transformed
AR039	colon	colon
AR040	colon (9808co65R)	colon (9808co65R)
AR041	colon (9809co15)	colon (9809co15)
AR042	colon cancer	colon cancer
AR043	colon cancer (9808co64R)	colon cancer
		(9808co64R)
AR044	colon cancer 9809co14	colon cancer
		9809co14
AR045	corn clone 5	corn clone 5
AR046	corn clone 6	corn clone 6
AR047	corn clone 2	corn clone 2
AR048	corn clone 3	corn clone 3
AR049	Corn Clone 4	Corn Clone 4
AR050	Donor II B Cells 24 hrs	Donor II B Cells
		24 hrs
AR051	Donor II B Cells 72 hrs	Donor II B Cells
		72 hrs
AR052	Donor II B-Cells 24 hrs.	Donor II B-Cells 24
		hrs.
AR053	Donor II B-Cells 72 hrs	Donor II B-Cells
		72 hrs
AR054	Donor II Resting B Cells	Donor II Resting B
		Cells
AR055	Heart	Heart
AR056	Human Lung (clonetech)	Human Lung
		(clonetech)
AR057	Human Mammary	Human Mammary
	(clontech)	(clontech)
AR058	Human Thymus	Human Thymus
	(clonetech)	(clonetech)
AR059	Jurkat (unstimulated)	Jurkat
		(unstimulated)
AR060	Kidney	Kidney
AR061	Liver	Liver
AR062	Liver (Clontech)	Liver (Clontech)
AR063	Lymphocytes chronic	Lymphocytes
	lymphocytic leukaemia	chronic lymphocytic
		leukaemia
AR064	Lymphocytes diffuse large	Lymphocytes
	B cell lymphoma	diffuse large B cell
		lymphoma
AR065	Lymphocytes follicular	Lymphocytes
	lymphoma	follicular lymphoma
AR066	normal breast	normal breast
AR067	Normal Ovarian	Normal Ovarian
	(4004901)	(4004901)
AR068	Normal Ovary 9508G045	Normal Ovary
		9508G045
AR069	Normal Ovary 9701G208	Normal Ovary
		9701G208
AR070	Normal Ovary 9806G005	Normal Ovary
		9806G005
AR071	Ovarian Cancer	Ovarian Cancer
AR072	Ovarian Cancer	Ovarian Cancer
	(9702G001)	(9702G001)
AR073	Ovarian Cancer	Ovarian Cancer
	(9707G029)	(9707G029)
AR074	Ovarian Cancer	Ovarian Cancer
	(9804G011)	(9804G011)
AR075	Ovarian Cancer	Ovarian Cancer
	(9806G019)	(9806G019)
AR076	Ovarian Cancer	Ovarian Cancer
	(9807G017)	(9807G017)
AR077	Ovarian Cancer	Ovarian Cancer
	(9809G001)	(9809G001)
AR078	ovarian cancer 15799	ovarian cancer
		15799
AR079	Ovarian Cancer	Ovarian Cancer
	17717AID	17717AID
AR080	Ovarian Cancer	Ovarian Cancer
	4004664B1	4004664B1
AR081	Ovarian Cancer	Ovarian Cancer
	4005315A1	4005315A1
AR082	ovarian cancer 94127303	ovarian cancer
		94127303
AR083	Ovarian Cancer 96069304	Ovarian Cancer
		96069304
AR084	Ovarian Cancer 9707G029	Ovarian Cancer
		9707G029
AR085	Ovarian Cancer 9807G045	Ovarian Cancer
		9807G045
AR086	ovarian cancer 9809G001	ovarian cancer
		9809G001
AR087	Ovarian Cancer	Ovarian Cancer
	9905C032RC	9905C032RC
AR088	Ovarian cancer 9907 C00	Ovarian cancer 9907
	3rd	C00 3rd
AR089	Prostate	Prostate
AR090	Prostate (clonetech)	Prostate (clonetech)
AR091	prostate cancer	prostate cancer
AR092	prostate cancer #15176	prostate cancer
		#15176
AR093	prostate cancer #15509	prostate cancer
		#15509
AR094	prostate cancer #15673	prostate cancer
		#15673
AR095	Small Intestine (Clontech)	Small Intestine
		(Clontech)
AR096	Spleen	Spleen
AR097	Thymus T cells activated	Thymus T cells
		activated
AR098	Thymus T cells resting	Thymus T cells
		resting
AR099	Tonsil	Tonsil
AR100	Tonsil geminal center	Tonsil geminal
	centroblast	center centroblast
AR101	Tonsil germinal center B	Tonsil germinal
	cell	center B cell
AR102	Tonsil lymph node	Tonsil lymph node
AR103	Tonsil memory B cell	Tonsil memory B
		cell
AR104	Whole Brain	Whole Brain
AR105	Xenograft ES-2	Xenograft ES-2
AR106	Xenograft SW626	Xenograft SW626
H0004	Human Adult Spleen	Human Adult	Spleen			Uni-ZAP XR
		Spleen
H0008	Whole 6 Week Old					Uni-ZAP XR
	Embryo
H0009	Human Fetal Brain					Uni-ZAP XR
H0011	Human Fetal Kidney	Human Fetal Kidney	Kidney			Uni-ZAP XR
H0012	Human Fetal Kidney	Human Fetal Kidney	Kidney			Uni-ZAP XR
H0013	Human 8 Week Whole	Human 8 Week Old	Embryo			Uni-ZAP XR
	Embryo	Embryo
H0014	Human Gall Bladder	Human Gall Bladder	Gall Bladder			Uni-ZAP XR
H0015	Human Gall Bladder,	Human Gall Bladder	Gall Bladder			Uni-ZAP XR
	fraction II
H0022	Jurkat Cells	Jurkat T-Cell Line				Lambda
						ZAP II
H0023	Human Fetal Lung					Uni-ZAP XR
H0024	Human Fetal Lung III	Human Fetal Lung	Lung			Uni-ZAP XR
H0025	Human Adult Lymph	Human Adult	Lymph Node			Lambda
	Node	Lymph Node				ZAP II
H0027	Human Ovarian Cancer				disease	Uni-ZAP XR
H0028	Human Old Ovary	Human Old Ovary	Ovary			pBluescript
H0029	Human Pancreas	Human Pancreas	Pancreas			Uni-ZAP XR
H0030	Human Placenta					Uni-ZAP XR
H0031	Human Placenta	Human Placenta	Placenta			Uni-ZAP XR
H0032	Human Prostate	Human Prostate	Prostate			Uni-ZAP XR
H0036	Human Adult Small	Human Adult Small	Small Int.			Uni-ZAP XR
	Intestine	Intestine
H0037	Human Adult Small	Human Adult Small	Small Int.			pBluescript
	Intestine	Intestine
H0038	Human Testes	Human Testes	Testis			Uni-ZAP XR
H0039	Human Pancreas Tumor	Human Pancreas	Pancreas		disease	Uni-ZAP XR
		Tumor
H0040	Human Testes Tumor	Human Testes	Testis		disease	Uni-ZAP XR
		Tumor
H0041	Human Fetal Bone	Human Fetal Bone	Bone			Uni-ZAP XR
H0042	Human Adult Pulmonary	Human Adult	Lung			Uni-ZAP XR
		Pulmonary
H0046	Human Endometrial	Human Endometrial	Uterus		disease	Uni-ZAP XR
	Tumor	Tumor
H0048	Human Pineal Gland	Human Pineal Gland				Uni-ZAP XR
H0050	Human Fetal Heart	Human Fetal Heart	Heart			Uni-ZAP XR
H0051	Human Hippocampus	Human	Brain			Uni-ZAP XR
		Hippocampus
H0052	Human Cerebellum	Human Cerebellum	Brain			Uni-ZAP XR
H0056	Human Umbilical Vein,	Human Umbilical	Umbilical			Uni-ZAP XR
	Endo. remake	Vein Endothelial	vein
		Cells
H0057	Human Fetal Spleen					Uni-ZAP XR
H0059	Human Uterine Cancer	Human Uterine	Uterus		disease	Lambda
		Cancer				ZAP II
H0063	Human Thymus	Human Thymus	Thymus			Uni-ZAP XR
H0068	Human Skin Tumor	Human Skin Tumor	Skin		disease	Uni-ZAP XR
H0069	Human Activated T-Cells	Activated T-Cells	Blood	Cell Line		Uni-ZAP XR
H0071	Human Infant Adrenal	Human Infant	Adrenal			Uni-ZAP XR
	Gland	Adrenal Gland	gland
H0075	Human Activated T-Cells	Activated T-Cells	Blood	Cell Line		Uni-ZAP XR
	(II)
H0081	Human Fetal Epithelium	Human Fetal Skin	Skin			Uni-ZAP XR
	(Skin)
H0083	HUMAN JURKAT	Jurkat Cells				Uni-ZAP XR
	MEMBRANE BOUND
	POLYSOMES
H0085	Human Colon	Human Colon				Lambda
						ZAP II
H0086	Human epithelioid	Epithelioid	Sk Muscle		disease	Uni-ZAP XR
	sarcoma	Sarcoma, muscle
H0087	Human Thymus	Human Thymus				pBluescript
H0090	Human T-Cell Lymphoma	T-Cell Lymphoma	T-Cell		disease	Uni-ZAP XR
H0098	Human Adult Liver,	Human Adult Liver	Liver			Uni-ZAP XR
	subtracted
H0100	Human Whole Six Week	Human Whole Six	Embryo			Uni-ZAP XR
	Old Embryo	Week Old
		Embryo
H0101	Human 7 Weeks Old	Human Whole 7	Embryo			Lambda
	Embryo, subtracted	Week Old Embryo				ZAP II
H0102	Human Whole 6 Week	Human Whole Six	Embryo			pBluescript
	Old Embryo (II), subt	Week Old Embryo
H0105	Human Fetal Heart,	Human Fetal Heart	Heart			pBluescript
	subtracted
H0108	Human Adult Lymph	Human Adult	Lymph Node			Uni-ZAP XR
	Node, subtracted	Lymph Node
H0116	Human Thymus Tumor,	Human Thymus	Thymus			pBluescript
	subtracted	Tumor
H0118	Human Adult Kidney	Human Adult	Kidney			Uni-ZAP XR
		Kidney
H0122	Human Adult Skeletal	Human Skeletal	Sk Muscle			Uni-ZAP XR
	Muscle	Muscle
H0123	Human Fetal Dura Mater	Human Fetal Dura	Brain			Uni-ZAP XR
		Mater
H0124	Human	Human	Sk Muscle		disease	Uni-ZAP XR
	Rhabdomyosarcoma	Rhabdomyosarcoma
H0125	Cem cells cyclohexamide	Cyclohexamide	Blood	Cell Line		Uni-ZAP XR
	treated	Treated Cem, Jurkat,
		Raji, and Supt
H0130	LNCAP untreated	LNCAP Cell Line	Prostate	Cell Line		Uni-ZAP XR
H0131	LNCAP + o.3 nM R1881	LNCAP Cell Line	Prostate	Cell Line		Uni-ZAP XR
H0132	LNCAP + 30 nM R1881	LNCAP Cell Line	Prostate	Cell Line		Uni-ZAP XR
H0134	Raji Cells, cyclohexamide	Cyclohexamide	Blood	Cell Line		Uni-ZAP XR
	treated	Treated Cem, Jurkat,
		Raji, and Supt
H0135	Human Synovial Sarcoma	Human Synovial	Synovium			Uni-ZAP XR
		Sarcoma
H0136	Supt Cells, cyclohexamide	Cyclohexamide	Blood	Cell Line		Uni-ZAP XR
	treated	Treated Cem, Jurkat,
		Raji, and Supt
H0141	Activated T-Cells, 12 hrs.	Activated T-Cells	Blood	Cell Line		Uni-ZAP XR
H0144	Nine Week Old Early	9 Wk Old Early	Embryo			Uni-ZAP XR
	Stage Human	Stage Human
H0149	7 Week Old Early Stage	Human Whole 7	Embryo			Uni-ZAP XR
	Human, subtracted	Week Old Embryo
H0150	Human Epididymus	Epididymis	Testis			Uni-ZAP XR
H0154	Human Fibrosarcoma	Human Skin	Skin		disease	Uni-ZAP XR
		Fibrosarcoma
H0156	Human Adrenal Gland	Human Adrenal	Adrenal		disease	Uni-ZAP XR
	Tumor	Gland Tumor	Gland
H0159	Activated T-Cells, 8 hrs.,	Activated T-Cells	Blood	Cell Line		Uni-ZAP XR
	ligation 2
H0163	Human Synovium	Human Synovium	Synovium			Uni-ZAP XR
H0165	Human Prostate Cancer,	Human Prostate	Prostate		disease	Uni-ZAP XR
	Stage B2	Cancer, stage B2
H0166	Human Prostate Cancer,	Human Prostate	Prostate		disease	Uni-ZAP XR
	Stage B2 fraction	Cancer, stage B2
H0169	Human Prostate Cancer,	Human Prostate	Prostate		disease	Uni-ZAP XR
	Stage C fraction	Cancer, stage C
H0170	12 Week Old Early Stage	Twelve Week Old	Embryo			Uni-ZAP XR
	Human	Early Stage Human
H0171	12 Week Old Early Stage	Twelve Week Old	Embryo			Uni-ZAP XR
	Human, II	Early Stage Human
H0172	Human Fetal Brain,	Human Fetal Brain	Brain			Lambda
	random primed					ZAP II
H0175	H. Adult Spleen, ziplox					pSport1
H0176	CAMA1Ee Cell Line	CAMA1Ee Cell	Breast	Cell Line		Uni-ZAP XR
		Line
H0178	Human Fetal Brain	Human Fetal Brain	Brain			Uni-ZAP XR
H0179	Human Neutrophil	Human Neutrophil	Blood	Cell Line		Uni-ZAP XR
H0181	Human Primary Breast	Human Primary	Breast		disease	Uni-ZAP XR
	Cancer	Breast Cancer
H0182	Human Primary Breast	Human Primary	Breast		disease	Uni-ZAP XR
	Cancer	Breast Cancer
H0187	Resting T-Cell	T-Cells	Blood	Cell Line		Lambda
						ZAP II
H0188	Human Normal Breast	Human Normal	Breast			Uni-ZAP XR
		Breast
H0192	Cem Cells, cyclohexamide	Cyclohexamide	Blood	Cell Line		Uni-ZAP XR
	treated, subtra	Treated Cem, Jurkat,
		Raji, and Supt
H0194	Human Cerebellum,	Human Cerebellum	Brain			pBluescript
	subtracted
H0196	Human Cardiomyopathy,	Human	Heart			Uni-ZAP XR
	subtracted	Cardiomyopathy
H0201	Human Hippocampus,	Human	Brain			pBluescript
	subtracted	Hippocampus
H0205	Human Colon Cancer,	Human Colon	Colon			pBluescript
	differential	Cancer
H0208	Early Stage Human Lung,	Human Fetal Lung	Lung			pBluescript
	subtracted
H0212	Human Prostate,	Human Prostate	Prostate			pBluescript
	subtracted
H0213	Human Pituitary,	Human Pituitary				Uni-ZAP XR
	subtracted
H0214	Raji cells, cyclohexamide	Cyclohexamide	Blood	Cell Line		pBluescript
	treated, subtracted	Treated Cem, Jurkat,
		Raji, and Supt
H0222	Activated T-Cells, 8 hrs,	Activated T-Cells	Blood	Cell Line		Uni-ZAP XR
	subtracted
H0229	Early Stage Human Brain,	Early Stage Human	Brain			Lambda
	random primed	Brain				ZAP II
H0230	Human Cardiomyopathy,	Human	Heart		disease	Uni-ZAP XR
	diff exp	Cardiomyopathy
H0231	Human Colon, subtraction	Human Colon				pBluescript
H0239	Human Kidney Tumor	Human Kidney	Kidney		disease	Uni-ZAP XR
		Tumor
H0242	Human Fetal Heart,	Human Fetal Heart	Heart			pBluescript
	Differential (Fetal-
	Specific)
H0244	Human 8 Week Whole	Human 8 Week Old	Embryo			Uni-ZAP XR
	Embryo, subtracted	Embryo
H0250	Human Activated	Human Monocytes				Uni-ZAP XR
	Monocytes
H0251	Human Chondrosarcoma	Human	Cartilage		disease	Uni-ZAP XR
		Chondrosarcoma
H0252	Human Osteosarcoma	Human	Bone		disease	Uni-ZAP XR
		Osteosarcoma
H0253	Human adult testis, large	Human Adult Testis	Testis			Uni-ZAP XR
	inserts
H0254	Breast Lymph node cDNA	Breast Lymph Node	Lymph Node			Uni-ZAP XR
	library
H0255	breast lymph node CDNA	Breast Lymph Node	Lymph Node			Lambda
	library					ZAP II
H0261	H. cerebellum, Enzyme	Human Cerebellum	Brain			Uni-ZAP XR
	subtracted
H0263	human colon cancer	Human Colon	Colon		disease	Lambda
		Cancer				ZAP II
H0264	human tonsils	Human Tonsil	Tonsil			Uni-ZAP XR
H0265	Activated T-Cell	T-Cells	Blood	Cell Line		Uni-ZAP XR
	(12hs)/Thiouridine
	labelledEco
H0266	Human Microvascular	HMEC	Vein	Cell Line		Lambda
	Endothelial Cells, fract. A					ZAP II
H0268	Human Umbilical Vein	HUVE Cells	Umbilical	Cell Line		Lambda
	Endothelial Cells, fract. A		vein			ZAP II
H0269	Human Umbilical Vein	HUVE Cells	Umbilical	Cell Line		Lambda
	Endothelial Cells, fract. B		vein			ZAP II
H0270	HPAS (human pancreas,	Human Pancreas	Pancreas			Uni-ZAP XR
	subtracted)
H0271	Human Neutrophil,	Human Neutrophil -	Blood	Cell Line		Uni-ZAP XR
	Activated	Activated
H0272	HUMAN TONSILS,	Human Tonsil	Tonsil			Uni-ZAP XR
	FRACTION 2
H0274	Human Adult Spleen,	Human Adult	Spleen			Uni-ZAP XR
	fractionII	Spleen
H0280	K562 + PMA (36 hrs)	K562 Cell line	cell line	Cell Line		ZAP Express
H0284	Human OB MG63 control	Human	Bone	Cell Line		Uni-ZAP XR
	fraction I	Osteoblastoma
		MG63 cell line
H0286	Human OB MG63 treated	Human	Bone	Cell Line		Uni-ZAP XR
	(10 nM E2) fraction I	Osteoblastoma
		MG63 cell line
H0288	Human OB HOS control	Human	Bone	Cell Line		Uni-ZAP XR
	fraction I	Osteoblastoma HOS
		cell line
H0290	Human OB HOS treated	Human	Bone	Cell Line		Uni-ZAP XR
	(1 nM E2) fraction I	Osteoblastoma HOS
		cell line
H0292	Human OB HOS treated	Human	Bone	Cell Line		Uni-ZAP XR
	(10 nM E2) fraction I	Osteoblastoma HOS
		cell line
H0293	WI 38 cells					Uni-ZAP XR
H0294	Amniotic Cells - TNF	Amniotic Cells -	Placenta	Cell Line		Uni-ZAP XR
	induced	TNF induced
H0295	Amniotic Cells - Primary	Amniotic Cells -	Placenta	Cell Line		Uni-ZAP XR
	Culture	Primary Culture
H0305	CD34 positive cells (Cord	CD34 Positive Cells	Cord Blood			ZAP Express
	Blood)
H0306	CD34 depleted Buffy Coat	CD34 Depleted	Cord Blood			ZAP Express
	(Cord Blood)	Buffy Coat (Cord
		Blood)
H0309	Human Chronic Synovitis	Synovium, Chronic	Synovium		disease	Uni-ZAP XR
		Synovitis/
		Osteoarthritis
H0310	human caudate nucleus	Brain	Brain			Uni-ZAP XR
H0316	HUMAN STOMACH	Human Stomach	Stomach			Uni-ZAP XR
H0318	HUMAN B CELL	Human B Cell	Lymph Node		disease	Uni-ZAP XR
	LYMPHOMA	Lymphoma
H0320	Human frontal cortex	Human Frontal	Brain			Uni-ZAP XR
		Cortex
H0327	human corpus colosum	Human Corpus	Brain			Uni-ZAP XR
		Callosum
H0328	human ovarian cancer	Ovarian Cancer	Ovary		disease	Uni-ZAP XR
H0329	Dermatofibrosarcoma	Dermatofibrosarcoma	Skin		disease	Uni-ZAP XR
	Protuberance	Protuberans
H0331	Hepatocellular Tumor	Hepatocellular	Liver		disease	Lambda
		Tumor				ZAP II
H0333	Hemangiopericytoma	Hemangiopericytoma	Blood vessel		disease	Lambda
						ZAP II
H0334	Kidney cancer	Kidney Cancer	Kidney		disease	Uni-ZAP XR
H0339	Duodenum	Duodenum				Uni-ZAP XR
H0340	Corpus Callosum	Corpus Collosum-				Uni-ZAP XR
		93052
H0341	Bone Marrow Cell Line	Bone Marrow Cell	Bone Marrow	Cell Line		Uni-ZAP XR
	(RS4; 11)	Line RS4; 11
H0343	stomach cancer (human)	Stomach Cancer -			disease	Uni-ZAP XR
		5383A (human)
H0345	SKIN	Skin - 4000868H	Skin			Uni-ZAP XR
H0349	human adult liver cDNA	Human Adult Liver	Liver			pCMVSport
	library					1
H0351	Glioblastoma	Glioblastoma	Brain		disease	Uni-ZAP XR
H0352	wilm″s tumor	Wilm″s Tumor			disease	Uni-ZAP XR
H0355	Human Liver	Human Liver,				pCMVSport
		normal Adult				1
H0359	KMH2 cell line	KMH2				ZAP Express
H0361	Human rejected kidney	Human Rejected			disease	pBluescript
		Kidney
H0364	Human Osteoclastoma,	Human			disease	pBluescript
	excised	Osteoclastoma
H0369	H. Atrophic Endometrium	Atrophic				Uni-ZAP XR
		Endometrium and
		myometrium
H0370	H. Lymph node breast	Lymph node with			disease	Uni-ZAP XR
	Cancer	Met. Breast Cancer
H0373	Human Heart	Human Adult Heart	Heart			pCMVSport
						1
H0374	Human Brain	Human Brain				pCMVSport
						1
H0375	Human Lung	Human Lung				pCMVSport
						1
H0379	Human Tongue, frac 1	Human Tongue				pSport1
H0386	Leukocyte and Lung; 4	Human Leukocytes	Blood	Cell Line		pCMVSport
	screens					1
H0390	Human Amygdala	Human Amygdala			disease	pBluescript
	Depression, re-excision	Depression
H0391	H. Meniingima, M6	Human Meningima	brain			pSport1
H0392	H. Meningima, M1	Human Meningima	brain			pSport1
H0393	Fetal Liver, subtraction II	Human Fetal Liver	Liver			pBluescript
H0394	A-14 cell line	Redd-Sternberg cell				ZAP Express
H0395	A1-CELL LINE	Redd-Sternberg cell				ZAP Express
H0396	L1 Cell line	Redd-Sternberg cell				ZAP Express
H0399	Human Kidney Cortex, re-	Human Kidney				Lambda
	rescue	Cortex				ZAP II
H0402	CD34 depleted Buffy Coat	CD34 Depleted	Cord Blood			ZAP Express
	(Cord Blood), re-excision	Buffy Coat (Cord
		Blood)
H0403	H. Umbilical Vein	HUVE Cells	Umbilical	Cell Line		Uni-ZAP XR
	Endothelial Cells, IL4		vein
	induced
H0404	H. Umbilical Vein	HUVE Cells	Umbilical	Cell Line		Uni-ZAP XR
	endothelial cells,		vein
	uninduced
H0409	H. Striatum Depression,	Human Brain,	Brain			pBluescript
	subtracted	Striatum Depression
H0411	H Female Bladder, Adult	Human Female	Bladder			pSport1
		Adult Bladder
H0412	Human umbilical vein	HUVE Cells	Umbilical	Cell Line		pSport1
	endothelial cells, IL-4		vein
	induced
H0413	Human Umbilical Vein	HUVE Cells	Umbilical	Cell Line		pSport1
	Endothelial Cells,		vein
	uninduced
H0414	Ovarian Tumor I, OV5232	Ovarian Tumor,	Ovary		disease	pSport1
		OV5232
H0415	H. Ovarian Tumor, II,	Ovarian Tumor,	Ovary		disease	pCMVSport
	OV5232	OV5232				2.0
H0416	Human Neutrophils,	Human Neutrophil -	Blood	Cell Line		pBluescript
	Activated, re-excision	Activated
H0421	Human Bone Marrow, re-	Bone Marrow				pBluescript
	excision
H0422	T-Cell PHA 16 hrs	T-Cells	Blood	Cell Line		pSport1
H0423	T-Cell PHA 24 hrs	T-Cells	Blood	Cell Line		pSport1
H0424	Human Pituitary, subt IX	Human Pituitary				pBluescript
H0427	Human Adipose	Human Adipose, left				pSport1
		hiplipoma
H0428	Human Ovary	Human Ovary	Ovary			pSport1
		Tumor
H0429	K562 + PMA (36 hrs), re-	K562 Cell line	cell line	Cell Line		ZAP Express
	excision
H0431	H. Kidney Medulla, re-	Kidney medulla	Kidney			pBluescript
	excision
H0433	Human Umbilical Vein	HUVE Cells	Umbilical	Cell Line		pBluescript
	Endothelial cells, frac B,		vein
	re-excision
H0434	Human Brain, striatum,	Human Brain,				pBluescript
	re-excision	Striatum
H0435	Ovarian Tumor 10-3-95	Ovarian Tumor,	Ovary			pCMVSport
		OV350721				2.0
H0436	Resting T-Cell Library, II	T-Cells	Blood	Cell Line		pSport1
H0437	H Umbilical Vein	HUVE Cells	Umbilical	Cell Line		Lambda
	Endothelial Cells, frac A,		vein			ZAP II
	re-excision
H0438	H. Whole Brain #2, re-	Human Whole Brain				ZAP Express
	excision	#2
H0441	H. Kidney Cortex,	Kidney cortex	Kidney			pBluescript
	subtracted
H0444	Spleen metastic melanoma	Spleen, Metastic	Spleen		disease	pSport1
		malignant
		melanoma
H0445	Spleen, Chronic	Human Spleen, CLL	Spleen		disease	pSport1
	lymphocytic leukemia
H0455	H. Striatum Depression,	Human Brain,	Brain			pBluescript
	subt	Striatum Depression
H0456	H Kidney Cortex,	Human Kidney				pBluescript
	subtracted III	Cortex
H0457	Human Eosinophils	Human Eosinophils				pSport1
H0459	CD34 + cells, II,	CD34 positive cells				pCMVSport
	FRACTION 2					2.0
H0477	Human Tonsil, Lib 3	Human Tonsil	Tonsil			pSport1
H0478	Salivary Gland, Lib 2	Human Salivary	Salivary			pSport1
		Gland	gland
H0479	Salivary Gland, Lib 3	Human Salivary	Salivary			pSport1
		Gland	gland
H0483	Breast Cancer cell line,	Breast Cancer Cell				pSport1
	MDA 36	line, MDA 36
H0484	Breast Cancer Cell line,	Breast Cancer Cell				pSport1
	angiogenic	line, Angiogenic,
		36T3
H0485	Hodgkin″s Lymphoma I	Hodgkin″s			disease	pCMVSport
		Lymphoma I				2.0
H0486	Hodgkin″s Lymphoma II	Hodgkin″s			disease	pCMVSport
		Lymphoma II				2.0
H0487	Human Tonsils, lib I	Human Tonsils				pCMVSport
						2.0
H0488	Human Tonsils, Lib 2	Human Tonsils				pCMVSport
						2.0
H0489	Crohn″s Disease	Ileum	Intestine		disease	pSport1
H0494	Keratinocyte	Keratinocyte				pCMVSport
						2.0
H0497	HEL cell line	HEL cell line		HEL		pSport1
				92.1.7
H0505	Human Astrocyte	Human Astrocyte				pSport1
H0506	Ulcerative Colitis	Colon	Colon			pSport1
H0509	Liver, Hepatoma	Human Liver,	Liver		disease	pCMVSport
		Hepatoma, patient 8				3.0
H0510	Human Liver, normal	Human Liver,	Liver			pCMVSport
		normal, Patient #8				3.0
H0517	Nasal polyps	Nasal polyps				pCMVSport
						2.0
H0518	pBMC stimulated w/poly	pBMC stimulated				pCMVSport
	I/C	with poly I/C				3.0
H0519	NTERA2, control	NTERA2,				pCMVSport
		Teratocarcinoma				3.0
		cell line
H0520	NTERA2 + retinoic acid,	NTERA2,				pSport1
	14 days	Teratocarcinoma
		cell line
H0521	Primary Dendritic Cells,	Primary Dendritic				pCMVSport
	lib 1	cells				3.0
H0522	Primary Dendritic	Primary Dendritic				pCMVSport
	cells,frac 2	cells				3.0
H0528	Poly[I]/Poly[C] Normal	Poly[I]/Poly[C]				pCMVSport
	Lung Fibroblasts	Normal Lung				3.0
		Fibroblasts
H0529	Myoloid Progenitor Cell	TF-1 Cell Line;				pCMVSport
	Line	Myoloid progenitor				3.0
		cell line
H0530	Human Dermal	Human Dermal				pSport1
	Endothelial	Endothelial Cells;
	Cells, untreated	untreated
H0538	Merkel Cells	Merkel cells	Lymph node			pSport1
H0539	Pancreas Islet Cell Tumor	Pancreas Islet Cell	Pancreas		disease	pSport1
		Tumour
H0540	Skin, burned	Skin, leg burned	Skin			pSport1
H0542	T Cell helper I	Helper T cell				pCMVSport
						3.0
H0543	T cell helper II	Helper T cell				pCMVSport
						3.0
H0544	Human endometrial	Human endometrial				pCMVSport
	stromal cells	stromal cells				3.0
H0545	Human endometrial	Human endometrial				pCMVSport
	stromal cells-treated with	stromal cells-treated				3.0
	progesterone	with proge
H0546	Human endometrial	Human endometrial				pCMVSport
	stromal cells-treated with	stromal cells-treated				3.0
	estradiol	with estra
H0547	NTER A2 teratocarcinoma	NTERA2,				pSport1
	cell line + retinoic acid (14	Teratocarcinoma
	days)	cell line
H0549	H. Epididiymus, caput &	Human				Uni-ZAP XR
	corpus	Epididiyrnus, caput
		and corpus
H0550	H. Epididiymus, cauda	Human				Uni-ZAP XR
		Epididiymus, cauda
H0551	Human Thymus Stromal	Human Thymus				pCMVSport
	Cells	Stromal Cells				3.0
H0553	Human Placenta	Human Placenta				pCMVSport
						3.0
H0555	Rejected Kidney, lib 4	Human Rejected	Kidney		disease	pCMVSport
		Kidney				3.0
H0556	Activated T-	T-Cells	Blood	Cell Line		Uni-ZAP XR
	cell(12 h)/Thiouridine-re-
	excision
H0559	HL-60, PMA 4H, re-	HL-60 Cells, PMA	Blood	Cell Line		Uni-ZAP XR
	excision	stimulated 4H
H0560	KMH2	KMH2				pCMVSport
						3.0
H0561	L428	L428				pCMVSport
						3.0
H0562	Human Fetal Brain,	Human Fetal Brain				pCMVSport
	normalized c5-11-26					2.0
H0563	Human Fetal Brain,	Human Fetal Brain				pCMVSport
	normalized 50021F					2.0
H0564	Human Fetal Brain,	Human Fetal Brain				pCMVSport
	normalized C5001F					2.0
H0566	Human Fetal	Human Fetal Brain				pCMVSport
	Brain,normalized c50F					2.0
H0569	Human Fetal Brain,	Human Fetal Brain				pCMVSport
	normalized CO					2.0
H0570	Human Fetal Brain,	Human Fetal Brain				pCMVSport
	normalized C500H					2.0
H0571	Human Fetal Brain,	Human Fetal Brain				pCMVSport
	normalized C500HE					2.0
H0572	Human Fetal Brain,	Human Fetal Brain				pCMVSport
	normalized AC5002					2.0
H0574	Hepatocellular Tumor; re-	Hepatocellular	Liver		disease	Lambda
	excision	Tumor				ZAP II
H0575	Human Adult	Human Adult	Lung			Uni-ZAP XR
	Pulmonary; re-excision	Pulmonary
H0576	Resting T-Cell; re-	T-Cells	Blood	Cell Line		Lambda
	excision					ZAP II
H0579	Pericardium	Pericardium	Heart			pSport1
H0580	Dendritic cells, pooled	Pooled dendritic				pCMVSport
		cells				3.0
HO581	Human Bone Marrow,	Human Bone	Bone Marrow			pCMVSport
	treated	Marrow				3.0
H0583	B Cell lymphoma	B Cell Lymphoma	B Cell		disease	pCMVSport
						3.0
H0586	Healing groin wound, 6.5	healing groin	groin		disease	pCMVSport
	hours post incision	wound, 6.5 hours				3.0
		post incision - 2/
H0587	Healing groin wound; 7.5	Groin-2/19/97	groin		disease	pCMVSport
	hours post incision					3.0
H0589	CD34 positive cells (cord	CD34 Positive Cells	Cord Blood			ZAP Express
	blood), re-ex
H0590	Human adult small	Human Adult Small	Small Int.			Uni-ZAP XR
	intestine, re-excision	Intestine
H0591	Human T-cell	T-Cell Lymphoma	T-Cell		disease	Uni-ZAP XR
	lymphoma; re-excision
H0592	Healing groin wound -	HGS wound healing			disease	pCMVSport
	zero hr post-incision	project; abdomen				3.0
	(control)
H0593	Olfactory	Olfactory epithelium				pCMVSport
	epithelium; nasalcavity	from roof of left				3.0
		nasal cacit
H0594	Human Lung Cancer; re-	Human Lung Cancer	Lung		disease	Lambda
	excision					ZAP II
H0595	Stomach cancer	Stomach Cancer -			disease	Uni-ZAP XR
	(human); re-excision	5383A (human)
H0596	Human Colon Cancer; re-	Human Colon	Colon			Lambda
	excision	Cancer				ZAP II
H0597	Human Colon; re-excision	Human Colon				Lambda
						ZAP II
H0598	Human Stomach; re-	Human Stomach	Stomach			Uni-ZAP XR
	excision
H0599	Human Adult Heart; re-	Human Adult Heart	Heart			Uni-ZAP XR
	excision
H0600	Healing Abdomen	Abdomen			disease	pCMVSport
	wound; 70&90 min post					3.0
	incision
H0601	Healing Abdomen	Abdomen			disease	pCMVSport
	Wound; 15 days post					3.0
	incision
H0604	Human Pituitary, re-	Human Pituitary				pBluescript
	excision
H0606	Human Primary Breast	Human Primary	Breast		disease	Uni-ZAP XR
	Cancer; re-excision	Breast Cancer
H0608	H. Leukocytes, control	H. Leukocytes				pCMVSport
						1
H0609	H. Leukocytes,	H. Leukocytes				pCMVSport
	normalized cot > 500 A					1
H0614	H. Leukocytes,	H. Leukocytes				pCMVSport
	normalized cot 500 A
H0615	Human Ovarian Cancer	Ovarian Cancer	Ovary		disease	Uni-ZAP XR
	Reexcision
H0616	Human Testes, Reexcision	Human Testes	Testis			Uni-ZAP XR
H0617	Human Primary Breast	Human Primary	Breast		disease	Uni-ZAP XR
	Cancer Reexcision	Breast Cancer
H0618	Human Adult Testes,	Human Adult Testis	Testis			Uni-ZAP XR
	Large Inserts, Reexcision
H0619	Fetal Heart	Human Fetal Heart	Heart			Uni-ZAP XR
H0620	Human Fetal Kidney;	Human Fetal Kidney	Kidney			Uni-ZAP XR
	Reexcision
H0622	Human Pancreas Tumor;	Human Pancreas	Pancreas		disease	Uni-ZAP XR
	Reexcision	Tumor
H0623	Human Umbilical Vein;	Human Umbilical	Umbilical			Uni-ZAP XR
	Reexcision	Vein Endothelial	vein
		Cells
H0624	12 Week Early Stage	Twelve Week Old	Embryo			Uni-ZAP XR
	Human II; Reexcision	Early Stage Human
H0625	Ku 812F Basophils Line	Ku 812F Basophils				pSport1
H0626	Saos2 Cells; Untreated	Saos2 Cell Line;				pSport1
		Untreated
H0628	Human Pre-Differentiated	Human Pre-				Uni-ZAP XR
	Adipocytes	Differentiated
		Adipocytes
H0631	Saos2, Dexamethosome	Saos2 Cell Line;				pSport1
	Treated	Dexamethosome
		Treated
H0632	Hepatocellular Tumor; re-	Hepatocellular	Liver			Lambda
	excision	Tumor				ZAP II
H0633	Lung Carcinoma A549	TNF alpha activated			disease	pSport1
	TNF alpha activated	A549--Lung
		Carcinoma
H0634	Human Testes Tumor, re-	Human Testes	Testis		disease	Uni-ZAP XR
	excision	Tumor
H0635	Human Activated T-Cells,	Activated T-Cells	Blood	Cell Line		Uni-ZAP XR
	re-excision
H0637	Dendritic Cells From	Dentritic cells from				pSport1
	CD34 Cells	CD34 cells
H0638	CD40 activated monocyte	CD40 activated				pSport1
	dendridic cells	monocyte dendridic
		cells
H0639	Ficolled Human Stromal	Ficolled Human				Other
	Cells, 5Fu treated	Stromal Cells, 5Fu
		treated
H0641	LPS activated derived	LPS activated				pSport1
	dendritic cells	monocyte derived
		dendritic cells
H0642	Hep G2 Cells, lambda	Hep G2 Cells				Other
	library
H0643	Hep G2 Cells, PCR library	Hep G2 Cells				Other
H0644	Human Placenta (re-	Human Placenta	Placenta			Uni-ZAP XR
	excision)
H0645	Fetal Heart, re-excision	Human Fetal Heart	Heart			Uni-ZAP XR
H0646	Lung, Cancer (4005313	Metastatic				pSport1
	A3): Invasive Poorly	squamous cell lung
	Differentiated Lung	carcinoma, poorly di
	Adenocarcinoma,
H0647	Lung, Cancer (4005163	Invasive poorly			disease	pSport1
	B7): Invasive, Poorly Diff,	differentiated lung
	Adenocarcinoma,	adenocarcinoma
	Metastatic
H0648	Ovary, Cancer: (4004562	Papillary Cstic			disease	pSport1
	B6) Papillary Serous	neoplasm of low
	Cystic Neoplasm, Low	malignant potentia
	Malignant Pot
H0649	Lung, Normal: (4005313	Normal Lung				pSport1
	B1)
H0650	B-Cells	B-Cells				pCMVSport
						3.0
H0651	Ovary, Normal:	Normal Ovary				pSport1
	(9805C040R)
H0652	Lung, Normal: (4005313B1)	Normal Lung				pSport1
H0653	Stromal Cells	Stromal Cells				pSport1
H0656	B-cells (unstimulated)	B-cells				pSport1
		(unstimulated)
H0657	B-cells (stimulated)	B-cells (stimulated)				pSport1
H0658	Ovary, Cancer	9809C332-Poorly	Ovary &		disease	pSport1
	(9809C332): Poorly	differentiate	Fallopian
	differentiated		Tubes
	adenocarcinoma
H0659	Ovary, Cancer	Grade II Papillary	Ovary		disease	pSport1
	(15395A1F): Grade II	Carcinoma, Ovary
	Papillary Carcinoma
H0660	Ovary, Cancer:	Poorly differentiated			disease	pSport1
	(15799A1F) Poorly	carcinoma, ovary
	differentiated carcinoma
H0661	Breast, Cancer: (4004943A5)	Breast cancer			disease	pSport1
H0662	Breast, Normal:	Normal Breast -	Breast			pSport1
	(4005522B2)	#4005522(B2)
H0663	Breast, Cancer: (4005522A2)	Breast Cancer -	Breast		disease	pSport1
		#4005522(A2)
H0664	Breast, Cancer:	Breast Cancer	Breast		disease	pSport1
	(9806C012R)
H0665	Stromal cells 3.88	Stromal cells 3.88				pSport1
H0666	Ovary, Cancer: (4004332A2)	Ovarian Cancer,			disease	pSport1
		Sample
		#4004332A2
H0667	Stromal cells(HBM3.18)	Stromal cell(HBM				pSport1
		3.18)
H0668	stromal cell clone 2.5	stromal cell clone				pSport1
		2.5
H0670	Ovary, Cancer(4004650A3):	Ovarian Cancer -				pSport1
	Well-Differentiated	4004650A3
	Micropapillary Serous
	Carcinoma
H0672	Ovary, Cancer: (4004576A8)	Ovarian	Ovary			pSport1
		Cancer(4004576A8)
H0673	Human Prostate Cancer,	Human Prostate	Prostate			Uni-ZAP XR
	Stage B2; re-excision	Cancer, stage B2
H0674	Human Prostate Cancer,	Human Prostate	Prostate			Uni-ZAP XR
	Stage C; re-excission	Cancer, stage C
H0675	Colon, Cancer:	Colon Cancer				pCMVSport
	(9808C064R)	9808C064R				3.0
H0676	Colon, Cancer:	Colon Cancer				pCMVSport
	(9808C064R)-total RNA	9808C064R				3.0
H0677	TNFR degenerate oligo	B-Cells				PCRII
H0682	Serous Papillary	serous papillary				pCMVSport
	Adenocarcinoma	adenocarcinoma				3.0
		(9606G304SPA3B)
H0683	Ovarian Serous Papillary	Serous papillary				pCMVSport
	Adenocarcinoma	adenocarcinoma,				3.0
		stage 3C (9804G01
H0684	Serous Papillary	Ovarian Cancer-	Ovaries			pCMVSport
	Adenocarcinoma	9810G606				3.0
H0685	Adenocarcinoma of	Adenocarcinoma of				pCMVSport
	Ovary, Human Cell Line,	Ovary, Human Cell				3.0
	# OVCAR-3	Line, # OVCAR-
H0686	Adenocarcinoma of	Adenocarcinoma of				pCMVSport
	Ovary, Human Cell Line	Ovary, Human Cell				3.0
		Line, # SW-626
H0687	Human normal	Human normal	Ovary			pCMVSport
	ovary (#9610G215)	ovary (#9610G215)				3.0
H0688	Human Ovarian	Human Ovarian				pCMVSport
	Cancer (#9807G017)	cancer (#9807G017),				3.0
		mRNA from Maura
		Ru
H0689	Ovarian Cancer	Ovarian Cancer,				pCMVSport
		#9806G019				3.0
H0690	Ovarian Cancer, #	Ovarian Cancer,				pCMVSport
	9702G001	#9702G001				3.0
H0692	BLyS Receptor from	B Cell Lymphoma	B Cell			pCMVSport
	Expression Cloning					3.0
H0693	Normal Prostate	Normal Prostate				pCMVSport
	#ODQ3958EN	Tissue				3.0
		#ODQ3958EN
H0695	mononucleocytes from	mononucleocytes				pCMVSport
	patient	from patient at				3.0
		Shady Grove Hospit
N0006	Human Fetal Brain	Human Fetal Brain
S0001	Brain frontal cortex	Brain frontal cortex	Brain			Lambda
						ZAP II
S0002	Monocyte activated	Monocyte-activated	blood	Cell Line		Uni-ZAP XR
S0003	Human Osteoclastoma	Osteoclastoma	bone		disease	Uni-ZAP XR
S0005	Heart	Heart-left ventricle	Heart			pCDNA
S0007	Early Stage Human Brain	Human Fetal Brain				Uni-ZAP XR
S0010	Human Amygdala	Amygdala				Uni-ZAP XR
S0011	STROMAL -	Osteoclastoma	bone		disease	Uni-ZAP XR
	OSTEOCLASTOMA
S0013	Prostate	Prostate	prostate			Uni-ZAP XR
S0014	Kidney Cortex	Kidney cortex	Kidney			Uni-ZAP XR
S0022	Human Osteoclastoma	Osteoclastoma				Uni-ZAP XR
	Stromal Cells -	Stromal Cells
	unamplified
S0023	Human Kidney Cortex -	Human Kidney
	unamplified	Cortex
S0024	Human Kidney Medulla -	Human Kidney
	unamplified	Medulla
S0026	Stromal cell TF274	stromal cell	Bone marrow	Cell Line		Uni-ZAP XR
S0027	Smooth muscle, serum	Smooth muscle	Pulmanary	Cell Line		Uni-ZAP XR
	treated		artery
S0028	Smooth muscle, control	Smooth muscle	Pulmanary	Cell Line		Uni-ZAP XR
			artery
S0029	brain stem	Brain stem	brain			Uni-ZAP XR
S0030	Brain pons	Brain Pons	Brain			Uni-ZAP XR
S0031	Spinal cord	Spinal cord	spinal cord			Uni-ZAP XR
S0032	Smooth muscle-ILb	Smooth muscle	Pulmanary	Cell Line		Uni-ZAP XR
	induced		artery
S0036	Human Substantia Nigra	Human Substantia				Uni-ZAP XR
		Nigra
S0037	Smooth muscle, IL1b	Smooth muscle	Pulmanary	Cell Line		Uni-ZAP XR
	induced		artery
S0038	Human Whole Brain #2 -	Human Whole Brain				ZAP Express
	Oligo dT > 1.5 Kb	#2
S0040	Adipocytes	Human Adipocytes				Uni-ZAP XR
		from Osteoclastoma
S0042	Testes	Human Testes				ZAP Express
S0044	Prostate BPH	prostate BPH	Prostate		disease	Uni-ZAP XR
S0045	Endothelial cells-control	Endothelial cell	endothelial	Cell Line		Uni-ZAP XR
			cell-lung
S0046	Endothelial-induced	Endothelial cell	endothelial	Cell Line		Uni-ZAP XR
			cell-lung
S0049	Human Brain, Striatum	Human Brain,				Uni-ZAP XR
		Striatum
S0050	Human Frontal Cortex,	Human Frontal			disease	Uni-ZAP XR
	Schizophrenia	Cortex,
		Schizophrenia
S0051	Human	Human			disease	Uni-ZAP XR
	Hypothalmus,	Hypothalamus,
	Schizophrenia	Schizophrenia
S0052	neutrophils control	human neutrophils	blood	Cell Line		Uni-ZAP XR
S0053	Neutrophils IL-1 and LPS	human neutrophil	blood	Cell Line		Uni-ZAP XR
	induced	induced
S0106	STRIATUM		BRAIN		disease	Uni-ZAP XR
	DEPRESSION
S0112	Hypothalamus		Brain			Uni-ZAP XR
S0114	Anergic T-cell	Anergic T-cell		Cell Line		Uni-ZAP XR
S0116	Bone marrow	Bone marrow	Bone marrow			Uni-ZAP XR
S0122	Osteoclastoma-normalized	Osteoclastoma	bone		disease	pBluescript
	A
S0126	Osteoblasts	Osteoblasts	Knee	Cell Line		Uni-ZAP XR
S0132	Epithelial-TNFa and INF	Airway Epithelial				Uni-ZAP XR
	induced
S0134	Apoptotic T-cell	apoptotic cells		Cell Line		Uni-ZAP XR
S0136	PERM TF274	stromal cell	Bone marrow	Cell Line		Lambda
						ZAP II
S0142	Macrophage-oxLDL	macrophage-	blood	Cell Line		Uni-ZAP XR
		oxidized LDL
		treated
S0144	Macrophage (GM-CSF	Macrophage (GM-				Uni-ZAP XR
	treated)	CSF treated)
S0146	prostate-edited	prostate BPH	Prostate			Uni-ZAP XR
S0148	Normal Prostate	Prostate	prostate			Uni-ZAP XR
S0150	LNCAP prostate cell line	LNCAP Cell Line	Prostate	Cell Line		Uni-ZAP XR
S0152	PC3 Prostate cell line	PC3 prostate cell				Uri-ZAP XR
		line
S0168	Prostate/LNCAP,	PC3 prostate cell				pBluescript
	subtraction I	line
S0174	Prostate-BPH subtracted II	Human Prostate				pBluescript
		BPH
S0182	Human B Cell 8866	Human B- Cell 8866				Uni-ZAP XR
S0192	Synovial Fibroblasts	Synovial Fibroblasts				pSport1
	(control)
S0194	Synovial hypoxia	Synovial Fibroblasts				pSport1
S0196	Synovial IL-1/TNF	Synovial Fibroblasts				pSport1
	stimulated
S0198	7TM-pbfd	PBLS, 7TM				PCRII
		receptor enriched
S0206	Smooth Muscle- HASTE	Smooth muscle	Pulmanary	Cell Line		pBluescript
	normalized		artery
S0208	Messangial cell, frac 1	Messangial cell				pSort1
S0210	Messangial cell, frac 2	Messangial cell				pSport1
S0212	Bone Marrow Stromal	Bone Marrow				pSport1
	Cell, untreated	Stromal
		Cell, untreated
S0214	Human Osteoclastoma, re-	Osteoclastoma	bone		disease	Uni-ZAP XR
	excision
S0216	Neutrophils IL-1 and LPS	human neutrophil	blood	Cell Line		Uni-ZAP XR
	induced	induced
S0218	Apoptotic T-cell, re-	apoptotic cells		Cell Line		Uni-ZAP XR
	excision
S0220	H. hypothalamus, frac	Hypothalamus	Brain			ZAP Express
	A; re-excision
S0222	H. Frontal	H. Brain, Frontal	Brain		disease	Uni-ZAP XR
	cortex, epileptic; re-	Cortex, Epileptic
	excision
S0228	PSMIX	PBLS, 7TM				PCRII
		receptor enriched
S0242	Synovial Fibroblasts	Synovial Fibroblasts				pSport1
	(II1/TNF), subt
S0250	Human Osteoblasts II	Human Osteoblasts	Femur		disease	pCMVSport
						2.0
S0252	7TM-PIMIX	PBLS, 7TM				PCRII
		receptor enriched
S0260	Spinal Cord, re-excision	Spinal cord	spinal cord			Uni-ZAP XR
S0264	PPMIX	PPMIX (Human	Pituitary			PCRII
		Pituitary)
S0268	PRMIX	PRMIX (Human	prostate			PCRII
		Prostate)
S0270	PTMIX	PTMIX (Human	Thymus			PCRII
		Thymus)
S0274	PCMIX	PCMIX (Human	Brain			PCRII
		Cerebellum)
S0276	Synovial hypoxia-RSF	Synovial fobroblasts	Synovial			pSport1
	subtracted	(rheumatoid)	tissue
S0278	H Macrophage (GM-CSF	Macrophage (GM-				Uni-ZAP XR
	treated), re-excision	CSF treated)
S0280	Human Adipose Tissue,	Human Adipose				Uni-ZAP XR
	re-excision	Tissue
S0282	Brain Frontal Cortex, re-	Brain frontal cortex	Brain			Lambda
	excision					ZAP II
S0294	Larynx tumor	Larynx tumor	Larynx, vocal		disease	pSport1
			cord
S0298	Bone marrow	Bone marrow	Bone marrow			pSport1
	stroma, treated	stroma, treatedSB
S0300	Frontal lobe, dementia; re-	Frontal Lobe	Brain			Uni-ZAP XR
	excision	dementia/Alzheimer′′s
S0306	Larynx normal #10 261-	Larynx normal				pSport1
	273
S0308	Spleen/normal	Spleen normal				pSport1
S0310	Normal trachea	Normal trachea				pSport1
S0312	Human	Human			disease	pSport1
	osteoarthritic; fraction II	osteoarthritic
		cartilage
S0314	Human	Human			disease	pSport1
	osteoarthritis; fraction I	osteoarthritic
		cartilage
S0316	Human Normal	Human Normal				pSport1
	Cartilage, Fraction I	Cartilage
S0318	Human Normal Cartilage	Human Normal				pSport1
	Fraction II	Cartilage
S0328	Palate carcinoma	Palate carcinoma	Uvula		disease	pSport1
S0330	Palate normal	Palate normal	Uvula			pSport1
S0332	Pharynx carcinoma	Pharynx carcinoma	Hypopharynx			pSport1
S0334	Human Normal Cartilage	Human Normal				pSport1
	Fraction III	Cartilage
S0338	Human Osteoarthritic	Human			disease	pSport1
	Cartilage Fraction III	osteoarthritic
		cartilage
S0340	Human Osteoarthritic	Human			disease	pSport1
	Cartilage Fraction IV	osteoarthritic
		cartilage
S0342	Adipocytes; re-excision	Human Adipocytes				Uni-ZAP XR
		from Osteoclastoma
S0344	Macrophage-oxLDL; re-	macrophage-	blood	Cell Line		Uni-ZAP XR
	excision	oxidized LDL
		treated
S0346	Human Amygdala; re-	Amygdala				Uni-ZAP XR
	excision
S0350	Pharynx Carcinoma	Pharynx carcinoma	Hypopharynx		disease	pSport1
S0352	Larynx Carcinoma	Larynx carcinoma			disease	pSport1
S0354	Colon Normal II	Colon Normal	Colon			pSport1
S0356	Colon Carcinoma	Colon Carcinoma	Colon		disease	pSport1
S0358	Colon Normal III	Colon Normal	Colon			pSport1
S0360	Colon Tumor II	Colon Tumor	Colon		disease	pSport1
S0362	Human Gastrocnemius	Gastrocnemius				pSport1
		muscle
S0364	Human Quadriceps	Quadriceps muscle				pSport1
S0366	Human Soleus	Soleus Muscle				pSport1
S0370	Larynx carcinoma II	Larynx carcinoma			disease	pSport1
S0374	Normal colon	Normal colon				pSport1
S0376	Colon Tumor	Colon Tumor			disease	pSport1
S0378	Pancreas normal PCA4	Pancreas Normal				pSport1
	No	PCA4 No
S0380	Pancreas Tumor PCA4 Tu	Pancreas Tumor			disease	pSport1
		PCA4 Tu
S0386	Human Whole Brain, re-	Whole brain	Brain			ZAP Express
	excision
S0388	Human	Human			disease	Uni-ZAP XR
	Hypothalamus,	Hypothalamus,
	schizophrenia,	Schizophrenia
	re-excision
S0390	Smooth muscle, control;	Smooth muscle	Pulmanary	Cell Line		Uni-ZAP XR
	re-excision		artery
S0392	Salivary Gland	Salivary gland;				pSport1
		normal
S0400	Brain; normal	Brain; normal				pSport1
S0404	Rectum normal	Rectum, normal				pSport1
S0406	Rectum tumour	Rectum tumour				pSport1
S0408	Colon, normal	Colon, normal				pSport1
S0410	Colon, tumour	Colon, tumour				pSport1
S0412	Temporal cortex-	Temporal cortex,			disease	Other
	Alzheizmer; subtracted	alzheimer
S0414	Hippocampus, Alzheimer	Hippocampus,				Other
	Subtracted	Alzheimer
		Subtracted
S0418	CHME Cell Line; treated 5	CHME Cell Line;				pCMVSport
	hrs	treated				3.0
S0420	CHME Cell	CHME Cell line,				pSport1
	Line, untreated	untreatetd
S0422	Mo7e Cell Line GM-CSF	Mo7e Cell Line				pCMVSport
	treated (1 nglml)	GM-CSF treated				3.0
		(1 ng/ml)
S0424	TF-1 Cell Line GM-CSF	TF-1 Cell Line				pSport1
	Treated	GM-CSF Treated
S0426	Monocyte activated; re-	Monocyte-activated	blood	Cell Line		Uni-ZAP XR
	excision
S0428	Neutrophils control; re-	human neutrophils	blood	Cell Line		Uni-ZAP XR
	excision
S0430	Aryepiglottis Normal	Aryepiglottis				pSport1
		Normal
S0432	Sinus piniformis Tumour	Sinus piniformis				pSport1
		Tumour
S0434	Stomach Normal	Stomach Normal			disease	pSport1
S0436	Stomach Tumour	Stomach Tumour			disease	pSport1
S0438	Liver Normal Met5No	Liver Normal				pSport1
		Met5No
S0440	Liver Tumour Met 5 Tu	Liver Tumour				pSport1
S0442	Colon Normal	Colon Normal				pSport1
S0444	Colon Tumor	Colon Tumour			disease	pSport1
S0446	Tongue Tumour	Tongue Tumour				pSport1
S0448	Larynx Normal	Larynx Normal				pSport1
S0450	Larynx Tumour	Larynx Tumour				pSport1
S0452	Thymus	Thymus				pSport1
S0456	Tongue Normal	Tongue Normal				pSport1
S0458	Thyroid Normal (SDCA2	Thyroid normal				pSport1
	No)
S0460	Thyroid Tumour	Thyroid Tumour				pSport1
S0462	Thyroid Thyroiditis	Thyroid Thyroiditis				pSport1
S0464	Larynx Normal	Larynx Normal				pSport1
S0468	Ea.hy.926 cell line	Ea.hy.926 cell line				pSport1
S0472	Lung Mesothelium	PYBT				pSport1
S0474	Human blood platelets	Platelets	Blood			Other
			platelets
S0665	Human Amygdala; re-	Amygdala				Uni-ZAP XR
	excission
S3012	Smooth Muscle Serum	Smooth muscle	Pulmanary	Cell Line		pBluescript
	Treated, Norm		artery
S3014	Smooth muscle, serum	Smooth muscle	Pulmanary	Cell Line		pBluescript
	induced, re-exc		artery
S6014	H. hypothalamus, frac A	Hypothalamus	Brain			ZAP Express
S6016	H Frontal Cortex,	H. Brain, Frontal	Brain		disease	Uni-ZAP XR
	Epileptic	Cortex, Epileptic
S6022	H. Adipose Tissue	Human Adipose				Uni-ZAP XR
		Tissue
S6024	Alzheimers, spongy	Alzheimer″s/Spongy	Brain		disease	Uni-ZAP XR
	change	change
S6026	Frontal Lobe, Dementia	Frontal Lobe	Brain			Uni-ZAP XR
		dementia/Alzheimer′′s
S6028	Human Manic Depression	Human Manic	Brain		disease	Uni-ZAP XR
	Tissue	depression tissue
T0002	Activated T-cells	Activated T-Cell,	Blood	Cell Line		pBluescript
		PBL fraction				SK−
T0003	Human Fetal Lung	Human Fetal Lung				pBluescript
						SK−
T0004	Human White Fat	Human White Fat				pBluescript
						SK−
T0006	Human Pineal Gland	Human Pinneal				pBluescript
		Gland				SK−
T0008	Colorectal Tumor	Colorectal Tumor			disease	pBluescript
						SK−
T0010	Human Infant Brain	Human Infant Brain				Other
T0023	Human Pancreatic	Human Pancreatic			disease	pBluescript
	Carcinoma	Carcinoma				SK−
T0039	HSA 172 Cells	Human HSA172 cell				pBluescript
		line				SK−
T0040	HSC172 cells	SA172 Cells				pBluescript
						SK−
T004l	Jurkat T-cell G1 phase	Jurkat T-cell				pBluescript
						SK−
T0042	Jurkat T-Cell, S phase	Jurkat T-Cell Line				pBluescript
						SK−
T0048	Human Aortic	Human Aortic				pBluescript
	Endothelium	Endothilium				SK−
T0049	Aorta endothelial cells +	Aorta endothelial				pBluescript
	TNF-a	cells				SK−
T0060	Human White Adipose	Human White Fat				pBluescript
						SK−
T0067	Human Thyroid	Human Thyroid				pBluescript
						SK−
T0068	Normal Ovary,	Normal Ovary,				pBluescript
	Premenopausal	Premenopausal				SK−
T0069	Human Uterus, normal	Human Uterus,				pBluescript
		normal				SK−
T0071	Human Bone Marrow	Human Bone				pBluescript
		Marrow				SK−
T0082	Human Adult Retina	Human Adult Retina				pBluescript
						SK−
T0109	Human (HCC) cell line					pBluescript
	liver (mouse) metastasis,					SK−
	remake
T0110	Human colon carcinoma					pBluescript
	(HCC) cell line, remake					SK−
T0114	Human (Caco-2) cell line,					pBluescript
	adenocarcinoma, colon,					SK−
	remake
T0115	Human Colon Carcinoma					pBluescript
	(HCC) cell line					SK−
L0002	Atrium cDNA library
	Human heart
L0004	ClonTech HL 1065a
L0005	Clontech human aorta
	polyA+ mRNA (#6572)
L0015	Human
L0021	Human adult (K. Okubo)
L0022	Human adult lung 3″
	directed MboI CDNA
L0040	Human colon mucosa
L0053	Human pancreatic tumor
L0055	Human promyelocyte
L0096	Subtracted human retina
L0097	Subtracted human retinal
	pigment epithelium (RPE)
L0l03	DKFZphamy1	amygdala
L0105	Human aorta polyA+	aorta
	(TFujiwara)
L0109	Human brain cDNA	brain
L0118	Human fetal brain S.	brain
	Meier-Ewert
L0142	Human placenta eDNA	placenta
	(TFujiwara)
L0143	Human placenta polyA+	placenta
	(TFujiwara)
L0151	Human testis (C. De	testis
	Smet)
L0157	Human fetal brain	brain
	(TFujiwara)
L0163	Human heart cDNA		heart
	(YNakamura)
L0351	Infant brain, Bento Soares					BA, M13-
						derived
L0352	Normalized infant brain,					BA, M13-
	Bento Soares					derived
L0356	S, Human foetal Adrenals					Bluescript
	tissue
L0361	Stratagene ovary		ovary			Bluescript
	(#937217)					SK
L0362	Stratagene ovarian cancer					Bluescript
	(#937219)					SK−
L0363	NCI_CGAP_GC2	germ cell tumor				Bluescript
						SK−
L0364	NCI_CGAP_GC5	germ cell tumor				Bluescript
						SK−
L0365	NCI_CGAP_Phe1	pheochromocytoma				Bluescript
						SK−
L0366	Stratagene schizo brain	schizophrenic brain				Bluescript
	S11	S-11 frontal lobe				SK−
L0367	NCI_CGAP_Sch1	Schwannoma tumor				Bluescript
						SK−
L0368	NCI_CGAP_SS1	synovial sarcoma				Bluescript
						SK−
L0369	NCI_CGAP_AAI	adrenal adenoma	adrenal gland			Bluescript
						SK−
L0370	Johnston frontal cortex	pooled frontal lobe	brain			Bluescript
						SK−
L0371	NCI_CGAP_Br3	breast tumor	breast			Bluescript
						SK−
L0372	NCI_CGAP_Col2	colon tumor	colon			Bluescript
						SK−
L0373	NCI_CGAP_Co11	tumor	colon			Bluescript
						SK−
L0374	NCI_CGAP_Co2	tumor	colon			Bluescript
						SK−
L0375	NCI_CGAP_Kid6	kidney tumor	kidney			Bluescript
						SK−
L0376	NCI_CGAP_Lar1	larynx	larynx			Bluescript
						SK−
L0378	NCI_CGAP_Lu1	lung tumor	lung			Bluescript
						SK−
L0381	NCI_CGAP_HN4	squamous cell	pharynx			Bluescnipt
		carcinoma				SK−
L0383	NCI_CGAP_Pr24	invasive tumor (cell	prostate			Bluescript
		line)				SK−
L0384	NCI_CGAP_Pr23	prostate tumor	prostate			Bluescript
						SK−
L0386	NCI_CGAP_HN3	squamous cell	tongue			Bluescnipt
		carcinoma from base				SK−
		of tongue
L0387	NCI_CGAP_GCB0	germinal center B-	tonsil			Bluescnipt
		cells				SK−
L0388	NCI_CGAP_HN6	normal gingiva (cell				Bluescript
		line from				SK−
		immortalized kerati
L0389	NCI_CGAP_HN5	normal gingiva (cell				Bluescnipt
		line from primary				SK−
		keratinocyt
L0394	H, Human adult Brain					gt11
	Cortex tissue
L0415	b4HB3MA Cot8-HAP-Ft					Lafmid BA
L0418	b4HB3MA-Cot109 + l0−					Lafmid BA
	Bio
L0435	Infant brain, LLNL array					lafmid BA
	of Dr. M. Soares 1NIB
L0438	normalized infant brain	total brain	brain			lafmid BA
	cDNA
L0439	Soares infant brain 1NIB		whole brain			Lafmid BA
L0455	Human retina cDNA	retina	eye			lambda gt10
	randomly primed
	sublibrary
L0456	Human retina cDNA	retina	eye			lambda gt10
	Tsp5091-cleaved
	sublibrary
L0462	WATM1					lambda gt11
L0465	TEST1, Human adult					lambda
	Testis tissue					nm1149
L0471	Human fetal heart,					Lambda
	Lambda ZAP Express					ZAP Express
L0475	KG1-a Lambda Zap			KG1-a		Lambda Zap
	Express cDNA library					Express
						(Stratagene)
L0483	Human pancreatic islet					Lambda
						ZAPII
L0485	STRATAGENE Human	skeletal muscle	leg muscle			Lambda
	skeletal muscle cDNA					ZAPII
	library, cat. #936215.
L0502	NCI_CGAP_Brl5	adenocarcinoma	breast			pAMP1
L0514	NCI_CGAP_Ov31	papillary serous	ovary			pAMP1
		carcinoma
L0517	NCI_CGAP_Pr1					pAMP10
L0518	NCI_CGAP_Pr2					pAMP10
L0519	NCI_CGAP_Pr3					pAMP10
L0520	NCI_CGAP_Alv1	alveolar				pAMP10
		rhabdomyosarcoma
L0521	NCI_CGAP_Ew1	Ewing″s sarcoma				pAMP10
L0523	NCI_CGAP_Lip2	liposarcoma				pAMP10
L0526	NCI_CGAP_Pr12	metastatic prostate				pAMP10
		bone lesion
L0527	NCI_CGAP_Ov2	ovary				pAMP10
L0528	NCI_CGAP_Pr5	prostate				pAMP10
L0529	NCI_CGAP_Pr6	prostate				pAMP10
L0530	NCI_CGAP_Pr8	prostate				pAMP10
L0533	NCI_CGAP_HSC1	stem cells	bone marrow			pAMP10
L0534	Chromosome 7 Fetal	brain	brain			pAMP10
	Brain cDNA Library
L0540	NCI_CGAP_Pr10	invasive prostate	prostate			pAMP10
		tumor
L0542	NCI_CGAP_Pr11	normal prostatic	prostate			pAMP10
		epithelial cells
L0545	NCI_CGAP_Pr4.1	prostatic	prostate			pAMP10
		intraepithelial
		neoplasia - high
		grade
L0546	NCI_CGAP_Pr18	stroma	prostate			pAMP10
L0547	NCI_CGAP_Pr16	tumor	prostate			pAMP10
L0549	NCI_CGAP_HN10	carcinoma in situ				pAMP10
		from retromolar
		trigone
L0551	NCI_CGAP_HN7	normal squamous				pAMP10
		epithelium, floor of
		mouth
L0558	NCI_CGAP_Ov40	endometrioid	ovary			pAMP10
		ovarian metastasis
L0562	Chromosome 7 HeLa			HeLa cell		pAMP10
	cDNA Library			line;
				ATCC
L0563	Human Bone Marrow	bone marrow				pBluescript
	Stromal Fibroblast
L0564	Jia bone marrow stroma	bone marrow stroma				pBluescript
L0565	Normal Human	Bone	Hip			pBluescript
	Trabecular Bone Cells
L0581	Stratagene liver (#937224)		liver			pBluescript
						SK
L0584	Stratagene cDNA library					pBluescript
	Human heart, cat#936208					SK(+)
L0588	Stratagene endothelial cell					pBluescript
	937223					SK−
L0589	Stratagene fetal retina					pBluescript
	937202					SK−
L0590	Stratagene fibroblast					pBluescript
	(#937212)					SK−
L0591	Stratagene HeLa cell s3					pBluescript
	937216					SK−
L0592	Stratagene h, NT neuron					pBluescript
	(#937233)					SK−
L0593	Stragene					pBluescript
	neuroepithelium					SK−
	(#937231)
L0594	Stratagene					pBluescript
	neuroepithelium					SK−
	NT2RAMI 937234
L0595	Stratagene NT2 neuronal	neuroepithelial cells	brain			pBluescript
	precursor 937230					SK−
L0596	Stratagene colon		colon			pBluescript
	(#937204)					SK−
L0597	Stratagene corneal stroma		cornea			pBluescript
	(#937222)					SK−
L0598	Morton Fetal Cochlea	cochlea	ear			pBluescript
						SK−
L0599	Stratagene lung (#937210)		lung			pBluescript
						SK−
L0600	Weizmann Olfactory	olfactory epithelium	nose			pBluescript
	Epithelium					SK−
L0601	Stratagene pancreas		pancreas			pBluescript
	(#937208)					SK−
L0602	Pancreatic Islet	pancreatic islet	pancreas			pBluescript
						SK−
L0603	Stratagene placenta		placenta			pBluescript
	(#937225)					SK−
L0604	Stratagene muscle 937209	muscle	skeletal			pBluescript
			muscle			SK−
L0605	Stratagene fetal spleen	fetal spleen	spleen			pBluescript
	(#937205)					SK−
L0606	NCI_CGAP_Lym5	follicular lymphoma	lymph node			pBluescript
						SK−
L0608	Stratagene lung carcinoma	lung carcinoma	lung	NCI-H69		pBluescript
	937218					SK−
L0615	22 week old human fetal					pBluescriptII
	liver cDNA library					SK(-)
L0617	Chromosome 22 exon					pBluescriptII
						KS+
L0618	Chromosome 9 exon					pBluescriptII
						KS+
L0619	Chromosome 9 exon II					pBluescriptII
						KS+
L0622	HM1					pcDNAII
						(Invitrogen)
L0623	HM3	pectoral muscle				pcDNAII
		(after mastectomy)				(Invitrogen)
L0629	NCI_CGAP_Me13	metastatic	bowel (skin			pCMV-
		melanoma to bowel	primary)			SPORT4
L0630	NCI_CGAP_CNS1	substantia nigra	brain			pCMV-
						SPORT4
L0631	NCI_CGAP_Br7		breast			pCMV-
						SPORT4
L0635	NCI_CGAP_PNS1	dorsal root ganglion	peripheral			pCMV-
			nervous			SPORT4
			system
L0636	NCI_CGAP_Pit1	four pooled pituitary	brain			pCMV-
		adenomas				SPORT6
L0637	NCI_CGAP_Brn53	three pooled	brain			pCMV-
		meningiomas				SPORT6
L0638	NCI_CGAP_Brn35	tumor, 5 pooled (see	brain			pCMV-
		description)				SPORT6
L0639	NCI_CGAP_Brn52	tumor, 5 pooled (see	brain			pCMV-
		description)				SPORT6
L0640	NCI_CGAP_Brl8	four pooled high-	breast			pCMV-
		grade tumors,				SPORT6
		including two prima
L0641	NCI_CGAP_Co17	juvenile granulosa	colon			pCMV-
		tumor				SPORT6
L0642	NCI_CGAP_Co18	moderately	colon			pCMV-
		differentiated				SPORT6
		adenocarcinoma
L0643	NCI_CGAP_Co19	moderately	colon			pCMV-
		differentiated				SPORT6
		adenocarcinoma
L0644	NCI_CGAP_Co20	moderately	colon			pCMV-
		differentiated				SPORT6
		adenocarcinoma
L0645	NCI_CGAP_Co21	moderately	colon			pCMV-
		differentiated				SPORT6
		adenocarcinoma
L0646	NCI_CGAP_Co14	moderately-	colon			pCMV-
		differentiated				SPORT6
		adenocarcinoma
L0647	NCI_CGAP_Sar4	five pooled	connective			pCMV-
		sarcomas, including	tissue			SPORT6
		myxoid liposarcoma
L0648	NCI_CGAP_Eso2	squamous cell	esophagus			pCMV-
		carcinoma				SPORT6
L0649	NCI_CGAP_GU1	2 pooled high-grade	genitourinary			pCMV-
		transitional cell	tract			SPORT6
		tumors
L0650	NCI_CGAP_Kid13	2 pooled Wilms″	kidney			pCMV-
		tumors, one primary				SPORT6
		and one metast
L0651	NCI_CGAP_Kid8	renal cell tumor	kidney			pCMV-
						SPORT6
L0653	NCI_CGAP_Lu28	two pooled	lung			pCMV-
		squamous cell				SPORT6
		carcinomas
L0654	NCI_CGAP_Lu31		lung, cell line			pCMV-
						SPORT6
L0655	NCI_CGAP_Lym12	lymphoma,	lymph node			pCMV-
		follicular mixed				SPORT6
		small and large cell
L0656	NCI_CGAP_Ov38	normal epithelium	ovary			pCMV-
						SPORT6
L0657	NCI_CGAP_Ov23	tumor, 5 pooled (see	ovary			pCMV-
		description)				SPORT6
L0658	NCI_CGAP_Ov35	tumor, 5 pooled (see	ovary			pCMV-
		description)				SPORT6
L0659	NCI_CGAP_Pan1	adenocarcinoma	pancreas			pCMV-
						SPORT6
L0661	NCI_CGAP_Me115	malignant	skin			pCMV-
		melanoma,				SPORT6
		metastatic to lymph
		node
L0662	NCI_CGAP_Gas4	poorly differentiated	stomach			pCMV-
		adenocarcinoma				SPORT6
		with signet r
L0663	NCI_CGAP_Ut2	moderately-	uterus			pCMV-
		differentiated				SPORT6
		endometrial
		adenocarcino
L0664	NCI_CGAP_Ut3	poorly-differentiated	uterus			pCMV-
		endometrial				SPORT6
		adenocarcinoma,
L0665	NCI_CGAP_Ut4	serous papillary	uterus			pCMV-
		carcinoma, high				SPORT6
		grade, 2 pooled t
L0666	NCI_CGAP_Ut1	well-differentiated	uterus			pCMV-
		endometrial				SPORT6
		adenocarcinoma, 7
L0667	NCI_CGAP_CML1	myeloid cells, 18	whole blood			pCMV-
		pooled CML cases,				SPORT6
		BCR/ABL rearra
L0697	Testis 1					PGEM
						5zf(+)
L0717	Gessler Wilms tumor					pSPORT1
L0731	Soares_pregnant_uterus—		uterus			pT7T3-Pac
	NbHPU
L0738	Human colorectal cancer					pT7T3D
L0740	Soares melanocyte	melanocyte				pT7T3D
	2NbHM					(Pharmacia)
						with a
						modified
						polylinker
L0741	Soares adult brain		brain			pT7T3D
	N2b4HB55Y					(Pharmacia)
						with a
						modified
						polylinker
L0742	Soares adult brain	brain				pT7T3D
	N2b5HB55Y					(Pharmacia)
						with a
						modified
						polylinker
L0743	Soares breast 2NbHBst		breast			pT7T3D
						(Pharmacia)
						with a
						modified
						polylinker
L0744	Soares breast 3NbHBst		breast			pT7T3D
						(Pharmacia)
						with a
						modified
						polylinker
L0745	Soares retina N2b4HR	retina	eye			pT7T3D
						(Pharmacia)
						with a
						modified
						polylinker
L0746	Soares retina N2b5HR	retina	eye			pT7T3D
						(Pharmacia)
						with a
						modified
						polylinker
L0747	Soares_fetal_heart—		heart			pT7T3D
	NbHH19W					(Pharmacia)
						with a
						modified
						polylinker
L0748	Soares fetal liver spleen		Liver and			pT7T3D
	1NFLS		Spleen			(Pharmacia)
						with a
						modified
						polylinker
L0749	Soares_fetal_liver_spleen—		Liver and			pT7T3D
	1NFLS_S1		Spleen			(Pharmacia)
						with a
						modified
						polylinker
L0750	Soares_fetal_lung—		lung			pT7T3D
	NbHL19W					(Pharmacia)
						with a
						modified
						polylinker
L0751	Soares ovary tumor	ovarian tumor	ovary			pT7T3D
	NbHOT					(Pharmacia)
						with a
						modified
						polylinker
L0752	Soares_parathyroid_tumor—	parathyroid tumor	parathyroid			pT7T3D
	NbHPA		gland			(Pharmacia)
						with a
						modified
						polylinker
L0753	Soares_pineal_gland—		pineal gland			pT7T3D
	N3HPG					(Pharmacia)
						with a
						modified
						polylinker
L0754	Soares placenta Nb2HP		placenta			pT7T3D
						(Pharmacia)
						with a
						modified
						polylinker
L0755	Soares_placenta_8to9		placenta			pT7T3D
	weeks_2NbHP8to9W					(Pharmacia)
						with a
						modified
						polylinker
L0756	Soares_multiple_sclerosis—	multiple sclerosis				pT7T3D
	2NbHMSP	lesions				(Pharmacia)
						with a
						modified
						polylinker
						V_TYPE
L0757	Soares_senescent—	senescent fibroblast				pT7T3D
	fibroblasts_NbHSF					(Pharmacia)
						with a
						modified
						polylinker
						V_TYPE
L0758	Soares_testis_NHT					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0759	Soares_total_fetus—					pT7T3D-Pac
	Nb2HF8_9w					(Pharmacia)
						with a
						modified
						polylinker
L0761	NCI_CGAP_CLL1	B-cell, chronic				pT7T3D-Pac
		lymphotic leukemia				(Pharmacia)
						with a
						modified
						polylinker
L0762	NCI_CGAP_Br1.1	breast				pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0763	NCI_CGAP_Br2	breast				pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0764	NCI_CGAP_Co3	colon				pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0766	NCI_CGAP_GCB1	germinal center B				pT7T3D-Pac
		cell				(Pharmacia)
						with a
						modified
						polylinker
L0767	NCI_CGAP_GC3	pooled germ cell				pT7T3D-Pac
		tumors				(Pharmacia)
						with a
						modified
						polylinker
L0768	NCI_CGAP_GC4	pooled germ cell				pT7T3D-Pac
		tumors				(Pharmacia)
						with a
						modified
						polylinker
L0769	NCI_CGAP_Brn25	anaplastic	brain			pT7T3D-Pac
		oligodendroglioma				(Pharmacia)
						with a
						modified
						polylinker
L0770	NCI_CGAP_Brn23	glioblastoma	brain			pT7T3D-Pac
		(pooled)				(Pharmacia)
						with a
						modified
						polylinker
L0771	NCI_CGAP_Co8	adenocarcinoma	colon			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0772	NCI_CGAP_Co10	colon tumor RER+	colon			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0773	NCI_CGAP_Co9	colon tumor RER+	colon			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0774	NCI_CGAP_Kid3		kidney			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0775	NCI_CGAP_Kid5	2pooled tumors	kidney			pT7T3D-Pac
		(clear cell type)				(Pharmacia)
						with a
						modified
						polylinker
L0776	NCI_CGAP_Lu5	carcinoid	lung			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0777	Soares_NhHMPu_S1	Pooled human	mixed (see			pT7T3D-Pac
		melanocyte, fetal	below)			(Pharmacia)
		heart, and pregnant				with a
						modified
						polylinker
L0778	Barstead pancreas		pancreas			pT7T3D-Pac
	HPLRB1					(Pharmacia)
						with a
						modified
						polylinker
L0779	Soares_NFL_T_GBC_S1	pooled				pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0780	Soares_NSF_FS_9W_OT—		pooled			pT7T3D-Pac
	PA_P_S1					(Pharmacia)
						with a
						modified
						polylinker
L0782	NCI_CGAP_Pr21	normal prostate	prostate			pT7T3D-PaC
						(Pharmacia)
						with a
						modified
						polylinker
L0783	NCI_CGAP_Pr22	normal prostate	prostate			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0785	Barstead spleen HPLRB2		spleen			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0786	Soares_NbHFB		whole brain			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0787	NCI_CGAP_Sub1					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0788	NCI_CGAP_Sub2					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0789	NC_CGAP_Sub3					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0790	NCI_CGAP_Sub4					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0791	NCI_CGAP_Sub5					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0792	NCI_CGAP_Sub6					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0793	NCI_CGAP_Sub7					pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0794	NCI_CGAP_GC6	pooled germ cell				pT7T3D-Pac
		tumors				(Pharmacia)
						with a
						modified
						polylinker
L0796	NCI_CGAP_Brn50	medulloblastoma	brain			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0800	NCI_CGAP_Co16	colon tumor, RER+	colon			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0803	NCI_CGAP_Kid11		kidney			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0804	NCI_CGAP_Kid12	2 pooled tumors	kidney			pT7T3D-Pac
		(clear cell type)				(Pharmacia)
						with a
						modified
						polylinker
L0805	NCI_CGAP_Lu24	carcinoid	lung			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0806	NCI_CGAP_Lu19	squamous cell	lung			pT7T3D-Pac
		carcinoma, poorly				(Pharmacia)
		differentiated (4				with a
						modified
						polylinker
L0807	NCI_CGAP_Ov18	fibrotheoma	ovary			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L0808	Barstead prostate		prostate			pT7T3D-Pac
	BPHHPLRB4 1					(Pharmacia)
						with a
						modified
						polylinker
L0809	NCI_CGAP_Pr28		prostate			pT7T3D-Pac
						(Pharmacia)
						with a
						modified
						polylinker
L2251	Human fetal lung	Fetal lung

[0090]

TABLE 5
OMIM
Refer-
ence   Description
104770 Amyloidosis, secondary, susceptibility to
106165 Hypertension, essential, 145500
107670 Apolipoprotein A-II deficiency
108730 Brodymyopathy, 601003
109400 Basal cell nevus syndrome
110700 Vivax malaria, susceptibility to
117700 [Hypoceruloplasminemia, hereditary]
117700 Hemosiderosis, systemic, due to aceruloplasminemia
125264 Leukemia, acute nonlymphocytic
126650 Chloride diarrhea, congenital, Finnish type, 214700
126650 Colon cancer
132800 Basal cell carcinoma
132800 Epithelioma, self-healing, squamous 1, Ferguson-Smith type
134570 Factor XIIIA deficiency
135940 Ichthyosis vulgaris, 146700
145001 Hyperparathyroidism-jaw tumor syndrome
146790 Lupus nephritis, susceptibility to
147781 Atopy, susceptibility to
150210 Lactoferrin-deficient neutrophils, 245480
150240 Cutis laxa, marfanoid neonatal type
152445 Vohwinkel syndrome, 124500
152445 Erythrokeratoderma, progressive symmetric, 602036
154276 Malignant hyperthermia susceptibility 3
159001 Muscular dystrophy, limb-girdle, type lB
169600 Hailey-Hailey disease
172471 Glycogenosis, hepatic, autosomal
173360 Thrombophilia due to excessive plasminogen activator inhibitor
173360 Hemorrhagic diathesis due to PAI1 deficiency
174000 Medullary cystic kidney disease, AD
179755 Renal cell carcinoma, papillary, 1
180105 Retinitis pigmentosa-l0
180380 Night blindness, congenital stationery, rhodopsin-related
180380 Retinitis pigmentosa, autosomal recessive
180380 Retinitis pigmentosa-4, autosomal dominant
182860 Pyropoikilocytosis
182860 Spherocytosis, recessive
182860 Elliptocytosis-2
186580 Arthrocutaneouveal granulomatosis
186855 Leukemia-2, T-cell acute lymphoblastic
190000 Atransferrinemia
191315 Insensitivity to pain, congenital, with anhidrosis, 256800
203500 Alkaptonuria
222800 Hemolytic anemia due to bisphosphoglycerate mutase deficiency
222900 Sucrose intolerance
223900 Dysautonomia, familial
230800 Gaucher disease
230800 Gaucher disease with cardiovascular calcification
232050 Propionicacidemia, type II or pccB type
246900 Lipoamide dehydrogenase deficiency
253800 Walker-Warburg syndrome, 236670
253800 Fukuyama type congenital muscular dystrophy
264800 Pseudoxanthoma elasticum
266200 Anemia, hemolytic, due to PK deficiency
266600 Inflammatory bowel disease-1
276902 Usher syndrome, type 3
278700 Xeroderma pigmentosum, group A
278760 Xeroderma pigmentosum, group F
600511 Schizophrenia-3
600760 Pseudohypoaldosteronism, type I, 264350
600760 Liddle syndrome, 177200
600761 Pseudohypoaldosteronism, type I, 264350
600761 Liddle syndrome, 177200
600882 Charcot-Marie-Tooth neuropathy-2B
600897 Cataract, zonular pulverulent-1, 116200
601105 Pycnodysostosis, 265800
601199 Neonatal hyperparathyroidism, 239200
601199 Hypocalcemia, autosomal dominant, 601198
601199 Hypocalciuric hypercalcemia, type I, 145980
601412 Deafness, autosomal dominant 7
601471 Moebius syndrome-2
601556 Spinocerebellar ataxia-1, 164400
601652 Glaucoma 1A, primary open angle, juvenile-onset, 137750
601682 Glaucoma 1C, primary open angle
602066 Convulsions, infantile and paroxysmal choreoathetosis
602088 Nephronophthisis, infantile
602136 Refsum disease, infantile, 266510
602136 Zellweger syndrome-1, 214100
602136 Adrenoleukodystrophy, neonatal, 202370
602447 Coronary artery disease, susceptibility to
602491 Hyperlipidemia, familial combined, 1

[0091] Polynucleotide and Polypeptide Variants

[0092] The present invention is directed to variants of the polynucleotide sequence disclosed in SEQ ID NO:X or the complementary strand thereto, nucleotide sequences encoding the polypeptide of SEQ ID NO:Y, the nucleotide sequence of SEQ ID NO:X encoding the polypeptide sequence as defined in column 7 of Table 1A, nucleotide sequences encoding the polypeptide as defined in column 7 of Table 1A, the nucleotide sequence as defined in columns 8 and 9 of Table 2, nucleotide sequences encoding the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2, the nucleotide sequence as defined in column 6 of Table 1B, nucleotide sequences encoding the polypeptide encoded by the nucleotide sequence as defined in column 6 of Table 1B, the cDNA sequence contained in Clone ID NO:Z, and/or nucleotide sequences encoding the polypeptide encoded by the cDNA sequence contained in Clone ID NO:Z.

[0093] The present invention also encompasses variants of the polypeptide sequence disclosed in SEQ ID NO:Y, the polypeptide sequence as defined in column 7 of Table 1A, a polypeptide sequence encoded by the polynucleotide sequence in SEQ ID NO:X, a polypeptide sequence encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2, a polypeptide sequence encoded by the nucleotide sequence as defined in column 6 of Table 1B, a polypeptide sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X, and/or a polypeptide sequence encoded by the cDNA sequence contained in Clone ID NO:Z.

[0094] “Variant” refers to a polynucleotide or polypeptide differing from the polynucleotide or polypeptide of the present invention, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the polynucleotide or polypeptide of the present invention.

[0095] Thus, one aspect of the invention provides an isolated nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence described in SEQ ID NO:X or contained in the cDNA sequence of Clone ID NO:Z; (b) a nucleotide sequence in SEQ ID NO:X or the cDNA in Clone ID NO:Z which encodes the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO:Z; (c) a nucleotide sequence in SEQ ID NO:X or the cDNA in Clone ID NO:Z which encodes a mature polypeptide; (d) a nucleotide sequence in SEQ ID NO:X or the cDNA sequence of Clone ID NO:Z, which encodes a biologically active fragment of a polypeptide; (e) a nucleotide sequence in SEQ ID NO:X or the cDNA sequence of Clone ID NO:Z, which encodes an antigenic fragment of a polypeptide; (f) a nucleotide sequence encoding a polypeptide comprising the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO:Z; (g) a nucleotide sequence encoding a mature polypeptide of the amino acid sequence of SEQ ID NO:Y or the amino acid sequence encoded by the cDNA in Clone ID NO:Z; (h) a nucleotide sequence encoding a biologically active fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO:Z; (i) a nucleotide sequence encoding an antigenic fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO:Z; and (j) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h), or (i) above.

[0096] The present invention is also directed to nucleic acid molecules which comprise, or alternatively consist of, a nucleotide sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, any of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h), (i), or (j) above, the nucleotide coding sequence in SEQ ID NO:X or the complementary strand thereto, the nucleotide coding sequence of the cDNA contained in Clone ID NO:Z or the complementary strand thereto, a nucleotide sequence encoding the polypeptide of SEQ ID NO:Y, a nucleotide sequence encoding a polypeptide sequence encoded by the nucleotide sequence in SEQ ID NO:X, a polypeptide sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X, a nucleotide sequence encoding the polypeptide encoded by the cDNA contained in Clone ID NO:Z, the nucleotide coding sequence in SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto, a nucleotide sequence encoding the polypeptide encoded by the nucleotide sequence in SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto, the nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B or the complementary strand thereto, a nucleotide sequence encoding the polypeptide encoded by the nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B or the complementary strand thereto, the nucleotide sequence in SEQ ID NO:X encoding the polypeptide sequence as defined in column 7 of Table 1 A or the complementary strand thereto, nucleotide sequences encoding the polypeptide as defined in column 7 of Table 1A or the complementary strand thereto, and/or polynucleotide fragments of any of these nucleic acid molecules (e.g., those fragments described herein). Polynucleotides which hybridize to the complement of these nucleic acid molecules under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention, as are polypeptides encoded by these polynucleotides and nucleic acids.

[0097] In a preferred embodiment, the invention encompasses nucleic acid molecules which comprise, or alternatively, consist of a polynucleotide which hybridizes under stringent hybridization conditions, or alternatively, under lower stringency conditions, to a polynucleotide in (a), (b), (c), (d), (e), (f), (g), (h), or (i), above, as are polypeptides encoded by these polynucleotides. In another preferred embodiment, polynucleotides which hybridize to the complement of these nucleic acid molecules under stringent hybridization conditions, or alternatively, under lower stringency conditions, are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.

[0098] In another embodiment, the invention provides a purified protein comprising, or alternatively consisting of, a polypeptide having an amino acid sequence selected from the group consisting of: (a) the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO:Z; (b) the amino acid sequence of a mature form of a polypeptide having the amino acid sequence of SEQ ID NO:Y or the amino acid sequence encoded by the cDNA in Clone ID NO:Z; (c) the amino acid sequence of a biologically active fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO:Z; and (d) the amino acid sequence of an antigenic fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO:Z.

[0099] The present invention is also directed to proteins which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, any of the amino acid sequences in (a), (b), (c), or (d), above, the amino acid sequence shown in SEQ ID NO:Y, the amino acid sequence encoded by the cDNA contained in Clone ID NO:Z, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO:X as defined in columns 8 and 9 of Table 2, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B, the amino acid sequence as defined in column 7 of Table 1A, an amino acid sequence encoded by the nucleotide sequence in SEQ ID NO:X, and an amino acid sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X. Fragments of these polypeptides are also provided (e.g., those fragments described herein). Further proteins encoded by polynucleotides which hybridize to the complement of the nucleic acid molecules encoding these amino acid sequences under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention, as are the polynucleotides encoding these proteins.

[0100] By a nucleic acid having a nucleotide sequence at least, for example, 95% “identical” to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the nucleic acid is identical to the reference sequence except that the nucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the polypeptide. In other words, to obtain a nucleic acid having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. The query sequence may be an entire sequence referred to in Table 1A or 2 as the ORF (open reading frame), or any fragment specified as described herein.

[0101] As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the present invention can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. 6:237-245 (1990)). In a sequence alignment the query and subject sequences are both DNA sequences. An RNA sequence can be compared by converting U's to T's. The result of said global sequence alignment is expressed as percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identity are: Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the length of the subject nucleotide sequence, whichever is shorter.

[0102] If the subject sequence is shorter than the query sequence because of 5′ or 3′ deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for 5′ and 3′ truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5′ or 3′ ends, relative to the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are 5′ and 3′ of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only bases outside the 5′ and 3′ bases of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.

[0103] For example, a 90 base subject sequence is aligned to a 100 base query sequence to determine percent identity. The deletions occur at the 5′ end of the subject sequence and therefore, the FASTDB alignment does not show a matched/alignment of the first 10 bases at 5′ end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5′ and 3′ ends not matched/total number of bases in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 bases were perfectly matched the final percent identity would be 90%. In another example, a 90 base subject sequence is compared with a 100 base query sequence. This time the deletions are internal deletions so that there are no bases on the 5′ or 3′ of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only bases 5′ and 3′ of the subject sequence which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to be made for the purposes of the present invention.

[0104] By a polypeptide having an amino acid sequence at least, for example, 95% “identical” to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.

[0105] As a practical matter, whether any particular polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequence of a polypeptide referred to in Table 1A (e.g., the amino acid sequence identified in column 6) or Table 2 (e.g., the amino acid sequence of the polypeptide encoded by the polynucleotide sequence defined in columns 8 and 9 of Table 2) or a fragment thereof, the amino acid sequence of the polypeptide encoded by the polynucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B or a fragment thereof, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO:X or a fragment thereof, or the amino acid sequence of the polypeptide encoded by cDNA contained in Clone ID NO:Z, or a fragment thereof, can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci.6:237-245 (1990)). In a sequence alignment the query and subject sequences are either both nucleotide sequences or both amino acid sequences. The result of said global sequence alignment is expressed as percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty 5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter.

[0106] If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence.

[0107] For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence. This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.

[0108] The polynucleotide variants of the invention may contain alterations in the coding regions, non-coding regions, or both. Especially preferred are polynucleotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred. Moreover, polypeptide variants in which less than 50, less than 40, less than 30, less than 20, less than 10, or 5-50, 5-25, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host such as E. coli).

[0109] Naturally occurring variants are called “allelic variants,” and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985)). These allelic variants can vary at either the polynucleotide and/or polypeptide level and are included in the present invention. Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.

[0110] Using known methods of protein engineering and recombinant DNA technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be deleted from the N-terminus or C-terminus of the polypeptide of the present invention without substantial loss of biological function. As an example, Ron et al. (J. Biol. Chem. 268: 2984-2988 (1993)) reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-216 (1988).)

[0111] Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem. 268:22105-22111 (1993)) conducted extensive mutational analysis of human cytokine IL-1a. They used random mutagenesis to generate over 3,500 individual IL-1a mutants that averaged 2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that “[m]ost of the molecule could be altered with little effect on either [binding or biological activity].” In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.

[0112] Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.

[0113] Thus, the invention further includes polypeptide variants which show a functional activity (e.g., biological activity) of the polypeptides of the invention. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity.

[0114] The present application is directed to nucleic acid molecules at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleic acid sequences disclosed herein, (e.g., encoding a polypeptide having the amino acid sequence of an N and/or C terminal deletion), irrespective of whether they encode a polypeptide having functional activity. This is because even where a particular nucleic acid molecule does not encode a polypeptide having functional activity, one of skill in the art would still know how to use the nucleic acid molecule, for instance, as a hybridization probe or a polymerase chain reaction (PCR) primer. Uses of the nucleic acid molecules of the present invention that do not encode a polypeptide having functional activity include, inter alia, (1) isolating a gene or allelic or splice variants thereof in a cDNA library; (2) in situ hybridization (e.g., “FISH”) to metaphase chromosomal spreads to provide precise chromosomal location of the gene, as described in Verma et al., Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York (1988); (3) Northern Blot analysis for detecting mRNA expression in specific tissues (e.g., normal or diseased tissues); and (4) in situ hybridization (e.g., histochemistry) for detecting mRNA expression in specific tissues (e.g., normal or diseased tissues).

[0115] Preferred, however, are nucleic acid molecules having sequences at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleic acid sequences disclosed herein, which do, in fact, encode a polypeptide having functional activity. By a polypeptide having “functional activity” is meant, a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) protein of the invention. Such functional activities include, but are not limited to, biological activity, antigenicity [ability to bind (or compete with a polypeptide of the invention for binding) to an anti-polypeptide of the invention antibody], immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide of the invention.

[0116] The functional activity of the polypeptides, and fragments, variants and derivatives of the invention, can be assayed by various methods.

[0117] For example, in one embodiment where one is assaying for the ability to bind or compete with a full-length polypeptide of the present invention for binding to an anti-polypetide antibody, various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc. In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.

[0118] In another embodiment, where a ligand is identified, or the ability of a polypeptide fragment, variant or derivative of the invention to multimerize is being evaluated, binding can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123 (1995). In another embodiment, the ability of physiological correlates of a polypeptide of the present invention to bind to a substrate(s) of the polypeptide of the invention can be routinely assayed using techniques known in the art.

[0119] In addition, assays described herein (see Examples) and otherwise known in the art may routinely be applied to measure the ability of polypeptides of the present invention and fragments, variants and derivatives thereof to elicit polypeptide related biological activity (either in vitro or in vivo). Other methods will be known to the skilled artisan and are within the scope of the invention.

[0120] Of course, due to the degeneracy of the genetic code, one of ordinary skill in the art will immediately recognize that a large number of the nucleic acid molecules having a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to, for example, the nucleic acid sequence of the cDNA contained in Clone ID NO:Z, the nucleic acid sequence referred to in Table 1A (SEQ ID NO:X), the nucleic acid sequence disclosed in Table 2 (e.g,. the nucleic acid sequence delineated in columns 8 and 9) or fragments thereof, will encode polypeptides “having functional activity.” In fact, since degenerate variants of any of these nucleotide sequences all encode the same polypeptide, in many instances, this will be clear to the skilled artisan even without performing the above described comparison assay. It will be further recognized in the art that, for such nucleic acid molecules that are not degenerate variants, a reasonable number will also encode a polypeptide having functional activity. This is because the skilled artisan is fully aware of amino acid substitutions that are either less likely or not likely to significantly effect protein function (e.g., replacing one aliphatic amino acid with a second aliphatic amino acid), as further described below.

[0121] For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie et al., “Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.

[0122] The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.

[0123] The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be used. See Cunningham and Wells, Science 244:1081-1085 (1989). The resulting mutant molecules can then be tested for biological activity.

[0124] As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly. Besides conservative amino acid substitution, variants of the present invention include (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitutions with one or more of the amino acid residues having a substituent group, or (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), (iv) fusion of the polypeptide with additional amino acids, such as, for example, an IgG Fc fusion region peptide, serum albumin (preferably human serum albumin) or a fragment thereof, or leader or secretory sequence, or a sequence facilitating purification, or (v) fusion of the polypeptide with another compound, such as albumin (including but not limited to recombinant albumin (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)). Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.

[0125] For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. See Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967); Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier Systems 10:307-377 (1993).

[0126] A further embodiment of the invention relates to polypeptides which comprise the amino acid sequence of a polypeptide having an amino acid sequence which contains at least one amino acid substitution, but not more than 50 amino acid substitutions, even more preferably, not more than 40 amino acid substitutions, still more preferably, not more than 30 amino acid substitutions, and still even more preferably, not more than 20 amino acid substitutions from a polypeptide sequence disclosed herein. Of course it is highly preferable for a polypeptide to have an amino acid sequence which comprises the amino acid sequence of a polypeptide of SEQ ID NO:Y, an amino acid sequence encoded by SEQ ID NO:X, an amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, an amino acid sequence encoded by the complement of SEQ ID NO:X, and/or an amino acid sequence encoded by cDNA contained in Clone ID NO:Z which contains, in order of ever-increasing preference, at least one, but not more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions.

[0127] In specific embodiments, the polypeptides of the invention comprise, or alternatively, consist of, fragments or variants of a reference amino acid sequence selected from: (a) the amino acid sequence of SEQ ID NO:Y or fragments thereof (e.g., the mature form and/or other fragments described herein); (b) the amino acid sequence encoded by SEQ ID NO:X or fragments thereof; (c) the amino acid sequence encoded by the complement of SEQ ID NO:X or fragments thereof; (d) the amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or fragments thereof; and (e) the amino acid sequence encoded by cDNA contained in Clone ID NO:Z or fragments thereof; wherein the fragments or variants have 1-5,5-10, 5-25, 5-50, 10-50 or 50-150, amino acid residue additions, substitutions, and/or deletions when compared to the reference amino acid sequence. In preferred embodiments, the amino acid substitutions are conservative. Polynucleotides encoding these polypeptides are also encompassed by the invention.

[0128] Polynucleotide and Polypeptide Fragments

[0129] The present invention is also directed to polynucleotide fragments of the polynucleotides (nucleic acids) of the invention. In the present invention, a “polynucleotide fragment” refers to a polynucleotide having a nucleic acid sequence which, for example: is a portion of the cDNA contained in Clone ID NO:Z or the complementary strand thereto; is a portion of the polynucleotide sequence encoding the polypeptide encoded by the cDNA contained in Clone ID NO:Z or the complementary strand thereto; is a portion of a polynucleotide sequence encoding the amino acid sequence encoded by the region of SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto; is a portion of the polynucleotide sequence of SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto; is a portion of the polynucleotide sequence in SEQ ID NO:X or the complementary strand thereto; is a polynucleotide sequence encoding a portion of the polypeptide of SEQ ID NO:Y; is a polynucleotide sequence encoding a portion of a polypeptide encoded by SEQ ID NO:X; is a polynucleotide sequence encoding a portion of a polypeptide encoded by the complement of the polynucleotide sequence in SEQ ID NO:X; is a portion of a polynucleotide sequence encoding the amino acid sequence encoded by the region of SEQ ID NO:B as defined in column 6 of Table 1B or the complementary strand thereto; or is a portion of the polynucleotide sequence of SEQ ID NO:B as defined in column 6 of Table 1B or the complementary strand thereto.

[0130] The polynucleotide fragments of the invention are preferably at least about 15 nt, and more preferably at least about 20 nt, still more preferably at least about 30 nt, and even more preferably, at least about 40 nt, at least about 50 nt, at least about 75 nt, or at least about 150 nt in length. A fragment “at least 20 nt in length,” for example, is intended to include 20 or more contiguous bases from the cDNA sequence contained in Clone ID NO:Z, or the nucleotide sequence shown in SEQ ID NO:X or the complementary stand thereto. In this context “about” includes the particularly recited value or a value larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. These nucleotide fragments have uses that include, but are not limited to, as diagnostic probes and primers as discussed herein. Of course, larger fragments (e.g., at least 160, 170, 180, 190, 200, 250, 500, 600, 1000, or 2000 nucleotides in length) are also encompassed by the invention.

[0131] Moreover, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700, 701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250, 2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550, 2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850, 2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150, 3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450, 3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750, 3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050, 4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350, 4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650, 4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950, 4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250, 5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550, 5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850, 5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150, 6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450, 6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750, 6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050, 7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the end of SEQ ID NO:X, or the complementary strand thereto. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. Preferably, these fragments encode a polypeptide which has a functional activity (e.g., biological activity). More preferably, these polynucleotides can be used as probes or primers as discussed herein. Polynucleotides which hybridize to one or more of these polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.

[0132] Further representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700, 701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250, 2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550, 2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850, 2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150, 3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450, 3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750, 3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050, 4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350, 4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650, 4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950, 4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250, 5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550, 5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850, 5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150, 6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450, 6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750, 6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050, 7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the end of the cDNA sequence contained in Clone ID NO:Z, or the complementary strand thereto. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. Preferably, these fragments encode a polypeptide which has a functional activity (e.g., biological activity). More preferably, these polynucleotides can be used as probes or primers as discussed herein. Polynucleotides which hybridize to one or more of these polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.

[0133] Moreover, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a nucleic acid sequence comprising one, two, three, four, five, six, seven, eight, nine, ten, or more of the above described polynucleotide fragments of the invention in combination with a polynucleotide sequence delineated in Table 1B column 6. Additional, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a nucleic acid sequence comprising one, two, three, four, five, six, seven, eight, nine, ten, or more of the above described polynucleotide fragments of the invention in combination with a polynucleotide sequence that is the complementary strand of a sequence delineated in column 6 of Table 1B. In further embodiments, the above-described polynucleotide fragments of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotide fragments of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

[0134] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1B, column 2) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

[0135] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

[0136] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in the same row of column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

[0137] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:X are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0138] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X (e.g., as described herein) are directly contiguous Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0139] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0140] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 are directly contiguous. In preferred embodiments, the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B is directly contiguous with the 5′ 10 polynucleotides of the next sequential exon delineated in Table 1B, column 6. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0141] In the present invention, a “polypeptide fragment” refers to an amino acid sequence which is a portion of that contained in SEQ ID NO:Y, a portion of an amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, a portion of an amino acid sequence encoded by the polynucleotide sequence of SEQ ID NO:X, a portion of an amino acid sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X, and/or a portion of an amino acid sequence encoded by the cDNA contained in Clone ID NO:Z. Protein (polypeptide) fragments may be “free-standing,” or comprised within a larger polypeptide of which the fragment forms a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments comprising, or alternatively consisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, 101-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding region of cDNA and SEQ ID NO: Y. In a preferred embodiment, polypeptide fragments of the invention include, for example, fragments comprising, or alternatively consisting of, from about amino acid number 1-20, 21-40, 4L-60, 61-80, 81-100, 101-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding region of SEQ ID NO:Y. Moreover, polypeptide fragments of the invention may be at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, or 150 amino acids in length. In this context “about” includes the particularly recited ranges or values, or ranges or values larger or smaller by several (5, 4, 3, 2, or 1) amino acids, at either extreme or at both extremes. Polynucleotides encoding these polypeptide fragments are also encompassed by the invention.

[0142] Even if deletion of one or more amino acids from the N-terminus of a protein results in modification of loss of one or more biological functions of the protein, other functional activities (e.g., biological activities, ability to multimerize, ability to bind a ligand) may still be retained. For example, the ability of shortened muteins to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptides generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the N-terminus. Whether a particular polypeptide lacking N-terminal residues of a complete polypeptide retains such immunologic activities can readily be determined by routine methods described herein and otherwise known in the art. It is not unlikely that a mutein with a large number of deleted N-terminal amino acid residues may retain some biological or immunogenic activities. In fact, peptides composed of as few as six amino acid residues may often evoke an immune response.

[0143] Accordingly, polypeptide fragments include the secreted protein as well as the mature form. Further preferred polypeptide fragments include the secreted protein or the mature form having a continuous series of deleted residues from the amino or the carboxy terminus, or both. For example, any number of amino acids, ranging from 1-60, can be deleted from the amino terminus of either the secreted polypeptide or the mature form. Similarly, any number of amino acids, ranging from 1-30, can be deleted from the carboxy terminus of the secreted protein or mature form. Furthermore, any combination of the above amino and carboxy terminus deletions are preferred. Similarly, polynucleotides encoding these polypeptide fragments are also preferred.

[0144] The present invention further provides polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of a polypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, a polypeptide encoded by the polynucleotide sequence contained in SEQ ID NO:X or the complement thereof, a polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, a polypeptide encoded by the portion of SEQ ID NO:B as defined in column 6 of Table 1B, and/or a polypeptide encoded by the cDNA contained in Clone ID NO:Z). In particular, N-terminal deletions may be described by the general formula m−q, where q is a whole integer representing the total number of amino acid residues in a polypeptide of the invention (e.g., the polypeptide disclosed in SEQ ID NO:Y, or the polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2), and m is defined as any integer ranging from 2 to q−6. Polynucleotides encoding these polypeptides are also encompassed by the invention.

[0145] The present invention further provides polypeptides having one or more residues from the carboxy terminus of the amino acid sequence of a polypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, a polypeptide encoded by the polynucleotide sequence contained in SEQ ID NO:X, a polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/or a polypeptide encoded by the cDNA contained in Clone ID NO:Z). In particular, C-terminal deletions may be described by the general formula 1−n, where n is any whole integer ranging from 6 to q−1, and where n corresponds to the position of amino acid residue in a polypeptide of the invention. Polynucleotides encoding these polypeptides are also encompassed by the invention.

[0146] In addition, any of the above described N- or C-terminal deletions can be combined to produce a N- and C-terminal deleted polypeptide. The invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini, which may be described generally as having residues m-n of a polypeptide encoded by SEQ ID NO:X (e.g., including, but not limited to, the preferred polypeptide disclosed as SEQ ID NO:Y and the polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2), the cDNA contained in Clone ID NO:Z, and/or the complement thereof, where n and m are integers as described above. Polynucleotides encoding these polypeptides are also encompassed by the invention.

[0147] Also as mentioned above, even if deletion of one or more amino acids from the C-terminus of a protein results in modification of loss of one or more biological functions of the protein, other functional activities (e.g., biological activities, ability to multimerize, ability to bind a ligand) may still be retained. For example the ability of the shortened mutein to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptide generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the C-terminus. Whether a particular polypeptide lacking C-terminal residues of a complete polypeptide retains such immunologic activities can readily be determined by routine methods described herein and otherwise known in the art. It is not unlikely that a mutein with a large number of deleted C-terminal amino acid residues may retain some biological or immunogenic activities. In fact, peptides composed of as few as six amino acid residues may often evoke an immune response.

[0148] The present application is also directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a polypeptide sequence set forth herein. In preferred embodiments, the application is directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to polypeptides having the amino acid sequence of the specific N- and C-terminal deletions. Polynucleotides encoding these polypeptides are also encompassed by the invention.

[0149] Any polypeptide sequence encoded by, for example, the polynucleotide sequences set forth as SEQ ID NO:X or the complement thereof, (presented, for example, in Tables 1A and 2), the cDNA contained in Clone ID NO:Z, or the polynucleotide sequence as defined in column 6 of Table 1B, may be analyzed to determine certain preferred regions of the polypeptide. For example, the amino acid sequence of a polypeptide encoded by a polynucleotide sequence of SEQ ID NO:X (e.g., the polypeptide of SEQ ID NO:Y and the polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2) or the cDNA contained in Clone ID NO:Z may be analyzed using the default parameters of the DNASTAR computer algorithm (DNASTAR, Inc., 1228 S. Park St., Madison, Wis. 53715 USA; http://www.dnastar.com/).

[0150] Polypeptide regions that may be routinely obtained using the DNASTAR computer algorithm include, but are not limited to, Garnier-Robson alpha-regions, beta-regions, turn-regions, and coil-regions; Chou-Fasman alpha-regions, beta-regions, and turn-regions; Kyte-Doolittle hydrophilic regions and hydrophobic regions; Eisenberg alpha- and beta-amphipathic regions; Karplus-Schulz flexible regions; Emini surface-forming regions; and Jameson-Wolf regions of high antigenic index. Among highly preferred polynucleotides of the invention in this regard are those that encode polypeptides comprising regions that combine several structural features, such as several (e.g., 1, 2, 3 or 4) of the features set out above.

[0151] Additionally, Kyte-Doolittle hydrophilic regions and hydrophobic regions, Emini surface-forming regions, and Jameson-Wolf regions of high antigenic index (i.e., containing four or more contiguous amino acids having an antigenic index of greater than or equal to 1.5, as identified using the default parameters of the Jameson-Wolf program) can routinely be used to determine polypeptide regions that exhibit a high degree of potential for antigenicity. Regions of high antigenicity are determined from data by DNASTAR analysis by choosing values which represent regions of the polypeptide which are likely to be exposed on the surface of the polypeptide in an environment in which antigen recognition may occur in the process of initiation of an immune response.

[0152] Preferred polypeptide fragments of the invention are fragments comprising, or alternatively, consisting of, an amino acid sequence that displays a functional activity (e.g. biological activity) of the polypeptide sequence of which the amino acid sequence is a fragment. By a polypeptide displaying a “functional activity” is meant a polypeptide capable of one or more known functional activities associated with a full-length protein, such as, for example, biological activity, antigenicity, immunogenicity, and/or multimerization, as described herein.

[0153] Other preferred polypeptide fragments are biologically active fragments. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.

[0154] In preferred embodiments, polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the antigenic fragments of the polypeptide of SEQ ID NO:Y, or portions thereof. Polynucleotides encoding these polypeptides are also encompassed by the invention.

[0155] The present invention encompasses polypeptides comprising, or alternatively consisting of, an epitope of: the polypeptide sequence shown in SEQ ID NO:Y; a polypeptide sequence encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2; the polypeptide sequence encoded by the portion of SEQ ID NO:B as defined in column 6 of Table 1B or the complement thereto; the polypeptide sequence encoded by the cDNA contained in Clone ID NO:Z; or the polypeptide sequence encoded by a polynucleotide that hybridizes to the sequence of SEQ ID NO:X, the complement of the sequence of SEQ ID NO:X, the complement of a portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, or the cDNA sequence contained in Clone ID NO:Z under stringent hybridization conditions or alternatively, under lower stringency hybridization as defined supra. The present invention further encompasses polynucleotide sequences encoding an epitope of a polypeptide sequence of the invention (such as, for example, the sequence disclosed in SEQ ID NO:X, or a fragment thereof), polynucleotide sequences of the complementary strand of a polynucleotide sequence encoding an epitope of the invention, and polynucleotide sequences which hybridize to the complementary strand under stringent hybridization conditions or alternatively, under lower stringency hybridization conditions defined supra.

[0156] The term “epitopes,” as used herein, refers to portions of a polypeptide having antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human. In a preferred embodiment, the present invention encompasses a polypeptide comprising an epitope, as well as the polynucleotide encoding this polypeptide. An “immunogenic epitope,” as used herein, is defined as a portion of a protein that elicits an antibody response in an animal, as determined by any method known in the art, for example, by the methods for generating antibodies described infra. (See, for example, Geysen et al., Proc. Natl. Acad. Sci. USA 81:3998-4002 (1983)). The term “antigenic epitope,” as used herein, is defined as a portion of a protein to which an antibody can immunospecifically bind its antigen as determined by any method well known in the art, for example, by the immunoassays described herein. Immunospecific binding excludes non-specific binding but does not necessarily exclude cross-reactivity with other antigens. Antigenic epitopes need not necessarily be immunogenic.

[0157] Fragments which function as epitopes may be produced by any conventional means. (See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985) further described in U.S. Pat. No. 4,631,211.)

[0158] In the present invention, antigenic epitopes preferably contain a sequence of at least 4, at least 5, at least 6, at least 7, more preferably at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, and, most preferably, between about 15 to about 30 amino acids. Preferred polypeptides comprising immunogenic or antigenic epitopes are at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acid residues in length. Additional non-exclusive preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as portions thereof. Antigenic epitopes are useful, for example, to raise antibodies, including monoclonal antibodies, that specifically bind the epitope. Preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these antigenic epitopes. Antigenic epitopes can be used as the target molecules in immunoassays. (See, for instance, Wilson et al., Cell 37:767-778 (1984); Sutcliffe et al., Science 219:660-666 (1983)).

[0159] Non-limiting examples of epitopes of polypeptides that can be used to generate antibodies of the invention include a polypeptide comprising, or alternatively consisting of, at least one, two, three, four, five, six or more of the portion(s) of SEQ ID NO:Y specified in column 7 of Table 1A. These polypeptide fragments have been determined to bear antigenic epitopes of the proteins of the invention by the analysis of the Jameson-Wolf antigenic index which is included in the DNAStar suite of computer programs. By “comprise” it is intended that a polypeptide contains at least one, two, three, four, five, six or more of the portion(s) of SEQ ID NO:Y shown in column 7 of Table 1A, but it may contain additional flanking residues on either the amino or carboxyl termini of the recited portion. Such additional flanking sequences are preferably sequences naturally found adjacent to the portion; i.e., contiguous sequence shown in SEQ ID NO:Y. The flanking sequence may, however, be sequences from a heterolgous polypeptide, such as from another protein described herein or from a heterologous polypeptide not described herein. In particular embodiments, epitope portions of a polypeptide of the invention comprise one, two, three, or more of the portions of SEQ ID NO:Y shown in column 7 of Table 1A.

[0160] Similarly, immunogenic epitopes can be used, for example, to induce antibodies according to methods well known in the art. See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle et al., J. Gen. Virol. 66:2347-2354 (1985). Preferred immunogenic epitopes include the immunogenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these immunogenic epitopes. The polypeptides comprising one or more immunogenic epitopes may be presented for eliciting an antibody response together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse), or, if the polypeptide is of sufficient length (at least about 25 amino acids), the polypeptide may be presented without a carrier. However, immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting).

[0161] Epitope-bearing polypeptides of the present invention may be used to induce antibodies according to methods well known in the art including, but not limited to, in vivo immunization, in vitro immunization, and phage display methods. See, e.g., Sutcliffe et al., supra; Wilson et al., supra, and Bittle et al., J. Gen. Virol., 66:2347-2354 (1985). If in vivo immunization is used, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling the peptide to a macromolecular carrier, such as keyhole limpet hemacyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine residues may be coupled to a carrier using a linker such as maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carriers using a more general linking agent such as glutaraldehyde. Animals such as rabbits, rats and mice are immunized with either free or carrier-coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 μg of peptide or carrier protein and Freund's adjuvant or any other adjuvant known for stimulating an immune response. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art.

[0162] As one of skill in the art will appreciate, and as discussed above, the polypeptides of the present invention (e.g., those comprising an immunogenic or antigenic epitope) can be fused to heterologous polypeptide sequences. For example, polypeptides of the present invention (including fragments or variants thereof), may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof and portions thereof, resulting in chimeric polypeptides. By way of another non-limiting example, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) may be fused with albumin (including but not limited to recombinant human serum albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)). In a preferred embodiment, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) are fused with the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP Patent 0 322 094) which is herein incorporated by reference in its entirety. In another preferred embodiment, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) are fused with polypeptide fragments comprising, or alternatively consisting of, amino acid residues 1−z of human serum albumin, where z is an integer from 369 to 419, as described in U.S. Pat. No. 5,766,883 herein incorporated by reference in its entirety. Polypeptides and/or antibodies of the present invention (including fragments or variants thereof) may be fused to either the N- or C-terminal end of the heterologous protein (e.g., immunoglobulin Fc polypeptide or human serum albumin polypeptide). Polynucleotides encoding fusion proteins of the invention are also encompassed by the invention.

[0163] Such fusion proteins as those described above may facilitate purification and may increase half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of an antigen across the epithelial barrier to the immune system has been demonstrated for antigens (e.g., insulin) conjugated to an FcRn binding partner such as IgG or Fc fragments (see, e.g., PCT Publications WO 96/22024 and WO 99/04813). IgG fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion desulfide bonds have also been found to be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone. See, e.g., Fountoulakis et al., J. Biochem., 270:3958-3964 (1995). Nucleic acids encoding the above epitopes can also be recombined with a gene of interest as an epitope tag (e.g., the hemagglutinin (HA) tag or flag tag) to aid in detection and purification of the expressed polypeptide. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-897). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid such that the open reading frame of the gene is translationally fused to an amino-terminal tag consisting of six histidine residues. The tag serves as a matrix binding domain for the fusion protein. Extracts from cells infected with the recombinant vaccinia virus are loaded onto Ni2+ nitriloacetic acid-agarose column and histidine-tagged proteins can be selectively eluted with imidazole-containing buffers.

[0164] Fusion Proteins

[0165] Any polypeptide of the present invention can be used to generate fusion proteins. For example, the polypeptide of the present invention, when fused to a second protein, can be used as an antigenic tag. Antibodies raised against the polypeptide of the present invention can be used to indirectly detect the second protein by binding to the polypeptide. Moreover, because secreted proteins target cellular locations based on trafficking signals, polypeptides of the present invention which are shown to be secreted can be used as targeting molecules once fused to other proteins.

[0166] Examples of domains that can be fused to polypeptides of the present invention include not only heterologous signal sequences, but also other heterologous functional regions. The fusion does not necessarily need to be direct, but may occur through linker sequences.

[0167] In certain preferred embodiments, proteins of the invention are fusion proteins comprising an amino acid sequence that is an N and/or C-terminal deletion of a polypeptide of the invention. In preferred embodiments, the invention is directed to a fusion protein comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98% or 99% identical to a polypeptide sequence of the invention. Polynucleotides encoding these proteins are also encompassed by the invention.

[0168] Moreover, fusion proteins may also be engineered to improve characteristics of the polypeptide of the present invention. For instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence during purification from the host cell or subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to facilitate handling of polypeptides are familiar and routine techniques in the art.

[0169] As one of skill in the art will appreciate that, as discussed above, polypeptides of the present invention, and epitope-bearing fragments thereof, can be combined with heterologous polypeptide sequences. For example, the polypeptides of the present invention may be fused with heterologous polypeptide sequences, for example, the polypeptides of the present invention may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM) or portions thereof (CH1, CH2, CH3, and any combination thereof, including both entire domains and portions thereof), or albumin (including, but not limited to, native or recombinant human albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)), resulting in chimeric polypeptides. For example, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties (EP-A 0232 262). Alternatively, deleting the Fe part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fe portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fe portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. See, D. Bennett et al., J. Molecular Recognition 8:52-58 (1995); K. Johanson et al., J. Biol. Chem. 270:9459-9471 (1995).

[0170] Moreover, the polypeptides of the present invention can be fused to marker sequences, such as a polypeptide which facilitates purification of the fused polypeptide. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Another peptide tag useful for purification, the “HA” tag, corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)).

[0171] Additional fusion proteins of the invention may be generated through the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as “DNA shuffling”). DNA shuffling may be employed to modulate the activities of polypeptides of the invention, such methods can be used to generate polypeptides with altered activity, as well as agonists and antagonists of the polypeptides. See, generally, U.S. Pat. Nos. 5,605,793; 5,811,238; 5,830,721; 5,834,252; and 5,837,458, and Patten et al., Curr. Opinion Biotechnol. 8:724-33 (1997); Harayama, Trends Biotechnol. 16(2):76-82 (1998); Hansson, et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo and Blasco, Biotechniques 24(2):308-13 (1998) (each of these patents and publications are hereby incorporated by reference in its entirety). In one embodiment, alteration of polynucleotides corresponding to SEQ ID NO:X and the polypeptides encoded by these polynucleotides may be achieved by DNA shuffling. DNA shuffling involves the assembly of two or more DNA segments by homologous or site-specific recombination to generate variation in the polynucleotide sequence. In another embodiment, polynucleotides of the invention, or the encoded polypeptides, may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. In another embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of a polynucleotide encoding a polypeptide of the invention may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.

[0172] Thus, any of these above fusions can be engineered using the polynucleotides or the polypeptides of the present invention.

[0173] Recombinant and Synthetic Production of Polypeptides of the Invention

[0174] The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by synthetic and recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.

[0175] The polynucleotides of the invention may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

[0176] The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.

[0177] As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418, glutamine synthase, or neomycin resistance for eukaryotic cell culture, and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. coli and other bacteria. Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris (ATCC Accession No. 201178)); insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.

[0178] Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNH8A, pNH16a, pNH 18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Preferred expression vectors for use in yeast systems include, but are not limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, and PA0815 (all available from Invitrogen, Carlbad, Calif.). Other suitable vectors will be readily apparent to the skilled artisan.

[0179] Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NS0) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g., Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89/01036; WO89/10404; and WO91/06657, which are hereby incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors can be obtained from Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al., Bio/technology 10:169(1992) and in Biblia and Robinson Biotechnol. Prog. 11:1 (1995) which are herein incorporated by reference.

[0180] The present invention also relates to host cells containing the above-described vector constructs described herein, and additionally encompasses host cells containing nucleotide sequences of the invention that are operably associated with one or more heterologous control regions (e.g., promoter and/or enhancer) using techniques known of in the art. The host cell can be a higher eukaryotic cell, such as a mammalian cell (e.g., a human derived cell), or a lower eukaryotic cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. A host strain may be chosen which modulates the expression of the inserted gene sequences, or modifies and processes the gene product in the specific fashion desired. Expression from certain promoters can be elevated in the presence of certain inducers; thus expression of the genetically engineered polypeptide may be controlled. Furthermore, different host cells have characteristics and specific mechanisms for the translational and post-translational processing and modification (e.g., phosphorylation, cleavage) of proteins. Appropriate cell lines can be chosen to ensure the desired modifications and processing of the foreign protein expressed.

[0181] Introduction of the nucleic acids and nucleic acid constructs of the invention into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.

[0182] In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., the coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication Number WO 96/29411; International Publication Number WO 94/12650; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).

[0183] Polypeptides of the invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification.

[0184] Polypeptides of the present invention can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes. Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.

[0185] In one embodiment, the yeast Pichia pastoris is used to express polypeptides of the invention in a eukaryotic system. Pichia pastoris is a methylotrophic yeast which can metabolize methanol as its sole carbon source. A main step in the methanol metabolization pathway is the oxidation of methanol to formaldehyde using O2. This reaction is catalyzed by the enzyme alcohol oxidase. In order to metabolize methanol as its sole carbon source, Pichia pastoris must generate high levels of alcohol oxidase due, in part, to the relatively low affinity of alcohol oxidase for O2. Consequently, in a growth medium depending on methanol as a main carbon source, the promoter region of one of the two alcohol oxidase genes (AOX1) is highly active. In the presence of methanol, alcohol oxidase produced from the AOX1 gene comprises up to approximately 30% of the total soluble protein in Pichia pastoris. See Ellis, S. B., et al., Mol. Cell. Biol. 5:1111-21 (1985); Koutz, P. J, et al., Yeast 5:167-77 (1989); Tschopp, J. F., et al., Nucl. Acids Res. 15:3859-76 (1987). Thus, a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, under the transcriptional regulation of all or part of the AOX1 regulatory sequence is expressed at exceptionally high levels in Pichia yeast grown in the presence of methanol.

[0186] In one example, the plasmid vector pPIC9K is used to express DNA encoding a polypeptide of the invention, as set forth herein, in a Pichea yeast system essentially as described in “Pichia Protocols: Methods in Molecular Biology,” D. R. Higgins and J. Cregg, eds. The Humana Press, Totowa, N.J., 1998. This expression vector allows expression and secretion of a polypeptide of the invention by virtue of the strong AOX1 promoter linked to the Pichia pastoris alkaline phosphatase (PHO) secretory signal peptide (i.e., leader) located upstream of a multiple cloning site.

[0187] Many other yeast vectors could be used in place of pPIC9K, such as, pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, and PAO815, as one skilled in the art would readily appreciate, as long as the proposed expression construct provides appropriately located signals for transcription, translation, secretion (if desired), and the like, including an in-frame AUG as required.

[0188] In another embodiment, high-level expression of a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, may be achieved by cloning the heterologous polynucleotide of the invention into an expression vector such as, for example, pGAPZ or pGAPZalpha, and growing the yeast culture in the absence of methanol.

[0189] In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication No. WO 96/29411, published Sep. 26, 1996; International Publication No. WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).

[0190] In addition, polypeptides of the invention can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W. H. Freeman & Co., N.Y., and Hunkapiller et al., Nature, 310:105-111 (1984)). For example, a polypeptide corresponding to a fragment of a polypeptide can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, omithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoro-amino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary).

[0191] The invention encompasses polypeptides of the present invention which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; etc.

[0192] Additional post-translational modifications encompassed by the invention include, for example, e.g., N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of procaryotic host cell expression. The polypeptides may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the protein.

[0193] Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include iodine (121I, 123I, 125I, 131I), carbon (14C), sulfur (35S), tritium (3H), indium (111In, 112In, 113mIn, 115mIn), technetium (99Tc, 99mTc), thallium (201Ti), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142Pr, 105Rh, and 97Ru.

[0194] In specific embodiments, a polypeptide of the present invention or fragment or variant thereof is attached to macrocyclic chelators that associate with radiometal ions, including but not limited to, 177Lu, 90Y, 166Ho, and 153Sm, to polypeptides. In a preferred embodiment, the radiometal ion associated with the macrocyclic chelators is 111In. In another preferred embodiment, the radiometal ion associated with the macrocyclic chelator is 90Y. In specific embodiments, the macrocyclic chelator is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA). In other specific embodiments, DOTA is attached to an antibody of the invention or fragment thereof via a linker molecule. Examples of linker molecules useful for conjugating DOTA to a polypeptide are commonly known in the art—see, for example, DeNardo et al., Clin Cancer Res. 4(10):2483-90 (1998); Peterson et al., Bioconjug. Chem. 10(4):553-7 (1999); and Zimmerman et al, Nucl. Med. Biol. 26(8):943-50 (1999); which are hereby incorporated by reference in their entirety.

[0195] As mentioned, the proteins of the invention may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Polypeptides of the invention may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

[0196] Also provided by the invention are chemically modified derivatives of the polypeptides of the invention which may provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see U.S. Pat. No. 4,179,337). The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.

[0197] The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term “about” indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog). For example, the polyethylene glycol may have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.

[0198] As noted above, the polyethylene glycol may have a branched structure. Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol. 56:59-72 (1996); Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999); and Caliceti et al., Bioconjug. Chem. 10:638-646 (1999), the disclosures of each of which are incorporated herein by reference.

[0199] The polyethylene glycol molecules (or other chemical moieties) should be attached to the protein with consideration of effects on functional or antigenic domains of the protein. There are a number of attachment methods available to those skilled in the art, such as, for example, the method disclosed in EP 0 401 384 (coupling PEG to G-CSF), herein incorporated by reference; see also Malik et al., Exp. Hematol. 20:1028-1035 (1992), reporting pegylation of GM-CSF using tresyl chloride. For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.

[0200] As suggested above, polyethylene glycol may be attached to proteins via linkage to any of a number of amino acid residues. For example, polyethylene glycol can be linked to proteins via covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine residues. One or more reaction chemistries may be employed to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) of the protein or to more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof) of the protein.

[0201] One may specifically desire proteins chemically modified at the N-terminus. Using polyethylene glycol as an illustration of the present composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, etc.), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus modification may be accomplished by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.

[0202] As indicated above, pegylation of the proteins of the invention may be accomplished by any number of means. For example, polyethylene glycol may be attached to the protein either directly or by an intervening linker. Linkerless systems for attaching polyethylene glycol to proteins are described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992); Francis et al., Intern. J. of Hematol. 68:1-18 (1998); U.S. Pat. No. 4,002,531; U.S. Pat. No. 5,349,052; WO 95/06058; and WO 98/32466, the disclosures of each of which are incorporated herein by reference.

[0203] One system for attaching polyethylene glycol directly to amino acid residues of proteins without an intervening linker employs tresylated MPEG, which is produced by the modification of monmethoxy polyethylene glycol (MPEG) using tresylchloride (ClSO2CH2CF3). Upon reaction of protein with tresylated MPEG, polyethylene glycol is directly attached to amine groups of the protein. Thus, the invention includes protein-polyethylene glycol conjugates produced by reacting proteins of the invention with a polyethylene glycol molecule having a 2,2,2-trifluoreothane sulphonyl group.

[0204] Polyethylene glycol can also be attached to proteins using a number of different intervening linkers. For example, U.S. Pat. No. 5,612,460, the entire disclosure of which is incorporated herein by reference, discloses urethane linkers for connecting polyethylene glycol to proteins. Protein-polyethylene glycol conjugates wherein the polyethylene glycol is attached to the protein by a linker can also be produced by reaction of proteins with compounds such as MPEG-succinimidylsuccinate, MPEG activated with 1,1′-carbonyldiimidazole, MPEG-2,4,5-trichloropenylcarbonate, MPEG-p-nitrophenolcarbonate, and various MPEG-succinate derivatives. A number of additional polyethylene glycol derivatives and reaction chemistries for attaching polyethylene glycol to proteins are described in International Publication No. WO 98/32466, the entire disclosure of which is incorporated herein by reference. Pegylated protein products produced using the reaction chemistries set out herein are included within the scope of the invention.

[0205] The number of polyethylene glycol moieties attached to each protein of the invention (i.e., the degree of substitution) may also vary. For example, the pegylated proteins of the invention may be linked, on average, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, or more polyethylene glycol molecules. Similarly, the average degree of substitution within ranges such as 1-3,2-4, 3-5,4-6, 5-7,6-8, 7-9,8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, or 18-20 polyethylene glycol moieties per protein molecule. Methods for determining the degree of substitution are discussed, for example, in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992).

[0206] The polypeptides of the invention can be recovered and purified from chemical synthesis and recombinant cell cultures by standard methods which include, but are not limited to, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification. Well known techniques for refolding protein may be employed to regenerate active conformation when the polypeptide is denatured during isolation and/or purification.

[0207] The polypeptides of the invention may be in monomers or multimers (i.e., dimers, trimers, tetramers and higher multimers). Accordingly, the present invention relates to monomers and multimers of the polypeptides of the invention, their preparation, and compositions (preferably, Therapeutics) containing them. In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers or tetramers. In additional embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers.

[0208] Multimers encompassed by the invention may be homomers or heteromers. As used herein, the term homomer refers to a multimer containing only polypeptides corresponding to a protein of the invention (e.g., the amino acid sequence of SEQ ID NO:Y, an amino acid sequence encoded by SEQ ID NO:X or the complement of SEQ ID NO:X, the amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/or an amino acid sequence encoded by cDNA contained in Clone ID NO:Z (including fragments, variants, splice variants, and fusion proteins, corresponding to these as described herein)). These homomers may contain polypeptides having identical or different amino acid sequences. In a specific embodiment, a homomer of the invention is a multimer containing only polypeptides having an identical amino acid sequence. In another specific embodiment, a homomer of the invention is a multimer containing polypeptides having different amino acid sequences. In specific embodiments, the multimer of the invention is a homodimer (e.g., containing two polypeptides having identical or different amino acid sequences) or a homotrimer (e.g., containing three polypeptides having identical and/or different amino acid sequences). In additional embodiments, the homomeric multimer of the invention is at least a homodimer, at least a homotrimer, or at least a homotetramer.

[0209] As used herein, the term heteromer refers to a multimer containing one or more heterologous polypeptides (i.e., polypeptides of different proteins) in addition to the polypeptides of the invention. In a specific embodiment, the multimer of the invention is a heterodimer, a heterotrimer, or a heterotetramer. In additional embodiments, the heteromeric multimer of the invention is at least a heterodimer, at least a heterotrimer, or at least a heterotetramer.

[0210] Multimers of the invention may be the result of hydrophobic, hydrophilic, ionic and/or covalent associations and/or may be indirectly linked by, for example, liposome formation. Thus, in one embodiment, multimers of the invention, such as, for example, homodimers or homotrimers, are formed when polypeptides of the invention contact one another in solution. In another embodiment, heteromultimers of the invention, such as, for example, heterotrimers or heterotetramers, are formed when polypeptides of the invention contact antibodies to the polypeptides of the invention (including antibodies to the heterologous polypeptide sequence in a fusion protein of the invention) in solution. In other embodiments, multimers of the invention are formed by covalent associations with and/or between the polypeptides of the invention. Such covalent associations may involve one or more amino acid residues contained in the polypeptide sequence (e.g., that recited in SEQ ID NO:Y, encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/or encoded by the cDNA contained in Clone ID NO:Z). In one instance, the covalent associations are cross-linking between cysteine residues located within the polypeptide sequences which interact in the native (i.e., naturally occurring) polypeptide. In another instance, the covalent associations are the consequence of chemical or recombinant manipulation. Alternatively, such covalent associations may involve one or more amino acid residues contained in the heterologous polypeptide sequence in a fusion protein. In one example, covalent associations are between the heterologous sequence contained in a fusion protein of the invention (see, e.g., U.S. Pat. No. 5,478,925). In a specific example, the covalent associations are between the heterologous sequence contained in a Fe fusion protein of the invention (as described herein). In another specific example, covalent associations of fusion proteins of the invention are between heterologous polypeptide sequence from another protein that is capable of forming covalently associated multimers, such as for example, osteoprotegerin (see, e.g., International Publication NO: WO 98/49305, the contents of which are herein incorporated by reference in its entirety). In another embodiment, two or more polypeptides of the invention are joined through peptide linkers. Examples include those peptide linkers described in U.S. Pat. No. 5,073,627 (hereby incorporated by reference). Proteins comprising multiple polypeptides of the invention separated by peptide linkers may be produced using conventional recombinant DNA technology.

[0211] Another method for preparing multimer polypeptides of the invention involves use of polypeptides of the invention fused to a leucine zipper or isoleucine zipper polypeptide sequence. Leucine zipper and isoleucine zipper domains are polypeptides that promote multimerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA-binding proteins (Landschulz et al., Science 240:1759, (1988)), and have since been found in a variety of different proteins. Among the known leucine zippers are naturally occurring peptides and derivatives thereof that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble multimeric proteins of the invention are those described in PCT application WO 94/10308, hereby incorporated by reference. Recombinant fusion proteins comprising a polypeptide of the invention fused to a polypeptide sequence that dimerizes or trimerizes in solution are expressed in suitable host cells, and the resulting soluble multimeric fusion protein is recovered from the culture supernatant using techniques known in the art.

[0212] Trimeric polypeptides of the invention may offer the advantage of enhanced biological activity. Preferred leucine zipper moieties and isoleucine moieties are those that preferentially form trimers. One example is a leucine zipper derived from lung surfactant protein D (SPD), as described in Hoppe et al. (FEBS Letters 344:191, (1994)) and in U.S. patent application Ser. No. 08/446,922, hereby incorporated by reference. Other peptides derived from naturally occurring trimeric proteins may be employed in preparing trimeric polypeptides of the invention.

[0213] In another example, proteins of the invention are associated by interactions between Flag® polypeptide sequence contained in fusion proteins of the invention containing Flag® polypeptide sequence. In a further embodiment, proteins of the invention are associated by interactions between heterologous polypeptide sequence contained in Flag® fusion proteins of the invention and anti-Flag® antibody.

[0214] The multimers of the invention may be generated using chemical techniques known in the art. For example, polypeptides desired to be contained in the multimers of the invention may be chemically cross-linked using linker molecules and linker molecule length optimization techniques known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, multimers of the invention may be generated using techniques known in the art to form one or more inter-molecule cross-links between the cysteine residues located within the sequence of the polypeptides desired to be contained in the multimer (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Further, polypeptides of the invention may be routinely modified by the addition of cysteine or biotin to the C-terminus or N-terminus of the polypeptide and techniques known in the art may be applied to generate multimers containing one or more of these modified polypeptides (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, techniques known in the art may be applied to generate liposomes containing the polypeptide components desired to be contained in the multimer of the invention (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety).

[0215] Alternatively, multimers of the invention may be generated using genetic engineering techniques known in the art. In one embodiment, polypeptides contained in multimers of the invention are produced recombinantly using fusion protein technology described herein or otherwise known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In a specific embodiment, polynucleotides coding for a homodimer of the invention are generated by ligating a polynucleotide sequence encoding a polypeptide of the invention to a sequence encoding a linker polypeptide and then further to a synthetic polynucleotide encoding the translated product of the polypeptide in the reverse orientation from the original C-terminus to the N-terminus (lacking the leader sequence) (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In another embodiment, recombinant techniques described herein or otherwise known in the art are applied to generate recombinant polypeptides of the invention which contain a transmembrane domain (or hydrophobic or signal peptide) and which can be incorporated by membrane reconstitution techniques into liposomes (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety).

[0216] Antibodies

[0217] Further polypeptides of the invention relate to antibodies and T-cell antigen receptors (TCR) which immunospecifically bind a polypeptide, polypeptide fragment, or variant of the invention (e.g., a polypeptide or fragment or variant of the amino acid sequence of SEQ ID NO:Y or a polypeptide encoded by the cDNA contained in Clone ID No:Z, and/or an epitope, of the present invention) as determined by immunoassays well known in the art for assaying specific antibody-antigen binding. Antibodies of the invention include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′) fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), intracellularly-made antibodies (i.e., intrabodies), and epitope-binding fragments of any of the above. The term “antibody,” as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. In preferred embodiments, the immunoglobulin molecules of the invention are IgG1. In other preferred embodiments, the immunoglobulin molecules of the invention are IgG4.

[0218] Most preferably the antibodies are human antigen-binding antibody fragments of the present invention and include, but are not limited to, Fab, Fab′ and F(ab′)2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, and CH3 domains. Also included in the invention are antigen-binding fragments also comprising any combination of variable region(s) with a hinge region, CH1, CH2, and CH3 domains. The antibodies of the invention may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulin and that do not express endogenous immunoglobulins, as described infra and, for example in, U.S. Pat. No. 5,939,598 by Kucherlapati et al.

[0219] The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol. 148:1547-1553 (1992).

[0220] Antibodies of the present invention may be described or specified in terms of the epitope(s) or portion(s) of a polypeptide of the present invention which they recognize or specifically bind. The epitope(s) or polypeptide portion(s) may be specified as described herein, e.g., by N-terminal and C-terminal positions, or by size in contiguous amino acid residues, or listed in the Tables and Figures. Preferred epitopes of the invention include the predicted epitopes shown in column 7 of Table 1A, as well as polynucleotides that encode these epitopes. Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded. Therefore, the present invention includes antibodies that specifically bind polypeptides of the present invention, and allows for the exclusion of the same.

[0221] Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not bind any other analog, ortholog, or homolog of a polypeptide of the present invention are included. Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In specific embodiments, antibodies of the present invention cross-react with murine, rat and/or rabbit homologs of human proteins and the corresponding epitopes thereof. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In a specific embodiment, the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combination(s) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein. Further included in the present invention are antibodies which bind polypeptides encoded by polynucleotides which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10−2 M, 10−2 M, 5×10−3 M, 10−3 M, 5×10−−4 M, 10−4 M, 5×10−5 M, 10−5 M, 5×10−6 M, 10−6M, 5×10−7 M, 107 M, 5×10−8 M, 10−8 M, 5×10−9 M, 10−9 M, 5×10−10 M, 10−10 M, 5×10−11 M, 10−11 M, 5×10−12 M, 10−12 M, 5×10−13 M, 10−13 M, 5×10−14 M, 10−14 M, 5×10−15 M, or 10−15 M.

[0222] The invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of the invention as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein. In preferred embodiments, the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.

[0223] Antibodies of the present invention may act as agonists or antagonists of the polypeptides of the present invention. For example, the present invention includes antibodies which disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully. Preferably, antibodies of the present invention bind an antigenic epitope disclosed herein, or a portion thereof. The invention features both receptor-specific antibodies and ligand-specific antibodies. The invention also features receptor-specific antibodies which do not prevent ligand binding but prevent receptor activation. Receptor activation (i.e., signaling) may be determined by techniques described herein or otherwise known in the art. For example, receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by western blot analysis (for example, as described supra). In specific embodiments, antibodies are provided that inhibit ligand activity or receptor activity by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50% of the activity in absence of the antibody.

[0224] The invention also features receptor-specific antibodies which both prevent ligand binding and receptor activation as well as antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand. Likewise, included in the invention are neutralizing antibodies which bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies which bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor. Further included in the invention are antibodies which activate the receptor. These antibodies may act as receptor agonists, i.e., potentiate or activate either all or a subset of the biological activities of the ligand-mediated receptor activation, for example, by inducing dimerization of the receptor. The antibodies may be specified as agonists, antagonists or inverse agonists for biological activities comprising the specific biological activities of the peptides of the invention disclosed herein. The above antibody agonists can be made using methods known in the art. See, e.g., PCT publication WO 96/40281; U.S. Pat. No. 5,811,097; Deng et al., Blood 92(6):1981-1988 (1998); Chen et al., Cancer Res. 58(16):3668-3678 (1998); Harrop et al., J. Immunol. 161(4):1786-1794 (1998); Zhu et al., Cancer Res. 58(15):3209-3214 (1998); Yoon et al., J. Immunol. 160(7):3170-3179 (1998); Prat et al., J. Cell. Sci. 111(Pt2):237-247 (1998); Pitard et al., J. Immunol. Methods 205(2):177-190 (1997); Liautard et al., Cytokine 9(4):233-241 (1997); Carlson et al., J. Biol. Chem. 272(17):11295-11301 (1997); Taryman et al., Neuron 14(4):755-762 (1995); Muller et al., Structure 6(9):1153-1167 (1998); Bartunek et al., Cytokine 8(1):14-20 (1996) (which are all incorporated by reference herein in their entireties).

[0225] Antibodies of the present invention may be used, for example, to purify, detect, and target the polypeptides of the present invention, including both in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies have utility in immunoassays for qualitatively and quantitatively measuring levels of the polypeptides of the present invention in biological samples. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); incorporated by reference herein in its entirety.

[0226] As discussed in more detail below, the antibodies of the present invention may be used either alone or in combination with other compositions. The antibodies may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalent and non-covalent conjugations) to polypeptides or other compositions. For example, antibodies of the present invention may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, radionuclides, or toxins. See, e.g., PCT publications WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No. 5,314,995; and EP 396,387; the disclosures of which are incorporated herein by reference in their entireties.

[0227] The antibodies of the invention include derivatives that are modified, i.e, by the covalent attachment of any type of molecule to the antibody such that covalent attachment does not prevent the antibody from generating an anti-idiotypic response. For example, but not by way of limitation, the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids.

[0228] The antibodies of the present invention may be generated by any suitable method known in the art. Polyclonal antibodies to an antigen-of-interest can be produced by various procedures well known in the art. For example, a polypeptide of the invention can be administered to various host animals including, but not limited to, rabbits, mice, rats, etc. to induce the production of sera containing polyclonal antibodies specific for the antigen. Various adjuvants may be used to increase the immunological response, depending on the host species, and include but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum. Such adjuvants are also well known in the art.

[0229] Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981) (said references incorporated by reference in their entireties). The term “monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology. The term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.

[0230] Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art and are discussed in detail in the Examples. In a non-limiting example, mice can be immunized with a polypeptide of the invention or a cell expressing such peptide. Once an immune response is detected, e.g., antibodies specific for the antigen are detected in the mouse serum, the mouse spleen is harvested and splenocytes isolated. The splenocytes are then fused by well known techniques to any suitable myeloma cells, for example cells from cell line SP20 available from the ATCC. Hybridomas are selected and cloned by limited dilution. The hybridoma clones are then assayed by methods known in the art for cells that secrete antibodies capable of binding a polypeptide of the invention. Ascites fluid, which generally contains high levels of antibodies, can be generated by immunizing mice with positive hybridoma clones.

[0231] Accordingly, the present invention provides methods of generating monoclonal antibodies as well as antibodies produced by the method comprising culturing a hybridoma cell secreting an antibody of the invention wherein, preferably, the hybridoma is generated by fusing splenocytes isolated from a mouse immunized with an antigen of the invention with myeloma cells and then screening the hybridomas resulting from the fusion for hybridoma clones that secrete an antibody able to bind a polypeptide of the invention.

[0232] Another well known method for producing both polyclonal and monoclonal human B cell lines is transformation using Epstein Barr Virus (EBV). Protocols for generating EBV-transformed B cell lines are commonly known in the art, such as, for example, the protocol outlined in Chapter 7.22 of Current Protocols in Immunology, Coligan et al., Eds., 1994, John Wiley & Sons, NY, which is hereby incorporated in its entirety by reference. The source of B cells for transformation is commonly human peripheral blood, but B cells for transformation may also be derived from other sources including, but not limited to, lymph nodes, tonsil, spleen, tumor tissue, and infected tissues. Tissues are generally made into single cell suspensions prior to EBV transformation. Additionally, steps may be taken to either physically remove or inactivate T cells (e.g., by treatment with cyclosporin A) in B cell-containing samples, because T cells from individuals seropositive for anti-EBV antibodies can suppress B cell immortalization by EBV.

[0233] In general, the sample containing human B cells is innoculated with EBV, and cultured for 3-4 weeks. A typical source of EBV is the culture supernatant of the B95-8 cell line (ATCC #VR-1492). Physical signs of EBV transformation can generally be seen towards the end of the 3-4 week culture period. By phase-contrast microscopy, transformed cells may appear large, clear, hairy and tend to aggregate in tight clusters of cells. Initially, EBV lines are generally polyclonal. However, over prolonged periods of cell cultures, EBV lines may become monoclonal or polyclonal as a result of the selective outgrowth of particular B cell clones. Alternatively, polyclonal EBV transformed lines may be subcloned (e.g., by limiting dilution culture) or fused with a suitable fusion partner and plated at limiting dilution to obtain monoclonal B cell lines. Suitable fusion partners for EBV transformed cell lines include mouse myeloma cell lines (e.g., SP2/0, X63-Ag8.653), heteromyeloma cell lines (human x mouse; e.g, SPAM-8, SBC-H20, and CB-F7), and human cell lines (e.g., GM 1500, SKO-007, RPMI 8226, and KR-4). Thus, the present invention also provides a method of generating polyclonal or monoclonal human antibodies against polypeptides of the invention or fragments thereof, comprising EBV-transformation of human B cells.

[0234] Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, Fab and F(ab′)2 fragments of the invention may be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab′)2 fragments). F(ab′)2 fragments contain the variable region, the light chain constant region and the CH1 domain of the heavy chain.

[0235] For example, the antibodies of the present invention can also be generated using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them. In a particular embodiment, such phage can be utilized to display antigen binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine). Phage expressing an antigen binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. Examples of phage display methods that can be used to make the antibodies of the present invention include those disclosed in Brinkman et al., J. Immunol. Methods 182:41-50 (1995); Ames et al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol. 24:952-958 (1994); Persic et al., Gene 187 9-18 (1997); Burton et al., Advances in Immunology 57:191-280 (1994); PCT application No. PCT/GB91/01134; PCT publications WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108; each of which is incorporated herein by reference in its entirety.

[0236] As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described in detail below. For example, techniques to recombinantly produce Fab, Fab′ and F(ab′)2 fragments can also be employed using methods known in the art such as those disclosed in PCT publication WO 92/22324; Mullinax et al., BioTechniques 12(6):864-869 (1992); and Sawai et al., AJRI 34:26-34 (1995); and Better et al., Science 240:1041-1043 (1988) (said references incorporated by reference in their entireties).

[0237] Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Pat. Nos. 4,946,778 and 5,258,498; Huston et al., Methods in Enzymology 203:46-88 (1991); Shu et al., PNAS 90:7995-7999 (1993); and Skerra et al., Science 240:1038-1040 (1988). For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., (1989) J. Immunol. Methods 125:191-202; U.S. Pat. Nos. 5,807,715; 4,816,567; and 4,816397, which are incorporated herein by reference in their entirety. Humanized antibodies are antibody molecules from non-human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and a framework regions from a human immunoglobulin molecule. Often, framework residues in the human framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988), which are incorporated herein by reference in their entireties.) Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., PNAS 91:969-973 (1994)), and chain shuffling (U.S. Pat. No. 5,565,332).

[0238] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety.

[0239] Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes. The mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring which express human antibodies. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar, Int. Rev. Immunol. 13:65-93 (1995). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; 5,939,598; 6,075,181; and 6,114,598, which are incorporated by reference herein in their entirety. In addition, companies such as Abgenix, Inc. (Freemont, Calif.) and Genpharm (San Jose, Calif.) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.

[0240] Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as “guided selection.” In this approach a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. (Jespers et al., Bio/technology 12:899-903 (1988)).

[0241] Further, antibodies to the polypeptides of the invention can, in turn, be utilized to generate anti-idiotype antibodies that “mimic” polypeptides of the invention using techniques well known to those skilled in the art. (See, e.g., Greenspan & Bona, FASEB J. 7(5):437-444; (1989) and Nissinoff, J. Immunol. 147(8):2429-2438 (1991)). For example, antibodies which bind to and competitively inhibit polypeptide multimerization and/or binding of a polypeptide of the invention to a ligand can be used to generate anti-idiotypes that “mimic” the polypeptide multimerization and/or binding domain and, as a consequence, bind to and neutralize polypeptide and/or its ligand. Such neutralizing anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens to neutralize polypeptide ligand(s)/receptor(s). For example, such anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligand(s)/receptor(s), and thereby block its biological activity. Alternatively, antibodies which bind to and enhance polypeptide multimerization and/or binding, and/or receptor/ligand multimerization, binding and/or signaling can be used to generate anti-idiotypes that function as agonists of a polypeptide of the invention and/or its ligand/receptor. Such agonistic anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens as agonists of the polypeptides of the invention or its ligand(s)/receptor(s). For example, such anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligand(s)/receptor(s), and thereby promote or enhance its biological activity.

[0242] Intrabodies of the invention can be produced using methods known in the art, such as those disclosed and reviewed in Chen et al., Hum. Gene Ther. 5:595-601 (1994); Marasco, W. A., Gene Ther. 4:11-15 (1997); Rondon and Marasco, Annu. Rev. Microbiol. 51:257-283 (1997); Proba et al., J. Mol. Biol. 275:245-253 (1998); Cohen et al., Oncogene 17:2445-2456 (1998); Ohage and Steipe, J. Mol. Biol. 291:1119-1128 (1999); Ohage et al., J. Mol. Biol. 291:1129-1134 (1999); Wirtz and Steipe, Protein Sci. 8:2245-2250 (1999); Zhu et al., J. Immunol. Methods 231:207-222 (1999); and references cited therein.

[0243] Polynucleotides Encoding Antibodies

[0244] The invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody of the invention and fragments thereof. The invention also encompasses polynucleotides that hybridize under stringent or alternatively, under lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a polypeptide of the invention, preferably, an antibody that binds to a polypeptide having the amino acid sequence of SEQ ID NO:Y, to a polypeptide encoded by a portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/or to a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0245] The polynucleotides may be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art. For example, if the nucleotide sequence of the antibody is known, a polynucleotide encoding the antibody may be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., BioTechniques 17:242 (1994)), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.

[0246] Alternatively, a polynucleotide encoding an antibody may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody of the invention) by PCR amplification using synthetic primers hybridizable to the 3′ and 5′ ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR may then be cloned into replicable cloning vectors using any method well known in the art.

[0247] Once the nucleotide sequence and corresponding amino acid sequence of the antibody is determined, the nucleotide sequence of the antibody may be manipulated using methods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley & Sons, NY, which are both incorporated by reference herein in their entireties), to generate antibodies having a different amino acid sequence, for example to create amino acid substitutions, deletions, and/or insertions.

[0248] In a specific embodiment, the amino acid sequence of the heavy and/or light chain variable domains may be inspected to identify the sequences of the complementarity determining regions (CDRs) by methods that are well know in the art, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. Using routine recombinant DNA techniques, one or more of the CDRs may be inserted within framework regions, e.g., into human framework regions to humanize a non-human antibody, as described supra. The framework regions may be naturally occurring or consensus framework regions, and preferably human framework regions (see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for a listing of human framework regions). Preferably, the polynucleotide generated by the combination of the framework regions and CDRs encodes an antibody that specifically binds a polypeptide of the invention. Preferably, as discussed supra, one or more amino acid substitutions may be made within the framework regions, and, preferably, the amino acid substitutions improve binding of the antibody to its antigen. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds. Other alterations to the polynucleotide are encompassed by the present invention and within the skill of the art.

[0249] In addition, techniques developed for the production of “chimeric antibodies” (Morrison et al., Proc. Natl. Acad. Sci. 81:851-855 (1984); Neuberger et al., Nature 312:604-608 (1984); Takeda et al., Nature 314:452-454 (1985)) by splicing genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. As described supra, a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region, e.g., humanized antibodies.

[0250] Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Ward et al., Nature 334:544-54 (1989)) can be adapted to produce single chain antibodies. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide. Techniques for the assembly of functional Fv fragments in E. coli may also be used (Skerra et al., Science 242:1038-1041 (1988)).

[0251] Methods of Producing Antibodies

[0252] The antibodies of the invention can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques. Methods of producing antibodies include, but are not limited to, hybridoma technology, EBV transformation, and other methods discussed herein as well as through the use recombinant DNA technology, as discussed below.

[0253] Recombinant expression of an antibody of the invention, or fragment, derivative or analog thereof, (e.g., a heavy or light chain of an antibody of the invention or a single chain antibody of the invention), requires construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.

[0254] The expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody of the invention. Thus, the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody of the invention, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chained antibodies, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.

[0255] A variety of host-expression vector systems may be utilized to express the antibody molecules of the invention. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).

[0256] In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., EMBO J. 2:1791 (1983)), in which the antibody coding sequence may be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione-agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0257] In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The antibody coding sequence may be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).

[0258] In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the antibody coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts. (e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)). Specific initiation signals may also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bittner et al., Methods in Enzymol. 153:51-544 (1987)).

[0259] In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK, 293, 3T3, WI38, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary gland cell line such as, for example, CRL7030 and Hs578Bst.

[0260] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the antibody molecule may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the antibody molecule. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the antibody molecule.

[0261] A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:817 (1980)) genes can be employed in tk-, hgprt- or aprt-cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, 1993, TIB TECH 11(5):155-215 (1993)); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)). Methods commonly known in the art of recombinant DNA technology may be routinely applied to select the desired recombinant clone, and such methods are described, for example, in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981), which are incorporated by reference herein in their entireties.

[0262] The expression levels of an antibody molecule can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol.3. (Academic Press, New York, 1987)). When a marker in the vector system expressing antibody is amplifiable, increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the antibody gene, production of the antibody will also increase (Crouse et al., Mol. Cell. Biol. 3:257 (1983)).

[0263] Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NS0) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g. Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89101036; WO89/10404; and WO91/06657 which are incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors that may be used according to the present invention are commercially available from suplliers, including, for example Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al., Bio/technology 10:169(1992) and in Biblia and Robinson Biotechnol. Prog. 11:1 (1995) which are incorporated in their entirities by reference herein.

[0264] The host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2197 (1980)). The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA.

[0265] Once an antibody molecule of the invention has been produced by an animal, chemically synthesized, or recombinantly expressed, it may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. In addition, the antibodies of the present invention or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification.

[0266] The present invention encompasses antibodies recombinantly fused or chemically conjugated (including both covalently and non-covalently conjugations) to a polypeptide (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention to generate fusion proteins. The fusion does not necessarily need to be direct, but may occur through linker sequences. The antibodies may be specific for antigens other than polypeptides (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention. For example, antibodies may be used to target the polypeptides of the present invention to particular cell types, either in vitro or in vivo, by fusing or conjugating the polypeptides of the present invention to antibodies specific for particular cell surface receptors. Antibodies fused or conjugated to the polypeptides of the present invention may also be used in in vitro immunoassays and purification methods using methods known in the art. See e.g., Harbor et al., supra, and PCT publication WO 93/21232; EP 439,095; Naramura et al., Immunol. Lett. 39:91-99 (1994); U.S. Pat. No. 5,474,981; Gillies et al., PNAS 89:1428-1432 (1992); Fell et al., J. Immunol. 146:2446-2452 (1991), which are incorporated by reference in their entireties.

[0267] The present invention further includes compositions comprising the polypeptides of the present invention fused or conjugated to antibody domains other than the variable regions. For example, the polypeptides of the present invention may be fused or conjugated to an antibody Fc region, or portion thereof. The antibody portion fused to a polypeptide of the present invention may comprise the constant region, hinge region, CH1 domain, CH2 domain, and CH3 domain or any combination of whole domains or portions thereof. The polypeptides may also be fused or conjugated to the above antibody portions to form multimers. For example, Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bonding between the Fc portions. Higher multimeric forms can be made by fusing the polypeptides to portions of IgA and IgM. Methods for fusing or conjugating the polypeptides of the present invention to antibody portions are known in the art. See, e.g., U.S. Pat. Nos. 5,336,603; 5,622,929; 5,359,046; 5,349,053; 5,447,851; 5,112,946; EP 307,434; EP 367,166; PCT publications WO 96/04388; WO 91/06570; Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535-10539 (1991); Zheng et al., J. Immunol. 154:5590-5600 (1995); and Vil et al., Proc. Natl. Acad. Sci. USA 89:11337-11341 (1992) (said references incorporated by reference in their entireties).

[0268] As discussed, supra, the polypeptides corresponding to a polypeptide, polypeptide fragment, or a variant of SEQ ID NO:Y may be fused or conjugated to the above antibody portions to increase the in vivo half life of the polypeptides or for use in immunoassays using methods known in the art. Further, the polypeptides corresponding to SEQ ID NO:Y may be fused or conjugated to the above antibody portions to facilitate purification. One reported example describes chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See EP 394,827; and Traunecker et al., Nature 331:84-86 (1988). The polypeptides of the present invention fused or conjugated to an antibody having disulfide-linked dimeric structures (due to the IgG) may also be more efficient in binding and neutralizing other molecules, than the monomeric secreted protein or protein fragment alone. See, for example, Fountoulakis et al., J. Biochem. 270:3958-3964 (1995). In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. See, for example, EP A 232,262. Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. (See, Bennett et al., J. Molecular Recognition 8:52-58 (1995); Johanson et al., J. Biol. Chem. 270:9459-9471 (1995)).

[0269] Moreover, the antibodies or fragments thereof of the present invention can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the “HA” tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)) and the “flag” tag.

[0270] The present invention further encompasses antibodies or fragments thereof conjugated to a diagnostic or therapeutic agent. The antibodies can be used diagnostically to, for example, monitor the development or progression of a tumor as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals using various positron emission tomographies, and nonradioactive paramagnetic metal ions. The detectable substance may be coupled or conjugated either directly to the antibody (or fragment thereof) or indirectly, through an intermediate (such as, for example, a linker known in the art) using techniques known in the art. See, for example, U.S. Pat. No. 4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics according to the present invention. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include 125I, 131I, 111In or 99Tc.

[0271] Further, an antibody or fragment thereof may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

[0272] The conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, a-interferon, β-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See, International Publication No. WO 97/33899), AIM II (See, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al., Int. Immunol., 6:1567-1574 (1994)), VEGI (See, International Publication No. WO 99/23105), a thrombotic agent or an anti-angiogenic agent, e.g., angiostatin or endostatin; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.

[0273] Antibodies may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.

[0274] Techniques for conjugating such therapeutic moiety to antibodies are well known. See, for example, Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”, Immunol. Rev. 62:119-58 (1982).

[0275] Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980, which is incorporated herein by reference in its entirety.

[0276] An antibody, with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factor(s) and/or cytokine(s) can be used as a therapeutic.

[0277] Immunophenotyping

[0278] The antibodies of the invention may be utilized for immunophenotyping of cell lines and biological samples. Translation products of the gene of the present invention may be useful as cell-specific markers, or more specifically as cellular markers that are differentially expressed at various stages of differentiation and/or maturation of particular cell types. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No. 5,985,660; and Morrison et al., Cell, 96:737-49 (1999)).

[0279] These techniques allow for the screening of particular populations of cells, such as might be found with hematological malignancies (i.e. minimal residual disease (MRD) in acute leukemic patients) and “non-self” cells in transplantations to prevent Graft-versus-Host Disease (GVHD). Alternatively, these techniques allow for the screening of hematopoietic stem and progenitor cells capable of undergoing proliferation and/or differentiation, as might be found in human umbilical cord blood.

[0280] Assays For Antibody Binding

[0281] The antibodies of the invention may be assayed for immunospecific binding by any method known in the art. The immunoassays which can be used include but are not limited to competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, which is incorporated by reference herein in its entirety). Exemplary immunoassays are described briefly below (but are not intended by way of limitation).

[0282] Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding the antibody of interest to the cell lysate, incubating for a period of time (e.g., 1-4 hours) at 4° C., adding protein A and/or protein G sepharose beads to the cell lysate, incubating for about an hour or more at 4° C., washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the antibody of interest to immunoprecipitate a particular antigen can be assessed by, e.g., western blot analysis. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al., eds., (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, section 10. 16.1.

[0283] Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%-20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), blocking the membrane with primary antibody (the antibody of interest) diluted in blocking buffer, washing the membrane in washing buffer, blocking the membrane with a secondary antibody (which recognizes the primary antibody, e.g., an anti-human antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g., 32P or 125I) diluted in blocking buffer, washing the membrane in wash buffer, and detecting the presence of the antigen. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected and to reduce the background noise. For further discussion regarding western blot protocols see, e.g., Ausubel et al, eds, (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, section 10.8.1.

[0284] ELISAs comprise preparing antigen, coating the well of a 96 well microtiter plate with the antigen, adding the antibody of interest conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the well and incubating for a period of time, and detecting the presence of the antigen. In ELISAs the antibody of interest does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes the antibody of interest) conjugated to a detectable compound may be added to the well. Further, instead of coating the well with the antigen, the antibody may be coated to the well. In this case, a second antibody conjugated to a detectable compound may be added following the addition of the antigen of interest to the coated well. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al, eds, (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, section 11.2.1.

[0285] The binding affinity of an antibody to an antigen and the off-rate of an antibody-antigen interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., 3H or 125I) with the antibody of interest in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the binding off-rates can be determined from the data by scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, the antigen is incubated with antibody of interest conjugated to a labeled compound (e.g., 3H or 125I) in the presence of increasing amounts of an unlabeled second antibody.

[0286] Antibodies of the invention may be characterized using immunocytochemisty methods on cells (e.g., mammalian cells, such as CHO cells) transfected with a vector enabling the expression of an antigen or with vector alone using techniques commonly known in the art. Antibodies that bind antigen transfected cells, but not vector-only transfected cells, are antigen specific.

[0287] Therapeutic Uses

[0288] The present invention is further directed to antibody-based therapies which involve administering antibodies of the invention to an animal, preferably a mammal, and most preferably a human, patient for treating one or more of the disclosed diseases, disorders, or conditions. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (including fragments, analogs and derivatives thereof as described herein) and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to treat, inhibit or prevent diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein. The treatment and/or prevention of diseases, disorders, or conditions associated with aberrant expression and/or activity of a polypeptide of the invention includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions. Antibodies of the invention may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.

[0289] In a specific and preferred embodiment, the present invention is directed to antibody-based therapies which involve administering antibodies of the invention to an animal, preferably a mammal, and most preferably a human, patient for treating one or more diseases, disorders, or conditions, including but not limited to: neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions., and/or as described elsewhere herein. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (e.g., antibodies directed to the full length protein expressed on the cell surface of a mammalian cell; antibodies directed to an epitope of a polypeptide of the invention (such as, for example, a predicted linear epitope shown in column 7 of Table 1A; or a conformational epitope, including fragments, analogs and derivatives thereof as described herein) and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to treat, inhibit or prevent diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein. The treatment and/or prevention of diseases, disorders, or conditions associated with aberrant expression and/or activity of a polypeptide of the invention includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions. Antibodies of the invention may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.

[0290] A summary of the ways in which the antibodies of the present invention may be used therapeutically includes binding polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody, e.g. as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the present invention for diagnostic, monitoring or therapeutic purposes without undue experimentation.

[0291] The antibodies of this invention may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors (such as, e.g., IL-2, IL-3 and IL-7), for example, which serve to increase the number or activity of effector cells which interact with the antibodies.

[0292] The antibodies of the invention may be administered alone or in combination with other types of treatments (e.g., radiation therapy, chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents). Generally, administration of products of a species origin or species reactivity (in the case of antibodies) that is the same species as that of the patient is preferred. Thus, in a preferred embodiment, human antibodies, fragments derivatives, analogs, or nucleic acids, are administered to a human patient for therapy or prophylaxis.

[0293] It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for both immunoassays directed to and therapy of disorders related to polynucleotides or polypeptides, including fragments thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides of the invention, including fragments thereof. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10−2 M, 10−2 M, 5×10−3 M, 10−3 M, 5×10−4 M, 10−4 M, 5×10−5 M, 10−5 M, 5×10−6 M, 10−6 M, 5×10−7 M, 10−7 M, 5×10−8 M, 10−8 M, 5×10−9 M, 10−9 M, 5×10−10 M, 10−10 M, 5×10−11 M, 10−11 M, 5×10−12 M, 10−12 M, 5×10−13 M, 10−13 M, 5×10−14 M, 10−14 M, 5×10−15M, and 10−15 M.

[0294] Gene Therapy

[0295] In a specific embodiment, nucleic acids comprising sequences encoding antibodies or functional derivatives thereof, are administered to treat, inhibit or prevent a disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention, by way of gene therapy. Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid. In this embodiment of the invention, the nucleic acids produce their encoded protein that mediates a therapeutic effect.

[0296] Any of the methods for gene therapy available in the art can be used according to the present invention. Exemplary methods are described below.

[0297] For general reviews of the methods of gene therapy, see Goldspiel et al., Clinical Pharmacy 12:488-505 (1993); Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, TIBTECH 11(5):155-215 (1993). Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); and Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990).

[0298] In a preferred embodiment, the compound comprises nucleic acid sequences encoding an antibody, said nucleic acid sequences being part of expression vectors that express the antibody or fragments or chimeric proteins or heavy or light chains thereof in a suitable host. In particular, such nucleic acid sequences have promoters operably linked to the antibody coding region, said promoter being inducible or constitutive, and, optionally, tissue-specific. In another particular embodiment, nucleic acid molecules are used in which the antibody coding sequences and any other desired sequences are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the antibody encoding nucleic acids (Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989). In specific embodiments, the expressed antibody molecule is a single chain antibody; alternatively, the nucleic acid sequences include sequences encoding both the heavy and light chains, or fragments thereof, of the antibody.

[0299] Delivery of the nucleic acids into a patient may be either direct, in which case the patient is directly exposed to the nucleic acid or nucleic acid-carrying vectors, or indirect, in which case, cells are first transformed with the nucleic acids in vitro, then transplanted into the patient. These two approaches are known, respectively, as in vivo or ex vivo gene therapy.

[0300] In a specific embodiment, the nucleic acid sequences are directly administered in vivo, where it is expressed to produce the encoded product. This can be accomplished by any of numerous methods known in the art, e.g., by constructing them as part of an appropriate nucleic acid expression vector and administering it so that they become intracellular, e.g., by infection using defective or attenuated retrovirals or other viral vectors (see U.S. Pat. No. 4,980,286), or by direct injection of naked DNA, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, encapsulation in liposomes, microparticles, or microcapsules, or by administering them in linkage to a peptide which is known to enter the nucleus, by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)) (which can be used to target cell types specifically expressing the receptors), etc. In another embodiment, nucleic acid-ligand complexes can be formed in which the ligand comprises a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., PCT Publications WO 92/06180; WO 92/22635; WO92/20316; WO93/14188, WO 93/20221). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989)).

[0301] In a specific embodiment, viral vectors that contains nucleic acid sequences encoding an antibody of the invention are used. For example, a retroviral vector can be used (see Miller et al., Meth. Enzymol. 217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding the antibody to be used in gene therapy are cloned into one or more vectors, which facilitates delivery of the gene into a patient. More detail about retroviral vectors can be found in Boesen et al., Biotherapy 6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdr1 gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest. 93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson, Curr. Opin. in Genetics and Devel. 3:110-114 (1993).

[0302] Adenoviruses are other viral vectors that can be used in gene therapy. Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, Current Opinion in Genetics and Development 3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992); Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993); PCT Publication WO94/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). In a preferred embodiment, adenovirus vectors are used.

[0303] Adeno-associated virus (AAV) has also been proposed for use in gene therapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Pat. No. 5,436,146).

[0304] Another approach to gene therapy involves transferring a gene to cells in tissue culture by such methods as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene. Those cells are then delivered to a patient.

[0305] In this embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell. Such introduction can be carried out by any method known in the art, including but not limited to transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr, Meth. Enzymol. 217:599-618 (1993); Cohen et al., Meth. Enzymol. 217:618-644 (1993); Cline, Pharmac. Ther. 29:69-92m (1985) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted. The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible by its cell progeny.

[0306] The resulting recombinant cells can be delivered to a patient by various methods known in the art. Recombinant blood cells (e.g., hematopoietic stem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art.

[0307] Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetal liver, etc. 1290 In a preferred embodiment, the cell used for gene therapy is autologous to the patient.

[0308] In an embodiment in which recombinant cells are used in gene therapy, nucleic acid sequences encoding an antibody are introduced into the cells such that they are expressible by the cells or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention (see e.g. PCT Publication WO 94/08598; Stemple and Anderson, Cell 71:973-985 (1992); Rheinwald, Meth. Cell Bio. 21A:229 (1980); and Pittelkow and Scott, Mayo Clinic Proc. 61:771 (1986)).

[0309] In a specific embodiment, the nucleic acid to be introduced for purposes of gene therapy comprises an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by the presence or absence of an appropriate inducer of transcription.

[0310] Demonstration of Therapeutic or Prophylactic Activity

[0311] The compounds or pharmaceutical compositions of the invention are preferably tested in vitro, and then in vivo for the desired therapeutic or prophylactic activity, prior to use in humans. For example, in vitro assays to demonstrate the therapeutic or prophylactic utility of a compound or pharmaceutical composition include, the effect of a compound on a cell line or a patient tissue sample. The effect of the compound or composition on the cell line and/or tissue sample can be determined utilizing techniques known to those of skill in the art including, but not limited to, rosette formation assays and cell lysis assays. In accordance with the invention, in vitro assays which can be used to determine whether administration of a specific compound is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a compound, and the effect of such compound upon the tissue sample is observed.

[0312] Therapeutic/Prophylactic Administration and Composition

[0313] The invention provides methods of treatment, inhibition and prophylaxis by administration to a subject of an effective amount of a compound or pharmaceutical composition of the invention, preferably a polypeptide or antibody of the invention. In a preferred embodiment, the compound is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human.

[0314] Formulations and methods of administration that can be employed when the compound comprises a nucleic acid or an immunoglobulin are described above; additional appropriate formulations and routes of administration can be selected from among those described herein below.

[0315] Various delivery systems are known and can be used to administer a compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compounds or compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.

[0316] In a specific embodiment, it may be desirable to administer the pharmaceutical compounds or compositions of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody, of the invention, care must be taken to use materials to which the protein does not absorb.

[0317] In another embodiment, the compound or composition can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.)

[0318] In yet another embodiment, the compound or composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).

[0319] Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).

[0320] In a specific embodiment where the compound of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., Proc. Natl. Acad. Sci. USA 88:1864-1868 (1991)), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.

[0321] The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a compound, and a pharmaceutically acceptable carrier. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0322] In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0323] The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

[0324] The amount of the compound of the invention which will be effective in the treatment, inhibition and prevention of a disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0325] For antibodies, the dosage administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosage administered to a patient is between 0.1 mg/kg and 20 mg/kg of the patient's body weight, more preferably 1 mg/kg to 10 mg/kg of the patient's body weight. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the invention may be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.

[0326] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0327] Diagnosis and Imaging

[0328] Labeled antibodies, and derivatives and analogs thereof, which specifically bind to a polypeptide of interest can be used for diagnostic purposes to detect, diagnose, or monitor diseases, disorders, and/or conditions associated with the aberrant expression and/or activity of a polypeptide of the invention. The invention provides for the detection of aberrant expression of a polypeptide of interest, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of aberrant expression.

[0329] The invention provides a diagnostic assay for diagnosing a disorder, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of a particular disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.

[0330] Antibodies of the invention can be used to assay protein levels in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen et al., J. Cell . Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (125I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99Tc); luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.

[0331] One facet of the invention is the detection and diagnosis of a disease or disorder associated with aberrant expression of a polypeptide of interest in an animal, preferably a mammal and most preferably a human. In one embodiment, diagnosis comprises: a) administering (for example, parenterally, subcutaneously, or intraperitoneally) to a subject an effective amount of a labeled molecule which specifically binds to the polypeptide of interest; b) waiting for a time interval following the administering for permitting the labeled molecule to preferentially concentrate at sites in the subject where the polypeptide is expressed (and for unbound labeled molecule to be cleared to background level); c) determining background level; and d) detecting the labeled molecule in the subject, such that detection of labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with aberrant expression of the polypeptide of interest. Background level can be determined by various methods including, comparing the amount of labeled molecule detected to a standard value previously determined for a particular system.

[0332] It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99 mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the specific protein. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments.” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

[0333] Depending on several variables, including the type of label used and the mode of administration, the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment the time interval following administration is 5 to 20 days or 5 to 10 days.

[0334] In an embodiment, monitoring of the disease or disorder is carried out by repeating the method for diagnosing the disease or disease, for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.

[0335] Presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the invention include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography.

[0336] In a specific embodiment, the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et al., U.S. Pat. No. 5,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument. In another embodiment, the molecule is labeled with a positron emitting metal and is detected in the patent using positron emission-tomography. In yet another embodiment, the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).

[0337] Kits

[0338] The present invention provides kits that can be used in the above methods. In one embodiment, a kit comprises an antibody of the invention, preferably a purified antibody, in one or more containers. In a specific embodiment, the kits of the present invention contain a substantially isolated polypeptide comprising an epitope which is specifically immunoreactive with an antibody included in the kit. Preferably, the kits of the present invention further comprise a control antibody which does not react with the polypeptide of interest. In another specific embodiment, the kits of the present invention contain a means for detecting the binding of an antibody to a polypeptide of interest (e.g., the antibody may be conjugated to a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody which recognizes the first antibody may be conjugated to a detectable substrate).

[0339] In another specific embodiment of the present invention, the kit is a diagnostic kit for use in screening serum containing antibodies specific against proliferative and/or cancerous polynucleotides and polypeptides. Such a kit may include a control antibody that does not react with the polypeptide of interest. Such a kit may include a substantially isolated polypeptide antigen comprising an epitope which is specifically immunoreactive with at least one anti-polypeptide antigen antibody. Further, such a kit includes means for detecting the binding of said antibody to the antigen (e.g., the antibody may be conjugated to a fluorescent compound such as fluorescein or rhodamine which can be detected by flow cytometry). In specific embodiments, the kit may include a recombinantly produced or chemically synthesized polypeptide antigen. The polypeptide antigen of the kit may also be attached to a solid support.

[0340] In a more specific embodiment the detecting means of the above-described kit includes a solid support to which said polypeptide antigen is attached. Such a kit may also include a non-attached reporter-labeled anti-human antibody. In this embodiment, binding of the antibody to the polypeptide antigen can be detected by binding of the said reporter-labeled antibody.

[0341] In an additional embodiment, the invention includes a diagnostic kit for use in screening serum containing antigens of the polypeptide of the invention. The diagnostic kit includes a substantially isolated antibody specifically immunoreactive with polypeptide or polynucleotide antigens, and means for detecting the binding of the polynucleotide or polypeptide antigen to the antibody. In one embodiment, the antibody is attached to a solid support. In a specific embodiment, the antibody may be a monoclonal antibody. The detecting means of the kit may include a second, labeled monoclonal antibody. Alternatively, or in addition, the detecting means may include a labeled, competing antigen.

[0342] In one diagnostic configuration, test serum is reacted with a solid phase reagent having a surface-bound antigen obtained by the methods of the present invention. After binding with specific antigen antibody to the reagent and removing unbound serum components by washing, the reagent is reacted with reporter-labeled anti-human antibody to bind reporter to the reagent in proportion to the amount of bound anti-antigen antibody on the solid support. The reagent is again washed to remove unbound labeled antibody, and the amount of reporter associated with the reagent is determined. Typically, the reporter is an enzyme which is detected by incubating the solid phase in the presence of a suitable fluorometric, luminescent or colorimetric substrate (Sigma, St. Louis, Mo.).

[0343] The solid surface reagent in the above assay is prepared by known techniques for attaching protein material to solid support material, such as polymeric beads, dip sticks, 96-well plate or filter material. These attachment methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group. Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigen(s).

[0344] Thus, the invention provides an assay system or kit for carrying out this diagnostic method. The kit generally includes a support with surface-bound recombinant antigens, and a reporter-labeled anti-human antibody for detecting surface-bound anti-antigen antibody.

[0345] Uses of the Polynucleotides

[0346] Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.

[0347] The polynucleotides of the present invention are useful for chromosome identification. There exists an ongoing need to identify new chromosome markers, since few chromosome marking reagents, based on actual sequence data (repeat polymorphisms), are presently available. Each sequence is specifically targeted to and can hybridize with a particular location on an individual human chromosome, thus each polynucleotide of the present invention can routinely be used as a chromosome marker using techniques known in the art. Table 1A, column 9 provides the chromosome location of some of the polynucleotides of the invention.

[0348] Briefly, sequences can be mapped to chromosomes by preparing PCR primers (preferably at least 15 bp (e.g., 15-25 bp) from the sequences shown in SEQ ID NO:X. Primers can optionally be selected using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. These primers are then used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to SEQ ID NO:X will yield an amplified fragment.

[0349] Similarly, somatic hybrids provide a rapid method of PCR mapping the polynucleotides to particular chromosomes. Three or more clones can be assigned per day using a single thermal cycler. Moreover, sublocalization of the polynucleotides can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow-sorted chromosomes, preselection by hybridization to construct chromosome specific-cDNA libraries, and computer mapping techniques (See, e.g., Shuler, Trends Biotechnol 16:456-459 (1998) which is hereby incorporated by reference in its entirety).

[0350] Precise chromosomal location of the polynucleotides can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread. This technique uses polynucleotides as short as 500 or 600 bases; however, polynucleotides 2,000-4,000 bp are preferred. For a review of this technique, see Verma et al., “Human Chromosomes: a Manual of Basic Techniques,” Pergamon Press, New York (1988).

[0351] For chromosome mapping, the polynucleotides can be used individually (to mark a single chromosome or a single site on that chromosome) or in panels (for marking multiple sites and/or multiple chromosomes).

[0352] Thus, the present invention also provides a method for chromosomal localization which involves (a) preparing PCR primers from the polynucleotide sequences in Table 1A and/or Table 2 and SEQ ID NO:X and (b) screening somatic cell hybrids containing individual chromosomes.

[0353] The polynucleotides of the present invention would likewise be useful for radiation hybrid mapping, HAPPY mapping, and long range restriction mapping. For a review of these techniques and others known in the art, see, e.g. Dear, “Genome Mapping: A Practical Approach,” IRL Press at Oxford University Press, London (1997); Aydin, J. Mol. Med. 77:691-694 (1999); Hacia et al., Mol. Psychiatry 3:483-492 (1998); Herrick et al., Chromosome Res. 7:409-423 (1999); Hamilton et al., Methods Cell Biol. 62:265-280 (2000); and/or Ott, J. Hered. 90:68-70 (1999) each of which is hereby incorporated by reference in its entirety.

[0354] Once a polynucleotide has been mapped to a precise chromosomal location, the physical position of the polynucleotide can be used in linkage analysis. Linkage analysis establishes coinheritance between a chromosomal location and presentation of a particular disease. (Disease mapping data are found, for example, in V. McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library)). Column 10 of Table 1A provides an OMIM reference identification number of diseases associated with the cytologic band disclosed in column 9 of Table 1A, as determined using techniques described herein and by reference to Table 5. Assuming 1 megabase mapping resolution and one gene per 20 kb, a cDNA precisely localized to a chromosomal region associated with the disease could be one of 50-500 potential causative genes.

[0355] Thus, once coinheritance is established, differences in a polynucleotide of the invention and the corresponding gene between affected and unaffected individuals can be examined. First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicates that the mutation may cause the disease. However, complete sequencing of the polypeptide and the corresponding gene from several normal individuals is required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.

[0356] Furthermore, increased or decreased expression of the gene in affected individuals as compared to unaffected individuals can be assessed using the polynucleotides of the invention. Any of these alterations (altered expression, chromosomal rearrangement, or mutation) can be used as a diagnostic or prognostic marker. Diagnostic and prognostic methods, kits and reagents encompassed by the present invention are briefly described below and more thoroughly elsewhere herein (see e.g., the sections labeled “Antibodies”, “Diagnostic Assays”, and “Methods for Detecting Diseases”).

[0357] Thus, the invention also provides a diagnostic method useful during diagnosis of a disorder, involving measuring the expression level of polynucleotides of the present invention in cells or body fluid from an individual and comparing the measured gene expression level with a standard level of polynucleotide expression level, whereby an increase or decrease in the gene expression level compared to the standard is indicative of a disorder. Additional non-limiting examples of diagnostic methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., Example 12).

[0358] In still another embodiment, the invention includes a kit for analyzing samples for the presence of proliferative and/or cancerous polynucleotides derived from a test subject. In a general embodiment, the kit includes at least one polynucleotide probe containing a nucleotide sequence that will specifically hybridize with a polynucleotide of the invention and a suitable container. In a specific embodiment, the kit includes two polynucleotide probes defining an internal region of the polynucleotide of the invention, where each probe has one strand containing a 31′mer-end internal to the region. In a further embodiment, the probes may be useful as primers for polymerase chain reaction amplification.

[0359] Where a diagnosis of a related disorder, including, for example, diagnosis of a tumor, has already been made according to conventional methods, the present invention is useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed polynucleotide of the invention expression will experience a worse clinical outcome relative to patients expressing the gene at a level nearer the standard level.

[0360] By “measuring the expression level of polynucleotides of the invention” is intended qualitatively or quantitatively measuring or estimating the level of the polypeptide of the invention or the level of the mRNA encoding the polypeptide of the invention in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the polypeptide level or mRNA level in a second biological sample). Preferably, the polypeptide level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the related disorder or being determined by averaging levels from a population of individuals not having a related disorder. As will be appreciated in the art, once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.

[0361] By “biological sample” is intended any biological sample obtained from an individual, body fluid, cell line, tissue culture, or other source which contains polypeptide of the present invention or the corresponding mRNA. As indicated, biological samples include body fluids (such as semen, lymph, vaginal pool, sera, plasma, urine, synovial fluid and spinal fluid) which contain the polypeptide of the present invention, and tissue sources found to express the polypeptide of the present invention. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art. Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.

[0362] The method(s) provided above may preferably be applied in a diagnostic method and/or kits in which polynucleotides and/or polypeptides of the invention are attached to a solid support. In one exemplary method, the support may be a “gene chip” or a “biological chip” as described in U.S. Pat. Nos. 5,837,832, 5,874,219, and 5,856,174. Further, such a gene chip with polynucleotides of the invention attached may be used to identify polymorphisms between the isolated polynucleotide sequences of the invention, with polynucleotides isolated from a test subject. The knowledge of such polymorphisms (i.e. their location, as well as, their existence) would be beneficial in identifying disease loci for many disorders, such as for example, in neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, digestive disorders, metabolic disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions. Such a method is described in U.S. Pat. Nos. 5,858,659 and 5,856,104. The US Patents referenced supra are hereby incorporated by reference in their entirety herein.

[0363] The present invention encompasses polynucleotides of the present invention that are chemically synthesized, or reproduced as peptide nucleic acids (PNA), or according to other methods known in the art. The use of PNAs would serve as the preferred form if the polynucleotides of the invention are incorporated onto a solid support, or gene chip. For the purposes of the present invention, a peptide nucleic acid (PNA) is a polyamide type of DNA analog and the monomeric units for adenine, guanine, thymine and cytosine are available commercially (Perceptive Biosystems). Certain components of DNA, such as phosphorus, phosphorus oxides, or deoxyribose derivatives, are not present in PNAs. As disclosed by Nielsen et al., Science 254, 1497 (1991); and Egholm et al., Nature 365, 666 (1993), PNAs bind specifically and tightly to complementary DNA strands and are not degraded by nucleases. In fact, PNA binds more strongly to DNA than DNA itself does. This is probably because there is no electrostatic repulsion between the two strands, and also the polyamide backbone is more flexible. Because of this, PNA/DNA duplexes bind under a wider range of stringency conditions than DNA/DNA duplexes, making it easier to perform multiplex hybridization. Smaller probes can be used than with DNA due to the strong binding. In addition, it is more likely that single base mismatches can be determined with PNA/DNA hybridization because a single mismatch in a PNA/DNA 15-mer lowers the melting point (T.sub.m) by 8°-20° C., vs. 4°-16° C. for the DNA/DNA 15-mer duplex. Also, the absence of charge groups in PNA means that hybridization can be done at low ionic strengths and reduce possible interference by salt during the analysis.

[0364] The compounds of the present invention have uses which include, but are not limited to, detecting cancer in mammals. In particular the invention is useful during diagnosis of pathological cell proliferative neoplasias which include, but are not limited to: acute myelogenous leukemias including acute monocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia, and acute undifferentiated leukemia, etc.; and chronic myelogenous leukemias including chronic myelomonocytic leukemia, chronic granulocytic leukemia, etc. Preferred mammals include monkeys, apes, cats, dogs, cows, pigs, horses, rabbits and humans. Particularly preferred are humans.

[0365] Pathological cell proliferative disorders are often associated with inappropriate activation of proto-oncogenes. (Gelmann, E. P. et al., “The Etiology of Acute Leukemia: Molecular Genetics and Viral Oncology,” in Neoplastic Diseases of the Blood, Vol 1., Wiernik, P. H. et al. eds., 161-182 (1985)). Neoplasias are now believed to result from the qualitative alteration of a normal cellular gene product, or from the quantitative modification of gene expression by insertion into the chromosome of a viral sequence, by chromosomal translocation of a gene to a more actively transcribed region, or by some other mechanism. (Gelmann et al., supra) It is likely that mutated or altered expression of specific genes is involved in the pathogenesis of some leukemias, among other tissues and cell types. (Gelmann et al., supra) Indeed, the human counterparts of the oncogenes involved in some animal neoplasias have been amplified or translocated in some cases of human leukemia and carcinoma. (Gelmann et al., supra)

[0366] For example, c-myc expression is highly amplified in the non-lymphocytic leukemia cell line HL-60. When HL-60 cells are chemically induced to stop proliferation, the level of c-myc is found to be downregulated. (International Publication Number WO 91/15580). However, it has been shown that exposure of HL-60 cells to a DNA construct that is complementary to the 5′ end of c-myc or c-myb blocks translation of the corresponding mRNAs which downregulates expression of the c-myc or c-myb proteins and causes arrest of cell proliferation and differentiation of the treated cells. (International Publication Number WO 91/15580; Wickstrom et al., Proc. Natl. Acad. Sci. 85:1028 (1988); Anfossi et al., Proc. Natl. Acad. Sci. 86:3379 (1989)). However, the skilled artisan would appreciate the present invention's usefulness is not be limited to treatment, prevention, and/or prognosis of proliferative disorders of cells and tissues of hematopoietic origin, in light of the numerous cells and cell types of varying origins which are known to exhibit proliferative phenotypes.

[0367] In addition to the foregoing, a polynucleotide of the present invention can be used to control gene expression through triple helix formation or through antisense DNA or RNA. Antisense techniques are discussed, for example, in Okano, J. Neurochem. 56: 560 (1991); “Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Triple helix formation is discussed in, for instance Lee et al., Nucleic Acids Research 6: 3073 (1979); Cooney et al., Science 241: 456 (1988); and Dervan et al., Science 251: 1360 (1991). Both methods rely on binding of the polynucleotide to a complementary DNA or RNA. For these techniques, preferred polynucleotides are usually oligonucleotides 20 to 40 bases in length and complementary to either the region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J. Neurochem. 56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. The oligonucleotide described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of polypeptide of the present invention antigens. Both techniques are effective in model systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat disease, and in particular, for the treatment of proliferative diseases and/or conditions. Non-limiting antisense and triple helix methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., the section labeled “Antisense and Ribozyrne (Antagonists)”).

[0368] Polynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell. Additional non-limiting examples of gene therapy methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., the sections labeled “Gene Therapy Methods”, and Examples 16, 17 and 18).

[0369] The polynucleotides are also useful for identifying individuals from minute biological samples. The United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identifying personnel. This method does not suffer from the current limitations of “Dog Tags” which can be lost, switched, or stolen, making positive identification difficult. The polynucleotides of the present invention can be used as additional DNA markers for RFLP.

[0370] The polynucleotides of the present invention can also be used as an alternative to RFLP, by determining the actual base-by-base DNA sequence of selected portions of an individual's genome. These sequences can be used to prepare PCR primers for amplifying and isolating such selected DNA, which can then be sequenced. Using this technique, individuals can be identified because each individual will have a unique set of DNA sequences. Once an unique ID database is established for an individual, positive identification of that individual, living or dead, can be made from extremely small tissue samples.

[0371] Forensic biology also benefits from using DNA-based identification techniques as disclosed herein. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, synovial fluid, amniotic fluid, breast milk, lymph, pulmonary sputum or surfactant, urine, fecal matter, etc., can be amplified using PCR. In one prior art technique, gene sequences amplified from polymorphic loci, such as DQa class II HLA gene, are used in forensic biology to identify individuals. (Erlich, H., PCR Technology, Freeman and Co. (1992)). Once these specific polymorphic loci are amplified, they are digested with one or more restriction enzymes, yielding an identifying set of bands on a Southern blot probed with DNA corresponding to the DQa class II HLA gene. Similarly, polynucleotides of the present invention can be used as polymorphic markers for forensic purposes.

[0372] There is also a need for reagents capable of identifying the source of a particular tissue. Such need arises, for example, in forensics when presented with tissue of unknown origin. Appropriate reagents can comprise, for example, DNA probes or primers prepared from the sequences of the present invention, specific to tissues, including but not limited to those shown in Table 1A. Panels of such reagents can identify tissue by species and/or by organ type. In a similar fashion, these reagents can be used to screen tissue cultures for contamination. Additional non-limiting examples of such uses are further described herein.

[0373] The polynucleotides of the present invention are also useful as hybridization probes for differential identification of the tissue(s) or cell type(s) present in a biological sample. Similarly, polypeptides and antibodies directed to polypeptides of the present invention are useful to provide immunological probes for differential identification of the tissue(s) (e.g., immunohistochemistry assays) or cell type(s) (e.g., immunocytochemistry assays). In addition, for a number of disorders of the above tissues or cells, significantly higher or lower levels of gene expression of the polynucleotides/polypeptides of the present invention may be detected in certain tissues (e.g., tissues expressing polypeptides and/or polynucleotides of the present invention, for example, those disclosed in column 8 of Table A, and/or cancerous and/or wounded tissues) or bodily fluids (e.g., semen, lymph, vaginal pool, serum, plasma, urine, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” gene expression level, i.e., the expression level in healthy tissue from an individual not having the disorder.

[0374] Thus, the invention provides a diagnostic method of a disorder, which involves: (a) assaying gene expression level in cells or body fluid of an individual; (b) comparing the gene expression level with a standard gene expression level, whereby an increase or decrease in the assayed gene expression level compared to the standard expression level is indicative of a disorder.

[0375] In the very least, the polynucleotides of the present invention can be used as molecular weight markers on Southern gels, as diagnostic probes for the presence of a specific mRNA in a particular cell type, as a probe to “subtract-out” known sequences in the process of discovering novel polynucleotides, for selecting and making oligomers for attachment to a “gene chip” or other support, to raise anti-DNA antibodies using DNA immunization techniques, and as an antigen to elicit an immune response.

[0376] Uses of the Polypeptides

[0377] Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.

[0378] Polypeptides and antibodies directed to polypeptides of the present invention are useful to provide immunological probes for differential identification of the tissue(s) (e.g., immunohistochemistry assays such as, for example, ABC immunoperoxidase (Hsu et al., J. Histochem. Cytochem. 29:577-580 (1981)) or cell type(s) (e.g., immunocytochemistry assays).

[0379] Antibodies can be used to assay levels of polypeptides encoded by polynucleotides of the invention in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen, et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (131I, 125I, 123I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (115mIn, 113mIn, 112In, 111In), and technetium (99Tc, 99mTc), thallium (201Ti), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re 142Pr, 105Rh, 97Ru; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.

[0380] In addition to assaying levels of polypeptide of the present invention in a biological sample, proteins can also be detected in vivo by imaging. Antibody labels or markers for in vivo imaging of protein include those detectable by X-radiography, NMR or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma.

[0381] A protein-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example, 131I, 112In, 99mTc, (131I, 125I, 123I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (115mIn, 113mIn, 112In, 111In), and technetium (99Tc, 99mTc), thallium (201Ti), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F, 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 18Re, 88Re, 42Pr, 105Rh, 97Ru), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously or intraperitoneally) into the mammal to be examined for immune system disorder. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which express the polypeptide encoded by a polynucleotide of the invention. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

[0382] In one embodiment, the invention provides a method for the specific delivery of compositions of the invention to cells by administering polypeptides of the invention (e.g., polypeptides encoded by polynucleotides of the invention and/or antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a therapeutic protein into the targeted cell. In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell's genome or replicate episomally and that can be transcribed) into the targeted cell.

[0383] In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention in association with toxins or cytotoxic prodrugs.

[0384] By “toxin” is meant one or more compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. “Toxin” also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi, or other radioisotopes such as, for example, 103Pd, 133Xe, 131I, 68Ge, 57Co, 65Zn, 85Sr, 32P, 35S, 90Y, 153Sm, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, 90Yttrium, 117Tin, 186Rhenium, 166Holmium, and 188Rhenium; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin. In a specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope 90Y. In another specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope 111In. In a further specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope 131I.

[0385] Techniques known in the art may be applied to label polypeptides of the invention (including antibodies). Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see e.g., U.S. Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931; 5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and 5,808,003; the contents of each of which are hereby incorporated by reference in its entirety).

[0386] Thus, the invention provides a diagnostic method of a disorder, which involves (a) assaying the expression level of a polypeptide of the present invention in cells or body fluid of an individual; and (b) comparing the assayed polypeptide expression level with a standard polypeptide expression level, whereby an increase or decrease in the assayed polypeptide expression level compared to the standard expression level is indicative of a disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.

[0387] Moreover, polypeptides of the present invention can be used to treat or prevent diseases or conditions such as, for example, neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions. For example, patients can be administered a polypeptide of the present invention in an effort to replace absent or decreased levels of the polypeptide (e.g., insulin), to supplement absent or decreased levels of a different polypeptide (e.g., hemoglobin S for hemoglobin B, SOD, catalase, DNA repair proteins), to inhibit the activity of a polypeptide (e.g., an oncogene or tumor supressor), to activate the activity of a polypeptide (e.g., by binding to a receptor), to reduce the activity of a membrane bound receptor by competing with it for free ligand (e.g., soluble TNF receptors used in reducing inflammation), or to bring about a desired response (e.g., blood vessel growth inhibition, enhancement of the immune response to proliferative cells or tissues).

[0388] Similarly, antibodies directed to a polypeptide of the present invention can also be used to treat disease (as described supra, and elsewhere herein). For example, administration of an antibody directed to a polypeptide of the present invention can bind, and/or neutralize the polypeptide, and/or reduce overproduction of the polypeptide. Similarly, administration of an antibody can activate the polypeptide, such as by binding to a polypeptide bound to a membrane (receptor).

[0389] At the very least, the polypeptides of the present invention can be used as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods well known to those of skill in the art. Polypeptides can also be used to raise antibodies, which in turn are used to measure protein expression from a recombinant cell, as a way of assessing transformation of the host cell. Moreover, the polypeptides of the present invention can be used to test the biological activities described herein.

[0390] Diagnostic Assays

[0391] The compounds of the present invention are useful for diagnosis, treatment, prevention and/or prognosis of various disorders in mammals, preferably humans. Such disorders include, but are not limited to, those described herein under the section heading “Biological Activities”.

[0392] For a number of disorders, substantially altered (increased or decreased) levels of gene expression can be detected in tissues, cells or bodily fluids (e.g., sera, plasma, urine, semen, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” gene expression level, that is, the expression level in tissues or bodily fluids from an individual not having the disorder. Thus, the invention provides a diagnostic method useful during diagnosis of a disorder, which involves measuring the expression level of the gene encoding the polypeptide in tissues, cells or body fluid from an individual and comparing the measured gene expression level with a standard gene expression level, whereby an increase or decrease in the gene expression level(s) compared to the standard is indicative of a disorder. These diagnostic assays may be performed in vivo or in vitro, such as, for example, on blood samples, biopsy tissue or autopsy tissue.

[0393] The present invention is also useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed gene expression will experience a worse clinical outcome relative to patients expressing the gene at a level nearer the standard level.

[0394] In certain embodiments, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognose diseases and/or disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).

[0395] By “assaying the expression level of the gene encoding the polypeptide” is intended qualitatively or quantitatively measuring or estimating the level of the polypeptide of the invention or the level of the mRNA encoding the polypeptide of the invention in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the polypeptide level or mRNA level in a second biological sample). Preferably, the polypeptide expression level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the disorder or being determined by averaging levels from a population of individuals not having the disorder. As will be appreciated in the art, once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.

[0396] By “biological sample” is intended any biological sample obtained from an individual, cell line, tissue culture, or other source containing polypeptides of the invention (including portions thereof) or mRNA. As indicated, biological samples include body fluids (such as sera, plasma, urine, synovial fluid and spinal fluid) and tissue sources found to express the full length or fragments thereof of a polypeptide or mRNA. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art. Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.

[0397] Total cellular RNA can be isolated from a biological sample using any suitable technique such as the single-step guanidinium-thiocyanate-phenol-chloroform method described in Chomczynski and Sacchi, Anal. Biochem. 162:156-159 (1987). Levels of mRNA encoding the polypeptides of the invention are then assayed using any appropriate method. These include Northern blot analysis, S1 nuclease mapping, the polymerase chain reaction (PCR), reverse transcription in combination with the polymerase chain reaction (RT-PCR), and reverse transcription in combination with the ligase chain reaction (RT-LCR).

[0398] The present invention also relates to diagnostic assays such as quantitative and diagnostic assays for detecting levels of polypeptides of the invention, in a biological sample (e.g., cells and tissues), including determination of normal and abnormal levels of polypeptides. Thus, for instance, a diagnostic assay in accordance with the invention for detecting over-expression of polypeptides of the invention compared to normal control tissue samples may be used to detect the presence of tumors. Assay techniques that can be used to determine levels of a polypeptide, such as a polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays. Assaying polypeptide levels in a biological sample can occur using any art-known method.

[0399] Assaying polypeptide levels in a biological sample can occur using antibody-based techniques. For example, polypeptide expression in tissues can be studied with classical immunohistological methods (Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J. Cell . Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting polypeptide gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine (125I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99mTc), and fluorescent labels, such as fluorescein and rhodamine, and biotin.

[0400] The tissue or cell type to be analyzed will generally include those which are known, or suspected, to express the gene of inteest (such as, for example, cancer). The protein isolation methods employed herein may, for example, be such as those described in Harlow and Lane (Harlow, E. and Lane, D., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.), which is incorporated herein by reference in its entirety. The isolated cells can be derived from cell culture or from a patient. The analysis of cells taken from culture may be a necessary step in the assessment of cells that could be used as part of a cell-based gene therapy technique or, alternatively, to test the effect of compounds on the expression of the gene.

[0401] For example, antibodies, or fragments of antibodies, such as those described herein, may be used to quantitatively or qualitatively detect the presence of gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.

[0402] In a preferred embodiment, antibodies, or fragments of antibodies directed to any one or all of the predicted epitope domains of the polypeptides of the invention (shown in column 7 of Table 1A) may be used to quantitatively or qualitatively detect the presence of gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.

[0403] In an additional preferred embodiment, antibodies, or fragments of antibodies directed to a conformational epitope of a polypeptide of the invention may be used to quantitatively or qualitatively detect the presence of gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.

[0404] The antibodies (or fragments thereof), and/or polypeptides of the present invention may, additionally, be employed histologically, as in immunofluorescence, immunoelectron microscopy or non-immunological assays, for in situ detection of gene products or conserved variants or peptide fragments thereof. In situ detection may be accomplished by removing a histological specimen from a patient, and applying thereto a labeled antibody or polypeptide of the present invention. The antibody (or fragment thereof) or polypeptide is preferably applied by overlaying the labeled antibody (or fragment) onto a biological sample. Through the use of such a procedure, it is possible to determine not only the presence of the gene product, or conserved variants or peptide fragments, or polypeptide binding, but also its distribution in the examined tissue. Using the present invention, those of ordinary skill will readily perceive that any of a wide variety of histological methods (such as staining procedures) can be modified in order to achieve such in situ detection.

[0405] Immunoassays and non-immunoassays for gene products or conserved variants or peptide fragments thereof will typically comprise incubating a sample, such as a biological fluid, a tissue extract, freshly harvested cells, or lysates of cells which have been incubated in cell culture, in the presence of a detectably labeled antibody capable of binding gene products or conserved variants or peptide fragments thereof, and detecting the bound antibody by any of a number of techniques well-known in the art.

[0406] The biological sample may be brought in contact with and immobilized onto a solid phase support or carrier such as nitrocellulose, or other solid support which is capable of immobilizing cells, cell particles or soluble proteins. The support may then be washed with suitable buffers followed by treatment with the detectably labeled antibody or detectable polypeptide of the invention. The solid phase support may then be washed with the buffer a second time to remove unbound antibody or polypeptide. Optionally the antibody is subsequently labeled. The amount of bound label on solid support may then be detected by conventional means.

[0407] By “solid phase support or carrier” is intended any support capable of binding an antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite. The nature of the carrier can be either soluble to some extent or insoluble for the purposes of the present invention. The support material may have virtually any possible structural configuration so long as the coupled molecule is capable of binding to an antigen or antibody. Thus, the support configuration may be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface may be flat such as a sheet, test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know many other suitable carriers for binding antibody or antigen, or will be able to ascertain the same by use of routine experimentation.

[0408] The binding activity of a given lot of antibody or antigen polypeptide may be determined according to well known methods. Those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation.

[0409] In addition to assaying polypeptide levels or polynucleotide levels in a biological sample obtained from an individual, polypeptide or polynucleotide can also be detected in vivo by imaging. For example, in one embodiment of the invention, polypeptides and/or antibodies of the invention are used to image diseased cells, such as neoplasms. In another embodiment, polynucleotides of the invention (e.g., polynucleotides complementary to all or a portion of an mRNA) and/or antibodies (e.g., antibodies directed to any one or a combination of the epitopes of a polypeptide of the invention, antibodies directed to a conformational epitope of a polypeptide of the invention, or antibodies directed to the full length polypeptide expressed on the cell surface of a mammalian cell) are used to image diseased or neoplastic cells.

[0410] Antibody labels or markers for in vivo imaging of polypeptides of the invention include those detectable by X-radiography, NMR, MRI, CAT-scans or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma. Where in vivo imaging is used to detect enhanced levels of polypeptides for diagnosis in humans, it may be preferable to use human antibodies or “humanized” chimeric monoclonal antibodies. Such antibodies can be produced using techniques described herein or otherwise known in the art. For example methods for producing chimeric antibodies are known in the art. See, for review, Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985).

[0411] Additionally, any polypeptides of the invention whose presence can be detected, can be administered. For example, polypeptides of the invention labeled with a radio-opaque or other appropriate compound can be administered and visualized in vivo, as discussed, above for labeled antibodies. Further, such polypeptides can be utilized for in vitro diagnostic procedures.

[0412] A polypeptide-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example, 131I, 112In, 99mTc), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously or intraperitoneally) into the mammal to be examined for a disorder. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the antigenic protein. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

[0413] With respect to antibodies, one of the ways in which an antibody of the present invention can be detectably labeled is by linking the same to a reporter enzyme and using the linked product in an enzyme immunoassay (EIA) (Voller, A., “The Enzyme Linked Immunosorbent Assay (ELISA)”, 1978, Diagnostic Horizons 2:1-7, Microbiological Associates Quarterly Publication, Walkersville, Md.); Voller et al., J. Clin. Pathol. 31:507-520 (1978); Butler, J. E., Meth. Enzymol. 73:482-523 (1981); Maggio, E. (ed.), 1980, Enzyme Immunoassay, CRC Press, Boca Raton, Fla.,; Ishikawa, E. et al., (eds.), 1981, Enzyme Immunoassay, Kgaku Shoin, Tokyo). The reporter enzyme which is bound to the antibody will react with an appropriate substrate, preferably a chromogenic substrate, in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorimetric or by visual means. Reporter enzymes which can be used to detectably label the antibody include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-5-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. Additionally, the detection can be accomplished by colorimetric methods which employ a chromogenic substrate for the reporter enzyme. Detection may also be accomplished by visual comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepared standards.

[0414] Detection may also be accomplished using any of a variety of other immunoassays. For example, by radioactively labeling the antibodies or antibody fragments, it is possible to detect polypeptides through the use of a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by means including, but not limited to, a gamma counter, a scintillation counter, or autoradiography.

[0415] It is also possible to label the antibody with a fluorescent compound. When the fluorescently labeled antibody is exposed to light of the proper wave length, its presence can then be detected due to fluorescence. Among the most commonly used fluorescent labeling compounds are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, ophthaldehyde and fluorescamine.

[0416] The antibody can also be detectably labeled using fluorescence emitting metals such as 152Eu, or others of the lanthamide series. These metals can be attached to the antibody using such metal chelating groups as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).

[0417] The antibody also can be detectably labeled by coupling it to a chemiluminescent compound. The presence of the chemiluminescent-tagged antibody is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.

[0418] Likewise, a bioluminescent compound may be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in, which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Important bioluminescent compounds for purposes of labeling are luciferin, luciferase and aequorin.

[0419] Methods for Detecting Diseases

[0420] In general, a disease may be detected in a patient based on the presence of one or more proteins of the invention and/or polynucleotides encoding such proteins in a biological sample (for example, blood, sera, urine, and/or tumor biopsies) obtained from the patient. In other words, such proteins may be used as markers to indicate the presence or absence of a disease or disorder, including cancer and/or as described elsewhere herein. In addition, such proteins may be useful for the detection of other diseases and cancers. The binding agents provided herein generally permit detection of the level of antigen that binds to the agent in the biological sample. Polynucleotide primers and probes may be used to detect the level of mRNA encoding polypeptides of the invention, which is also indicative of the presence or absence of a disease or disorder, including cancer. In general, polypeptides of the invention should be present at a level that is at least three fold higher in diseased tissue than in normal tissue.

[0421] There are a variety of assay formats known to those of ordinary skill in the art for using a binding agent to detect polypeptide markers in a sample. See, e.g., Harlow and Lane, supra. In general, the presence or absence of a disease in a patient may be determined by (a) contacting a biological sample obtained from a patient with a binding agent; (b) detecting in the sample a level of polypeptide that binds to the binding agent; and (c) comparing the level of polypeptide with a predetermined cut-off value.

[0422] In a preferred embodiment, the assay involves the use of a binding agent(s) immobilized on a solid support to bind to and remove the polypeptide of the invention from the remainder of the sample. The bound polypeptide may then be detected using a detection reagent that contains a reporter group and specifically binds to the binding agent/polypeptide complex. Such detection reagents may comprise, for example, a binding agent that specifically binds to the polypeptide or an antibody or other agent that specifically binds to the binding agent, such as an anti-immunoglobulin, protein G, protein A or a lectin. Alternatively, a competitive assay may be utilized, in which a polypeptide is labeled with a reporter group and allowed to bind to the immobilized binding agent after incubation of the binding agent with the sample. The extent to which components of the sample inhibit the binding of the labeled polypeptide to the binding agent is indicative of the reactivity of the sample with the immobilized binding agent. Suitable polypeptides for use within such assays include polypeptides of the invention and portions thereof, or antibodies, to which the binding agent binds, as described above.

[0423] The solid support may be any material known to those of skill in the art to which polypeptides of the invention may be attached. For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane. Alternatively, the support may be a bead or disc, such as glass fiberglass, latex or a plastic material such as polystyrene or polyvinylchloride. The support may also be a magnetic particle or a fiber optic sensor, such as those disclosed, for example, in U.S. Pat. No. 5,359,681. The binding agent may be immobilized on the solid support using a variety of techniques known to those of skill in the art, which are amply described in the patent and scientific literature. In the context of the present invention, the term “immobilization” refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between the agent and functional groups on the support or may be a linkage by way of a cross-linking agent). Immobilization by adsorption to a well in a microtiter plate or to a membrane is preferred. In such cases, adsorption may be achieved by contacting the binding agent, in a suitable buffer, with the solid support for the suitable amount of time. The contact time varies with temperature, but is typically between about 1 hour and about 1 day. In general, contacting a well of plastic microtiter plate (such as polystyrene or polyvinylchloride) with an amount of binding agent ranging from about 10 ng to about 10 ug, and preferably about 100 ng to about 1 ug, is sufficient to immobilize an adequate amount of binding agent.

[0424] Covalent attachment of binding agent to a solid support may generally be achieved by first reacting the support with a bifunctional reagent that will react with both the support and a functional group, such as a hydroxyl or amino group, on the binding agent. For example, the binding agent may be covalently attached to supports having an appropriate polymer coating using benzoquinone or by condensation of an aldehyde group on the support with an amine and an active hydrogen on the binding partner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, at A12-A13).

[0425] Gene Therapy Methods

[0426] Also encompassed by the invention are gene therapy methods for treating or preventing disorders, diseases and conditions. The gene therapy methods relate to the introduction of nucleic acid (DNA, RNA and antisense DNA or RNA) sequences into an animal to achieve expression of the polypeptide of the present invention. This method requires a polynucleotide which codes for a polypeptide of the present invention operatively linked to a promoter and any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques are known in the art, see, for example, WO90/11092, which is herein incorporated by reference.

[0427] Thus, for example, cells from a patient may be engineered with a polynucleotide (DNA or RNA) comprising a promoter operably linked to a polynucleotide of the present invention ex vivo, with the engineered cells then being provided to a patient to be treated with the polypeptide of the present invention. Such methods are well-known in the art. For example, see Belldegrun, A., et al., J. Natl. Cancer Inst. 85: 207-216 (1993); Ferrantini, M. et al., Cancer Research 53: 1107-1112 (1993); Ferrantini, M. et al., J. Immunology 153: 4604-4615 (1994); Kaido, T., et al., Int. J. Cancer 60: 221-229 (1995); Ogura, H., et al., Cancer Research 50: 5102-5106 (1990); Santodonato, L., et al., Human Gene Therapy 7:1-10 (1996); Santodonato, L., et al., Gene Therapy 4:1246-1255 (1997); and Zbang, J.-F. et al., Cancer Gene Therapy 3: 31-38 (1996)), which are herein incorporated by reference. In one embodiment, the cells which are engineered are arterial cells. The arterial cells may be reintroduced into the patient through direct injection to the artery, the tissues surrounding the artery, or through catheter injection.

[0428] As discussed in more detail below, the polynucleotide constructs can be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, and the like). The polynucleotide constructs may be delivered in a pharmaceutically acceptable liquid or aqueous carrier.

[0429] In one embodiment, the polynucleotide of the present invention is delivered as a naked polynucleotide. The term “naked” polynucleotide, DNA or RNA refers to sequences that are free from any delivery vehicle that acts to assist, promote or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotide of the present invention can also be delivered in liposome formulations and lipofectin formulations and the like can be prepared by methods well known to those skilled in the art. Such methods are described, for example, in U.S. Pat. Nos. 5,593,972, 5,589,466, and 5,580,859, which are herein incorporated by reference.

[0430] The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Appropriate vectors include pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; pSVK3, pBPV, pMSG and pSVL available from Pharmacia; and pEF1/V5, pcDNA3.1, and pRc/CMV2 available from Invitrogen. Other suitable vectors will be readily apparent to the skilled artisan.

[0431] Any strong promoter known to those skilled in the art can be used for driving the expression of the polynucleotide sequence. Suitable promoters include adenoviral promoters, such as the adenoviral major late promoter; or heterologous promoters, such as the cytomegalovirus (CMV) promoter; the respiratory syncytial virus (RSV) promoter; inducible promoters, such as the MMT promoter, the metallothionein promoter; heat shock promoters; the albumin promoter; the ApoAI promoter; human globin promoters; viral thymidine kinase promoters, such as the Herpes Simplex thymidine kinase promoter; retroviral LTRs; the b-actin promoter; and human growth hormone promoters. The promoter also may be the native promoter for the polynucleotide of the present invention.

[0432] Unlike other gene therapy techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.

[0433] The polynucleotide construct can be delivered to the interstitial space of tissues within the an animal, including of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular, fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.

[0434] For the naked nucleic acid sequence injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 mg/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration.

[0435] The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked DNA constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.

[0436] The naked polynucleotides are delivered by any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, and so-called “gene guns”. These delivery methods are known in the art.

[0437] The constructs may also be delivered with delivery vehicles such as viral sequences, viral particles, liposome formulations, lipofectin, precipitating agents, etc. Such methods of delivery are known in the art.

[0438] In certain embodiments, the polynucleotide constructs are complexed in a liposome preparation. Liposomal preparations for use in the instant invention include cationic (positively charged), anionic (negatively charged) and neutral preparations. However, cationic liposomes are particularly preferred because a tight charge complex can be formed between the cationic liposome and the polyanionic nucleic acid. Cationic liposomes have been shown to mediate intracellular delivery of plasmid DNA (Felgner et al., Proc. Natl. Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporated by reference); mRNA (Malone et al., Proc. Natl. Acad. Sci. USA (1989) 86:6077-6081, which is herein incorporated by reference); and purified transcription factors (Debs et al., J. Biol. Chem. (1990) 265:10189-10192, which is herein incorporated by reference), in functional form.

[0439] Cationic liposomes are readily available. For example, N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are particularly useful and are available under the trademark Lipofectin, from GIBCO BRL, Grand Island, N.Y. (See, also, Felgner et al., Proc. Natl. Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporated by reference). Other commercially available liposomes include transfectace (DDAB/DOPE) and DOTAP/DOPE (Boehringer).

[0440] Other cationic liposomes can be prepared from readily available materials using techniques well known in the art. See, e.g. PCT Publication No. WO 90/11092 (which is herein incorporated by reference) for a description of the synthesis of DOTAP (1,2-bis(oleoyloxy)-3-(trimethylammonio)propane) liposomes. Preparation of DOTMA liposomes is explained in the literature, see, e.g., P. Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417, which is herein incorporated by reference. Similar methods can be used to prepare liposomes from other cationic lipid materials.

[0441] Similarly, anionic and neutral liposomes are readily available, such as from Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared using readily available materials. Such materials include phosphatidyl, choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with the DOTMA and DOTAP starting materials in appropriate ratios. Methods for making liposomes using these materials are well known in the art.

[0442] For example, commercially dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), and dioleoylphosphatidyl ethanolamine (DOPE) can be used in various combinations to make conventional liposomes, with or without the addition of cholesterol. Thus, for example, DOPG/DOPC vesicles can be prepared by drying 50 mg each of DOPG and DOPC under a stream of nitrogen gas into a sonication vial. The sample is placed under a vacuum pump overnight and is hydrated the following day with deionized water. The sample is then sonicated for 2 hours in a capped vial, using a Heat Systems model 350 sonicator equipped with an inverted cup (bath type) probe at the maximum setting while the bath is circulated at 15EC. Alternatively, negatively charged vesicles can be prepared without sonication to produce multilamellar vesicles or by extrusion through nucleopore membranes to produce unilamellar vesicles of discrete size. Other methods are known and available to those of skill in the art.

[0443] The liposomes can comprise multilamellar vesicles (MLVs), small unilamellar vesicles (SUVs), or large unilamellar vesicles (LUVs), with SUVs being preferred. The various liposome-nucleic acid complexes are prepared using methods well known in the art. See, e.g., Straubinger et al., Methods of Immunology (1983), 101:512-527, which is herein incorporated by reference. For example, MLVs containing nucleic acid can be prepared by depositing a thin film of phospholipid on the walls of a glass tube and subsequently hydrating with a solution of the material to be encapsulated. SUVs are prepared by extended sonication of MLVs to produce a homogeneous population of unilamellar liposomes. The material to be entrapped is added to a suspension of preformed MLVs and then sonicated. When using liposomes containing cationic lipids, the dried lipid film is resuspended in an appropriate solution such as sterile water or an isotonic buffer solution such as 10 mM Tris/NaCl, sonicated, and then the preformed liposomes are mixed directly with the DNA. The liposome and DNA form a very stable complex due to binding of the positively charged liposomes to the cationic DNA. SUVs find use with small nucleic acid fragments. LUVs are prepared by a number of methods, well known in the art. Commonly used methods include Ca2+-EDTA chelation (Papahadjopoulos et al., Biochim. Biophys. Acta (1975) 394:483; Wilson et al., Cell 17:77 (1979)); ether injection (Deamer, D. and Bangham, A., Biochim. Biophys. Acta 443:629 (1976); Ostro et al., Biochem. Biophys. Res. Commun. 76:836 (1977); Fraley et al., Proc. Natl. Acad. Sci. USA 76:3348 (1979)); detergent dialysis (Enoch, H. and Strittmatter, P., Proc. Natl. Acad. Sci. USA 76:145 (1979)); and reverse-phase evaporation (REV) (Fraley et al., J. Biol. Chem. 255:10431 (1980); Szoka, F. and Papahadjopoulos, D., Proc. Natl. Acad. Sci. USA 75:145 (1978); Schaefer-Ridder et al., Science 215:166 (1982)), which are herein incorporated by reference.

[0444] Generally, the ratio of DNA to liposomes will be from about 10:1 to about 1:10. Preferably, the ration will be from about 5:1 to about 1:5. More preferably, the ration will be about 3:1 to about 1:3. Still more preferably, the ratio will be about 1:1.

[0445] U.S. Pat. No. 5,676,954 (which is herein incorporated by reference) reports on the injection of genetic material, complexed with cationic liposomes carriers, into mice. U.S. Pat. Nos. 4,897,355, 4,946,787, 5,049,386, 5,459,127, 5,589,466, 5,693,622, 5,580,859, 5,703,055, and international publication no. WO 94/9469 (which are herein incorporated by reference) provide cationic lipids for use in transfecting DNA into cells and mammals. U.S. Pat. Nos. 5,589,466, 5,693,622, 5,580,859, 5,703,055, and international publication no. WO 94/9469 provide methods for delivering DNA-cationic lipid complexes to mammals.

[0446] In certain embodiments, cells are engineered, ex vivo or in vivo, using a retroviral particle containing RNA which comprises a sequence encoding a polypeptide of the present invention. Retroviruses from which the retroviral plasmid vectors may be derived include, but are not limited to, Moloney Murine Leukemia Virus, spleen necrosis virus, Rous sarcoma Virus, Harvey Sarcoma Virus, avian leukosis virus, gibbon ape leukemia virus, human immunodeficiency virus, Myeloproliferative Sarcoma Virus, and mammary tumor virus.

[0447] The retroviral plasmid vector is employed to transduce packaging cell lines to form producer cell lines. Examples of packaging cells which may be transfected include, but are not limited to, the PE501, PA317, R-2, R-AM, PA12, T19-14×, VT-19-17-H2, RCRE, RCRIP, GP+E-86, GP+envAm12, and DAN cell lines as described in Miller, Human Gene Therapy 1:5-14 (1990), which is incorporated herein by reference in its entirety. The vector may transduce the packaging cells through any means known in the art. Such means include, but are not limited to, electroporation, the use of liposomes, and CaPO4 precipitation. In one alternative, the retroviral plasmid vector may be encapsulated into a liposome, or coupled to a lipid, and then administered to a host.

[0448] The producer cell line generates infectious retroviral vector particles which include polynucleotide encoding a polypeptide of the present invention. Such retroviral vector particles then may be employed, to transduce eukaryotic cells, either in vitro or in vivo. The transduced eukaryotic cells will express a polypeptide of the present invention.

[0449] In certain other embodiments, cells are engineered, ex vivo or in vivo, with polynucleotide contained in an adenovirus vector. Adenovirus can be manipulated such that it encodes and expresses a polypeptide of the present invention, and at the same time is inactivated in terms of its ability to replicate in a normal lytic viral life cycle. Adenovirus expression is achieved without integration of the viral DNA into the host cell chromosome, thereby alleviating concerns about insertional mutagenesis. Furthermore, adenoviruses have been used as live enteric vaccines for many years with an excellent safety profile (Schwartz et al. Am. Rev. Respir. Dis.109:233-238 (1974)). Finally, adenovirus mediated gene transfer has been demonstrated in a number of instances including transfer of alpha-1-antitrypsin and CFTR to the lungs of cotton rats (Rosenfeld, M. A. et al. (1991) Science 252:431-434; Rosenfeld et al., (1992) Cell 68:143-155). Furthermore, extensive studies to attempt to establish adenovirus as a causative agent in human cancer were uniformly negative (Green, M. et al. (1979) Proc. Natl. Acad. Sci. USA 76:6606).

[0450] Suitable adenoviral vectors useful in the present invention are described, for example, in Kozarsky and Wilson, Curr. Opin. Genet. Devel. 3:499-503 (1993); Rosenfeld et al., Cell 68:143-155 (1992); Engelhardt et al., Human Genet. Ther. 4:759-769 (1993); Yang et al., Nature Genet. 7:362-369 (1994); Wilson et al., Nature 365:691-692 (1993); and U.S. Pat. No. 5,652,224, which are herein incorporated by reference. For example, the adenovirus vector Ad2 is useful and can be grown in human 293 cells. These cells contain the E1 region of adenovirus and constitutively express E1a and E1b, which complement the defective adenoviruses by providing the products of the genes deleted from the vector. In addition to Ad2, other varieties of adenovirus (e.g., Ad3, Ad5, and Ad7) are also useful in the present invention.

[0451] Preferably, the adenoviruses used in the present invention are replication deficient. Replication deficient adenoviruses require the aid of a helper virus and/or packaging cell line to form infectious particles. The resulting virus is capable of infecting cells and can express a polynucleotide of interest which is operably linked to a promoter, but cannot replicate in most cells. Replication deficient adenoviruses may be deleted in one or more of all or a portion of the following genes: E1a, E1b, E3, E4, E2a, or L1 through L5.

[0452] In certain other embodiments, the cells are engineered, ex vivo or in vivo, using an adeno-associated virus (AAV). AAVs are naturally occurring defective viruses that require helper viruses to produce infectious particles (Muzyczka, N., Curr. Topics in Microbiol. immunol. 158:97 (1992)). It is also one of the few viruses that may integrate its DNA into non-dividing cells. Vectors containing as little as 300 base pairs of AAV can be packaged and can integrate, but space for exogenous DNA is limited to about 4.5 kb. Methods for producing and using such AAVs are known in the art. See, for example, U.S. Pat. Nos. 5,139,941, 5,173,414, 5,354,678, 5,436,146, 5,474,935, 5,478,745, and 5,589,377.

[0453] For example, an appropriate AAV vector for use in the present invention will include all the sequences necessary for DNA replication, encapsidation, and host-cell integration. The polynucleotide construct is inserted into the AAV vector using standard cloning methods, such as those found in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press (1989). The recombinant AAV vector is then transfected into packaging cells which are infected with a helper virus, using any standard technique, including lipofection, electroporation, calcium phosphate precipitation, etc. Appropriate helper viruses include adenoviruses, cytomegaloviruses, vaccinia viruses, or herpes viruses. Once the packaging cells are transfected and infected, they will produce infectious AAV viral particles which contain the polynucleotide construct. These viral particles are then used to transduce eukaryotic cells, either ex vivo or in vivo. The transduced cells will contain the polynucleotide construct integrated into its genome, and will express a polypeptide of the invention.

[0454] Another method of gene therapy involves operably associating heterologous control regions and endogenous polynucleotide sequences (e.g. encoding a polypeptide of the present invention) via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication No. WO 96/29411, published Sep. 26, 1996; International Publication No. WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), which are herein encorporated by reference. This method involves the activation of a gene which is present in the target cells, but which is not normally expressed in the cells, or is expressed at a lower level than desired.

[0455] Polynucleotide constructs are made, using standard techniques known in the art, which contain the promoter with targeting sequences flanking the promoter. Suitable promoters are described herein. The targeting sequence is sufficiently complementary to an endogenous sequence to permit homologous recombination of the promoter-targeting sequence with the endogenous sequence. The targeting sequence will be sufficiently near the 5′ end of the desired endogenous polynucleotide sequence so the promoter will be operably linked to the endogenous sequence upon homologous recombination.

[0456] The promoter and the targeting sequences can be amplified using PCR. Preferably, the amplified promoter contains distinct restriction enzyme sites on the 5′ and 3′ ends. Preferably, the 3′ end of the first targeting sequence contains the same restriction enzyme site as the 5′ end of the amplified promoter and the 5′ end of the second targeting sequence contains the same restriction site as the 3′ end of the amplified promoter. The amplified promoter and targeting sequences are digested and ligated together.

[0457] The promoter-targeting sequence construct is delivered to the cells, either as naked polynucleotide, or in conjunction with transfection-facilitating agents, such as liposomes, viral sequences, viral particles, whole viruses, lipofection, precipitating agents, etc., described in more detail above. The P promoter-targeting sequence can be delivered by any method, included direct needle injection, intravenous injection, topical administration, catheter infusion, particle accelerators, etc. The methods are described in more detail below.

[0458] The promoter-targeting sequence construct is taken up by cells. Homologous recombination between the construct and the endogenous sequence takes place, such that an endogenous sequence is placed under the control of the promoter. The promoter then drives the expression of the endogenous sequence.

[0459] The polynucleotide encoding a polypeptide of the present invention may contain a secretory signal sequence that facilitates secretion of the protein. Typically, the signal sequence is positioned in the coding region of the polynucleotide to be expressed towards or at the 5′ end of the coding region. The signal sequence may be homologous or heterologous to the polynucleotide of interest and may be homologous or heterologous to the cells to be transfected. Additionally, the signal sequence may be chemically synthesized using methods known in the art.

[0460] Any mode of administration of any of the above-described polynucleotides constructs can be used so long as the mode results in the expression of one or more molecules in an amount sufficient to provide a therapeutic effect. This includes direct needle injection, systemic injection, catheter infusion, biolistic injectors, particle accelerators (i.e., “gene guns”), gelfoam sponge depots, other commercially available depot materials, osmotic pumps (e.g., Alza minipumps), oral or suppositorial solid (tablet or pill) pharmaceutical formulations, and decanting or topical applications during surgery. For example, direct injection of naked calcium phosphate-precipitated plasmid into rat liver and rat spleen or a protein-coated plasmid into the portal vein has resulted in gene expression of the foreign gene in the rat livers (Kaneda et al., Science 243:375 (1989)).

[0461] A preferred method of local administration is by direct injection. Preferably, a recombinant molecule of the present invention complexed with a delivery vehicle is administered by direct injection into or locally within the area of arteries. Administration of a composition locally within the area of arteries refers to injecting the composition centimeters and preferably, millimeters within arteries.

[0462] Another method of local administration is to contact a polynucleotide construct of the present invention in or around a surgical wound. For example, a patient can undergo surgery and the polynucleotide construct can be coated on the surface of tissue inside the wound or the construct can be injected into areas of tissue inside the wound.

[0463] Therapeutic compositions useful in systemic administration, include recombinant molecules of the present invention complexed to a targeted delivery vehicle of the present invention. Suitable delivery vehicles for use with systemic administration comprise liposomes comprising ligands for targeting the vehicle to a particular site. In specific embodiments, suitable delivery vehicles for use with systemic administration comprise liposomes comprising polypeptides of the invention for targeting the vehicle to a particular site.

[0464] Preferred methods of systemic administration, include intravenous injection, aerosol, oral and percutaneous (topical) delivery. Intravenous injections can be performed using methods standard in the art. Aerosol delivery can also be performed using methods standard in the art (see, for example, Stribling et al., Proc. Natl. Acad. Sci. USA 189:11277-11281, 1992, which is incorporated herein by reference). Oral delivery can be performed by complexing a polynucleotide construct of the present invention to a carrier capable of withstanding degradation by digestive enzymes in the gut of an animal. Examples of such carriers, include plastic capsules or tablets, such as those known in the art. Topical delivery can be performed by mixing a polynucleotide construct of the present invention with a lipophilic reagent (e.g., DMSO) that is capable of passing into the skin.

[0465] Determining an effective amount of substance to be delivered can depend upon a number of factors including, for example, the chemical structure and biological activity of the substance, the age and weight of the animal, the precise condition requiring treatment and its severity, and the route of administration. The frequency of treatments depends upon a number of factors, such as the amount of polynucleotide constructs administered per dose, as well as the health and history of the subject. The precise amount, number of doses, and timing of doses will be determined by the attending physician or veterinarian.

[0466] Therapeutic compositions of the present invention can be administered to any animal, preferably to mammals and birds. Preferred mammals include humans, dogs, cats, mice, rats, rabbits sheep, cattle, horses and pigs, with humans being particularly preferred.

[0467] Biological Activities

[0468] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, can be used in assays to test for one or more biological activities. If these polynucleotides or polypeptides, or agonists or antagonists of the present invention, do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides and polypeptides, and agonists or antagonists could be used to treat the associated disease.

[0469] Nervous system-associated proteins are believed to be involved in biological activities associated with nervous system functions. Accordingly, compositions of the invention (including polynucleotides, polypeptides and antibodies of the invention, and fragments and variants thereof) may be used in the diagnosis, prognosis, prevention, and/or treatment of diseases and/or disorders associated with inappropriate nervous system activity.

[0470] In preferred embodiments, compositions of the invention (including polynucleotides, polypeptides and antibodies of the invention, and fragments and variants thereof) may be used in the diagnosis, prognosis, prevention, and/or treatment of diseases and/or disorders relating to the nervous system, including, for example, cerebrovascular disorders (e.g., stroke, cerebral aneurysm, and/or as described below under “Cardiovascular Disorders” and “Neural Activity and Neurological Diseases”), metabolic brain diseases (e.g., Hartnup disease, hepatic encephalopathy, phenylketonuria, pyruvate carboxylase deficiency, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), neuromuscular disorders (e.g., amyotrophic lateral sclerosis, muscular dystrophy, myotonia atrophica, familial periodic paralysis, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), nervous system infections (e.g., AIDS dementia complex, encephalitis, meningitis, cerebral malaria, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), demyelinating diseases (e.g., multiple sclerosis, Canavan disease, metachromatic eukodystrophy, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), nervous system neoplasms (e.g., cerebellar neoplasms, infratenorial neoplasms, supratentorial neoplasms, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), spinal cord diseases (e.g., spinal muscular atrophy, Werdnig-Hoffmann disease, myelitis, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), developmental nervous system abnormalities (e.g., spinal dysraphism, neural tube defects, holoprosencephaly, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), neurologic manifestations (agnosia, dyslexia, hallucinations, ataxia, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), diseases of the peripheral nervous system (e.g., cranial nerve diseases, facial nerve disease, optic nerve diseases, and/or as described below in the section entitled “Neural Activity and Neurological Diseases”), inflammatory disorders of the nervous system (e.g., encephalitis, meningitis, and/or those described under “Immune Activity” and “Neural Activity and Neurological Diseases” below), and others described below in the section entitled “Neural Activity and Neurological Diseases”.

[0471] In another preferred embodiment, compositions of the invention (including polynucleotides, polypeptides and antibodies of the invention, and fragments and variants thereof) may be used in the diagnosis, prognosis, prevention, and/or treatment of traumatic injury to the nervous system (e.g., traumatic head injury, spinal cord injury, peripheral nerve damage, and/or as described in the section entitled “Neural Activity and Neurological Diseases”).

[0472] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose, prognose, prevent, and/or treat neurological disorders or injuries associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).

[0473] Thus, polynucleotides, translation products and antibodies of the invention are useful in the diagnosis, detection and/or treatment of diseases and/or disorders associated with activities that include, but are not limited to, neuromuscular disorders, infections of the nervous system, demyelinating diseases, cerebrovascular disorders, nervous system neoplasms, spinal cord diseases, inflammatory disorders of the nervous system, traumatic injury, nervous system abnormalities, neurologic manifestations, diseases of the peripheral nervous system, and metabolic brain diseases.

[0474] More generally, polynucleotides, translation products and antibodies corresponding to this gene may be useful for the diagnosis, detection and/or treatment of diseases and/or disorders associated with the following systems.

[0475] Neural Activity and Neurological Diseases

[0476] The polynucleotides, polypeptides and agonists or antagonists of the invention may be used for the diagnosis and/or treatment of diseases, disorders, damage or injury of the brain and/or nervous system. Nervous system disorders that can be treated with the compositions of the invention (e.g., polypeptides, polynucleotides, and/or agonists or antagonists), include, but are not limited to, nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the methods of the invention, include but are not limited to, the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems: (1) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia; (2) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries; (3) malignant lesions, in which a portion of the nervous system is destroyed or injured by malignant tissue which is either a nervous system associated malignancy or a malignancy derived from non-nervous system tissue; (4) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, or syphilis; (5) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to, degeneration associated with Parkinson's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis (ALS); (6) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including, but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration; (7) neurological lesions associated with systemic diseases including, but not limited to, diabetes (diabetic neuropathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis; (8) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and (9) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including, but not limited to, multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myclopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.

[0477] In one embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to protect neural cells from the damaging effects of hypoxia. In a further preferred embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to protect neural cells from the damaging effects of cerebral hypoxia. According to this embodiment, the compositions of the invention are used to treat or prevent neural cell injury associated with cerebral hypoxia. In one non-exclusive aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention, are used to treat or prevent neural cell injury associated with cerebral ischemia. In another non-exclusive aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent neural cell injury associated with cerebral infarction.

[0478] In another preferred embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent neural cell injury associated with a stroke. In a specific embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent cerebral neural cell injury associated with a stroke.

[0479] In another preferred embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent neural cell injury associated with a heart attack. In a specific embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent cerebral neural cell injury associated with a heart attack.

[0480] The compositions of the invention which are useful for treating or preventing a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, compositions of the invention which elicit any of the following effects may be useful according to the invention: (1) increased survival time of neurons in culture either in the presence or absence of hypoxia or hypoxic conditions; (2) increased sprouting of neurons in culture or in vivo; (3) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (4) decreased symptoms of neuron dysfunction in vivo. Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased survival of neurons may routinely be measured using a method set forth herein or otherwise known in the art, such as, for example, in Zhang et al., Proc Natl Acad Sci USA 97:3637-42 (2000) or in Arakawa et al., J. Neurosci., 10:3507-15 (1990); increased sprouting of neurons may be detected by methods known in the art, such as, for example, the methods set forth in Pestronk et al., Exp. Neurol., 70:65-82 (1980), or Brown et al, Ann. Rev. Neurosci., 4:17-42 (1981); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., using techniques known in the art and depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.

[0481] In specific embodiments, motor neuron disorders that may be treated according to the invention include, but are not limited to, disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including, but not limited to, progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).

[0482] Further, polypeptides or polynucleotides of the invention may play a role in neuronal survival; synapse formation; conductance; neural differentiation, etc. Thus, compositions of the invention (including polynucleotides, polypeptides, and agonists or antagonists) may be used to diagnose and/or treat or prevent diseases or disorders associated with these roles, including, but not limited to, learning and/or cognition disorders. The compositions of the invention may also be useful in the treatment or prevention of neurodegenerative disease states and/or behavioural disorders. Such neurodegenerative disease states and/or behavioral disorders include, but are not limited to, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, compositions of the invention may also play a role in the treatment, prevention and/or detection of developmental disorders associated with the developing embryo, or sexually-linked disorders.

[0483] Additionally, polypeptides, polynucleotides and/or agonists or antagonists of the invention, may be useful in protecting neural cells from diseases, damage, disorders, or injury, associated with cerebrovascular disorders including, but not limited to, carotid artery diseases (e.g., carotid artery thrombosis, carotid stenosis, or Moyamoya Disease), cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arterioyenous malformations, cerebral artery diseases, cerebral embolism and thrombosis (e.g., carotid artery thrombosis, sinus thrombosis, or Wallenberg's Syndrome), cerebral hemorrhage (e.g., epidural or subdural hematoma, or subarachnoid hemorrhage), cerebral infarction, cerebral ischemia (e.g., transient cerebral ischemia, Subclavian Steal Syndrome, or vertebrobasilar insufficiency), vascular dementia (e.g., multi-infarct), leukomalacia, periventricular, and vascular headache (e.g., cluster headache or migraines).

[0484] In accordance with yet a further aspect of the present invention, there is provided a process for utilizing polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, for therapeutic purposes, for example, to stimulate neurological cell proliferation and/or differentiation. Therefore, polynucleotides, polypeptides, agonists and/or antagonists of the invention may be used to treat and/or detect neurologic diseases. Moreover, polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used as a marker or detector of a particular nervous system disease or disorder.

[0485] Examples of neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include brain diseases, such as metabolic brain diseases which includes phenylketonuria such as maternal phenylketonuria, pyruvate carboxylase deficiency, pyruvate dehydrogenase complex deficiency, Wernicke's Encephalopathy, brain edema, brain neoplasms such as cerebellar neoplasms which include infratentorial neoplasms, cerebral ventricle neoplasms such as choroid plexus neoplasms, hypothalamic neoplasms, supratentorial neoplasms, canavan disease, cerebellar diseases such as cerebellar ataxia which include spinocerebellar degeneration such as ataxia telangiectasia, cerebellar dyssynergia, Friederich's Ataxia, Machado-Joseph Disease, olivopontocerebellar atrophy, cerebellar neoplasms such as infratentorial neoplasms, diffuse cerebral sclerosis such as encephalitis periaxialis, globoid cell leukodystrophy, metachromatic leukodystrophy and subacute sclerosing panencephalitis.

[0486] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include cerebrovascular disorders (such as carotid artery diseases which include carotid artery thrombosis, carotid stenosis and Moyamoya Disease), cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arterioyenous malformations, cerebral artery diseases, cerebral embolism and thrombosis such as carotid artery thrombosis, sinus thrombosis and Wallenberg's Syndrome, cerebral hemorrhage such as epidural hematoma, subdural hematoma and subarachnoid hemorrhage, cerebral infarction, cerebral ischemia such as transient cerebral ischemia, Subclavian Steal Syndrome and vertebrobasilar insufficiency, vascular dementia such as multi-infarct dementia, periventricular leukomalacia, vascular headache such as cluster headache and migraine.

[0487] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include dementia such as AIDS Dementia Complex, presenile dementia such as Alzheimer's Disease and Creutzfeldt-Jakob Syndrome, senile dementia such as Alzheimer's Disease and progressive supranuclear palsy, vascular dementia such as multi-infarct dementia, encephalitis which include encephalitis periaxialis, viral encephalitis such as epidemic encephalitis, Japanese Encephalitis, St. Louis Encephalitis, tick-borne encephalitis and West Nile Fever, acute disseminated encephalomyelitis, meningoencephalitis such as uveomeningoencephalitic syndrome, Postencephalitic Parkinson Disease and subacute sclerosing panencephalitis, encephalomalacia such as periventricular leukomalacia, epilepsy such as generalized epilepsy which includes infantile spasms, absence epilepsy, myoclonic epilepsy which includes MERRF Syndrome, tonic-clonic epilepsy, partial epilepsy such as complex partial epilepsy, frontal lobe epilepsy and temporal lobe epilepsy, post-traumatic epilepsy, status epilepticus such as Epilepsia Partialis Continua, and Hallervorden-Spatz Syndrome.

[0488] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include hydrocephalus such as Dandy-Walker Syndrome and normal pressure hydrocephalus, hypothalamic diseases such as hypothalamic neoplasms, cerebral malaria, narcolepsy which includes cataplexy, bulbar poliomyelitis, cerebri pseudotumor, Rett Syndrome, Reye's Syndrome, thalamic diseases, cerebral toxoplasmosis, intracranial tuberculoma and Zellweger Syndrome, central nervous system infections such as AIDS Dementia Complex, Brain Abscess, subdural empyema, encephalomyelitis such as Equine Encephalomyelitis, Venezuelan Equine Encephalomyelitis, Necrotizing Hemorrhagic Encephalomyelitis, Visna, and cerebral malaria.

[0489] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include meningitis such as arachnoiditis, aseptic meningtitis such as viral meningtitis which includes lymphocytic choriomeningitis, Bacterial meningtitis which includes Haemophilus Meningtitis, Listeria Meningtitis, Meningococcal Meningtitis such as Waterhouse-Friderichsen Syndrome, Pneumococcal Meningtitis and meningeal tuberculosis, fungal meningitis such as Cryptococcal Meningtitis, subdural effusion, meningoencephalitis such as uvemeningoencephalitic syndrome, myelitis such as transverse myelitis, neurosyphilis such as tabes dorsalis, poliomyelitis which includes bulbar poliomyelitis and postpoliomyelitis syndrome, prion diseases (such as Creutzfeldt-Jakob Syndrome, Bovine Spongiform Encephalopathy, Gerstmann-Straussler Syndrome, Kuru, Scrapie), and cerebral toxoplasmosis.

[0490] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include central nervous system neoplasms such as brain neoplasms that include cerebellar neoplasms such as infratentorial neoplasms, cerebral ventricle neoplasms such as choroid plexus neoplasms, hypothalamic neoplasms and supratentorial neoplasms, meningeal neoplasms, spinal cord neoplasms which include epidural neoplasms, demyelinating diseases such as Canavan Diseases, diffuse cerebral sceloris which includes adrenoleukodystrophy, encephalitis periaxialis, globoid cell leukodystrophy, diffuse cerebral sclerosis such as metachromatic leukodystrophy, allergic encephalomyelitis, necrotizing hemorrhagic encephalomyelitis, progressive multifocal leukoencephalopathy, multiple sclerosis, central pontine myelinolysis, transverse myelitis, neuromyelitis optica, Scrapie, Swayback, Chronic Fatigue Syndrome, Visna, High Pressure Nervous Syndrome, Meningism, spinal cord diseases such as amyotonia congenita, amyotrophic lateral sclerosis, spinal muscular atrophy such as Werdnig-Hoffmann Disease, spinal cord compression, spinal cord neoplasms such as epidural neoplasms, syringomyelia, Tabes Dorsalis, Stiff-Man Syndrome, mental retardation such as Angelman Syndrome, Cri-du-Chat Syndrome, De Lange's Syndrome, Down Syndrome, Gangliosidoses such as gangliosidoses G(M1), Sandhoff Disease, Tay-Sachs Disease, Hartnup Disease, homocystinuria, Laurence-Moon-Biedl Syndrome, Lesch-Nyhan Syndrome, Maple Syrup Urine Disease, mucolipidosis such as fucosidosis, neuronal ceroid-lipofuscinosis, oculocerebrorenal syndrome, phenylketonuria such as maternal phenylketonuria, Prader-Willi Syndrome, Rett Syndrome, Rubinstein-Taybi Syndrome, Tuberous Sclerosis, WAGR Syndrome, nervous system abnormalities such as holoprosencephaly, neural tube defects such as anencephaly which includes hydrangencephaly, Arnold-Chairi Deformity, encephalocele, meningocele, meningomyelocele, spinal dysraphism such as spina bifida cystica and spina bifida occulta.

[0491] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include hereditary motor and sensory neuropathies which include Charcot-Marie Disease, Hereditary optic atrophy, Refsum's Disease, hereditary spastic paraplegia, Werdnig-Hoffmann Disease, Hereditary Sensory and Autonomic Neuropathies such as Congenital Analgesia and Familial Dysautonomia, Neurologic manifestations (such as agnosia that include Gerstmann's Syndrome, Amnesia such as retrograde amnesia, apraxia, neurogenic bladder, cataplexy, communicative disorders such as hearing disorders that includes deafness, partial hearing loss, loudness recruitment and tinnitus, language disorders such as aphasia which include agraphia, anomia, broca aphasia, and Wernicke Aphasia, Dyslexia such as Acquired Dyslexia, language development disorders, speech disorders such as aphasia which includes anomia, broca aphasia and Wernicke Aphasia, articulation disorders, communicative disorders such as speech disorders which include dysarthria, echolalia, mutism and stuttering, voice disorders such as aphonia and hoarseness, decerebrate state, delirium, fasciculation, hallucinations, meningism, movement disorders such as angelman syndrome, ataxia, athetosis, chorea, dystonia, hypokinesia, muscle hypotonia, myoclonus, tic, torticollis and tremor, muscle hypertonia such as muscle rigidity such as stiff-man syndrome, muscle spasticity, paralysis such as facial paralysis which includes Herpes Zoster Oticus, Gastroparesis, Hemiplegia, ophthalmoplegia such as diplopia, Duane's Syndrome, Horner's Syndrome, Chronic progressive external ophthalmoplegia such as Kearns Syndrome, Bulbar Paralysis, Tropical Spastic Paraparesis, Paraplegia such as Brown-Sequard Syndrome, quadriplegia, respiratory paralysis and vocal cord paralysis, paresis, phantom limb, taste disorders such as ageusia and dysgeusia, vision disorders such as amblyopia, blindness, color vision defects, diplopia, hemianopsia, scotoma and subnormal vision, sleep disorders such as hypersomnia which includes Kleine-Levin Syndrome, insomnia, and somnambulism, spasm such as trismus, unconsciousness such as coma, persistent vegetative state and syncope and vertigo, neuromuscular diseases such as amyotonia congenita, amyotrophic lateral sclerosis, Lambert-Eaton Myasthenic Syndrome, motor neuron disease, muscular atrophy such as spinal muscular atrophy, Charcot-Marie Disease and Werdnig-Hoffmann Disease, Postpoliomyelitis Syndrome, Muscular Dystrophy, Myasthenia Gravis, Myotonia Atrophica, Myotonia Confenita, Nemaline Myopathy, Familial Periodic Paralysis, Multiplex Paramyloclonus, Tropical Spastic Paraparesis and Stiff-Man Syndrome, peripheral nervous system diseases such as acrodynia, amyloid neuropathies, autonomic nervous system diseases such as Adie's Syndrome, Barre-Lieou Syndrome, Familial Dysautonomia, Homer's Syndrome, Reflex Sympathetic Dystrophy and Shy-Drager Syndrome, Cranial Nerve Diseases such as Acoustic Nerve Diseases such as Acoustic Neuroma which includes Neurofibromatosis 2, Facial Nerve Diseases such as Facial Neuralgia, Melkersson-Rosenthal Syndrome, ocular motility disorders which includes amblyopia, nystagmus, oculomotor nerve paralysis, ophthalmoplegia such as Duane's Syndrome, Homer's Syndrome, Chronic Progressive External Ophthalmoplegia which includes Kearns Syndrome, Strabismus such as Esotropia and Exotropia, Oculomotor Nerve Paralysis, Optic Nerve Diseases such as Optic Atrophy which includes Hereditary Optic Atrophy, Optic Disk Drusen, Optic Neuritis such as Neuromyclitis Optica, Papilledema, Trigeminal Neuralgia, Vocal Cord Paralysis, Demyelinating Diseases such as Neuromyelitis Optica and Swayback, and Diabetic neuropathies such as diabetic foot.

[0492] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include nerve compression syndromes such as carpal tunnel syndrome, tarsal tunnel syndrome, thoracic outlet syndrome such as cervical rib syndrome, ulnar nerve compression syndrome, neuralgia such as causalgia, cervico-brachial neuralgia, facial neuralgia and trigeminal neuralgia, neuritis such as experimental allergic neuritis, optic neuritis, polyneuritis, polyradiculoneuritis and radiculities such as polyradiculitis, hereditary motor and sensory neuropathies such as Charcot-Marie Disease, Hereditary Optic Atrophy, Refsum's Disease, Hereditary Spastic Paraplegia and Werdnig-Hoffmann Disease, Hereditary Sensory and Autonomic Neuropathies which include Congenital Analgesia and Familial Dysautonomia, POEMS Syndrome, Sciatica, Gustatory Sweating and Tetany).

[0493] Immune Activity

[0494] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, diagnosing and/or prognosing diseases, disorders, and/or conditions of the immune system, by, for example, activating or inhibiting the proliferation, differentiation, or mobilization (chemotaxis) of immune cells. Immune cells develop through a process called hematopoiesis, producing myeloid (platelets, red blood cells, neutrophils, and macrophages) and lymphoid (B and T lymphocytes) cells from pluripotent stem cells. The etiology of these immune diseases, disorders, and/or conditions may be genetic, somatic, such as cancer and some autoimmune diseases, acquired (e.g., by chemotherapy or toxins), or infectious. Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention can be used as a marker or detector of a particular immune system disease or disorder.

[0495] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to treat diseases and disorders of the immune system and/or to inhibit or enhance an immune response generated by cells associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).

[0496] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, diagnosing, and/or prognosing immunodeficiencies, including both congenital and acquired immunodeficiencies. Examples of B cell immunodeficiencies in which immunoglobulin levels B cell function and/or B cell numbers are decreased include: X-linked agammaglobulinemia (Bruton's disease), X-linked infantile agammaglobulinemia, X-linked immunodeficiency with hyper IgM, non X-linked immunodeficiency with hyper IgM, X-linked lymphoproliferative syndrome (XLP), agammaglobulinemia including congenital and acquired agammaglobulinemia, adult onset agammaglobulinemia, late-onset agammaglobulinemia, dysgammaglobulinemia, hypogammaglobulinemia, unspecified hypogammaglobulinemia, recessive agammaglobulinemia (Swiss type), Selective IgM deficiency, selective IgA deficiency, selective IgG subclass deficiencies, IgG subclass deficiency (with or without IgA deficiency), Ig deficiency with increased IgM, IgG and IgA deficiency with increased IgM, antibody deficiency with normal or elevated Igs, Ig heavy chain deletions, kappa chain deficiency, B cell lymphoproliferative disorder (BLPD), common variable immunodeficiency (CVID), common variable immunodeficiency (CVI) (acquired), and transient hypogammaglobulinemia of infancy.

[0497] In specific embodiments, ataxia-telangiectasia or conditions associated with ataxia-telangiectasia are treated, prevented, diagnosed, and/or prognosing using the polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof.

[0498] Examples of congenital immunodeficiencies in which T cell and/or B cell function and/or number is decreased include, but are not limited to: DiGeorge anomaly, severe combined immunodeficiencies (SCID) (including, but not limited to, X-linked SCID, autosomal recessive SCID, adenosine deaminase deficiency, purine nucleoside phosphorylase (PNP) deficiency, Class II MHC deficiency (Bare lymphocyte syndrome), Wiskott-Aldrich syndrome, and ataxia telangiectasia), thymic hypoplasia, third and fourth pharyngeal pouch syndrome, 22q11.2 deletion, chronic mucocutaneous candidiasis, natural killer cell deficiency (NK), idiopathic CD4+ T-lymphocytopenia, immunodeficiency with predominant T cell defect (unspecified), and unspecified immunodeficiency of cell mediated immunity.

[0499] In specific embodiments, DiGeorge anomaly or conditions associated with DiGeorge anomaly are treated, prevented, diagnosed, and/or prognosed using polypeptides or polynucleotides of the invention, or antagonists or agonists thereof.

[0500] Other immunodeficiencies that may be treated, prevented, diagnosed, and/or prognosed using polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof, include, but are not limited to, chronic granulomatous disease, Chédiak-Higashi syndrome, myeloperoxidase deficiency, leukocyte glucose-6-phosphate dehydrogenase deficiency, X-linked lymphoproliferative syndrome (XLP), leukocyte adhesion deficiency, complement component deficiencies (including C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 deficiencies), reticular dysgenesis, thymic alymphoplasia-aplasia, immunodeficiency with thymoma, severe congenital leukopenia, dysplasia with immunodeficiency, neonatal neutropenia, short limbed dwarfism, and Nezelof syndrome-combined immunodeficiency with Igs.

[0501] In a preferred embodiment, the immunodeficiencies and/or conditions associated with the immunodeficiencies recited above are treated, prevented, diagnosed and/or prognosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

[0502] In a preferred embodiment polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used as an agent to boost immunoresponsiveness among immunodeficient individuals. In specific embodiments, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used as an agent to boost immunoresponsiveness among B cell and/or T cell immunodeficient individuals.

[0503] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, diagnosing and/or prognosing autoimmune disorders. Many autoimmune disorders result from inappropriate recognition of self as foreign material by immune cells. This inappropriate recognition results in an immune response leading to the destruction of the host tissue. Therefore, the administration of polynucleotides and polypeptides of the invention that can inhibit an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing autoimmune disorders.

[0504] Autoimmune diseases or disorders that may be treated, prevented, diagnosed and/or prognosed by polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, one or more of the following: systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, autoimmune thyroiditis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, hemolytic anemia, thrombocytopenia, autoimmune thrombocytopenia purpura, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenia purpura, purpura (e.g., Henloch-Scoenlein purpura), autoimmunocytopenia, Goodpasture's syndrome, Pemphigus vulgaris, myasthenia gravis, Grave's disease (hyperthyroidism), and insulin-resistant diabetes mellitus.

[0505] Additional disorders that are likely to have an autoimmune component that may be treated, prevented, and/or diagnosed with the compositions of the invention include, but are not limited to, type II collagen-induced arthritis, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, relapsing polychondritis, rheumatic heart disease, neuritis, uveitis ophthalmia, polyendocrinopathies, Reiter's Disease, Stiff-Man Syndrome, autoimmune pulmonary inflammation, autism, Guillain-Barre Syndrome, insulin dependent diabetes mellitus, and autoimmune inflammatory eye disorders.

[0506] Additional disorders that are likely to have an autoimmune component that may be treated, prevented, diagnosed and/or prognosed with the compositions of the invention include, but are not limited to, scleroderma with anti-collagen antibodies (often characterized, e.g., by nucleolar and other nuclear antibodies), mixed connective tissue disease (often characterized, e.g., by antibodies to extractable nuclear antigens (e.g., ribonucleoprotein)), polymyositis (often characterized, e.g., by nonhistone ANA), pernicious anemia (often characterized, e.g., by antiparietal cell, microsomes, and intrinsic factor antibodies), idiopathic Addison's disease (often characterized, e.g., by humoral and cell-mediated adrenal cytotoxicity, infertility (often characterized, e.g., by antispermatozoal antibodies), glomerulonephritis (often characterized, e.g., by glomerular basement membrane antibodies or immune complexes), bullous pemphigoid (often characterized, e.g., by IgG and complement in basement membrane), Sjogren's syndrome (often characterized, e.g., by multiple tissue antibodies, and/or a specific nonhistone ANA (SS-B)), diabetes mellitus (often characterized, e.g., by cell-mediated and humoral islet cell antibodies), and adrenergic drug resistance (including adrenergic drug resistance with asthma or cystic fibrosis) (often characterized, e.g., by beta-adrenergic receptor antibodies).

[0507] Additional disorders that may have an autoimmune component that may be treated, prevented, diagnosed and/or prognosed with the compositions of the invention include, but are not limited to, chronic active hepatitis (often characterized, e.g., by smooth muscle antibodies), primary biliary cirrhosis (often characterized, e.g., by mitochondria antibodies), other endocrine gland failure (often characterized, e.g., by specific tissue antibodies in some cases), vitiligo (often characterized, e.g., by melanocyte antibodies), vasculitis (often characterized, e.g., by Ig and complement in vessel walls and/or low serum complement), post-MI (often characterized, e.g., by myocardial antibodies), cardiotomy syndrome (often characterized, e.g., by myocardial antibodies), urticaria (often characterized, e.g., by IgG and IgM antibodies to IgE), atopic dermatitis (often characterized, e.g., by IgG and IgM antibodies to IgE), asthma (often characterized, e.g., by IgG and IgM antibodies to IgE), and many other inflammatory, granulomatous, degenerative, and atrophic disorders.

[0508] In a preferred embodiment, the autoimmune diseases and disorders and/or conditions associated with the diseases and disorders recited above are treated, prevented, diagnosed and/or prognosed using for example, antagonists or agonists, polypeptides or polynucleotides, or antibodies of the present invention. In a specific preferred embodiment, rheumatoid arthritis is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

[0509] In another specific preferred embodiment, systemic lupus erythematosus is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention. In another specific preferred embodiment, idiopathic thrombocytopenia purpura is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

[0510] In another specific preferred embodiment IgA nephropathy is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

[0511] In a preferred embodiment, the autoimmune diseases and disorders and/or conditions associated with the diseases and disorders recited above are treated, prevented, diagnosed and/or prognosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention

[0512] In preferred embodiments, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a immunosuppressive agent(s).

[0513] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, prognosing, and/or diagnosing diseases, disorders, and/or conditions of hematopoietic cells. Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat or prevent those diseases, disorders, and/or conditions associated with a decrease in certain (or many) types hematopoietic cells, including but not limited to, leukopenia, neutropenia, anemia, and thrombocytopenia. Alternatively, Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat or prevent those diseases, disorders, and/or conditions associated with an increase in certain (or many) types of hematopoietic cells, including but not limited to, histiocytosis.

[0514] Allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems, may also be treated, prevented, diagnosed and/or prognosed using polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof. Moreover, these molecules can be used to treat, prevent, prognose, and/or diagnose anaphylaxis, hypersensitivity to an antigenic molecule, or blood group incompatibility.

[0515] Additionally, polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof, may be used to treat, prevent, diagnose and/or prognose IgE-mediated allergic reactions. Such allergic reactions include, but are not limited to, asthma, rhinitis, and eczema. In specific embodiments, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate IgE concentrations in vitro or in vivo.

[0516] Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention have uses in the diagnosis, prognosis, prevention, and/or treatment of inflammatory conditions. For example, since polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists of the invention may inhibit the activation, proliferation and/or differentiation of cells involved in an inflammatory response, these molecules can be used to prevent and/or treat chronic and acute inflammatory conditions. Such inflammatory conditions include, but are not limited to, for example, inflammation associated with infection (e.g., septic shock, sepsis, or systemic inflammatory response syndrome), ischemia-reperfusion injury, endotoxin lethality, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine induced lung injury, inflammatory bowel disease, Crohn's disease, over production of cytokines (e.g., TNF or IL-1.), respiratory disorders (e.g., asthma and allergy); gastrointestinal disorders (e.g., inflammatory bowel disease); cancers (e.g., gastric, ovarian, lung, bladder, liver, and breast); CNS disorders (e.g., multiple sclerosis; ischemic brain injury and/or stroke, traumatic brain injury, neurodegenerative disorders (e.g., Parkinson's disease and Alzheimer's disease); AIDS-related dementia; and prion disease); cardiovascular disorders (e.g., atherosclerosis, myocarditis, cardiovascular disease, and cardiopulmonary bypass complications); as well as many additional diseases, conditions, and disorders that are characterized by inflammation (e.g., hepatitis, rheumatoid arthritis, gout, trauma, pancreatitis, sarcoidosis, dermatitis, renal ischemia-reperfusion injury, Grave's disease, systemic lupus erythematosus, diabetes mellitus, and allogenic transplant rejection).

[0517] Because inflammation is a fundamental defense mechanism, inflammatory disorders can effect virtually any tissue of the body. Accordingly, polynucleotides, polypeptides, and antibodies of the invention, as well as agonists or antagonists thereof, have uses in the treatment of tissue-specific inflammatory disorders, including, but not limited to, adrenalitis, alveolitis, angiocholecystitis, appendicitis, balanitis, blepharitis, bronchitis, bursitis, carditis, cellulitis, cervicitis, cholecystitis, chorditis, cochlitis, colitis, conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachitis, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis, laryngitis, lymphangitis, mastitis, media otitis, meningitis, metritis, mucitis, myocarditis, myosititis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, peritendonitis, peritonitis, pharyngitis, phlebitis, poliomyelitis, prostatitis, pulpitis, retinitis, rhinitis, salpingitis, scleritis, sclerochoroiditis, scrotitis, sinusitis, spondylitis, steatitis, stomatitis, synovitis, syringitis, tendonitis, tonsillitis, urethritis, and vaginitis.

[0518] In specific embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, are useful to diagnose, prognose, prevent, and/or treat organ transplant rejections and graft-versus-host disease. Organ rejection occurs by host immune cell destruction of the transplanted tissue through an immune response. Similarly, an immune response is also involved in GVHD, but, in this case, the foreign transplanted immune cells destroy the host tissues. Polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, that inhibit an immune response, particularly the activation, proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing organ rejection or GVHD. In specific embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, that inhibit an immune response, particularly the activation, proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing experimental allergic and hyperacute xenograft rejection.

[0519] In other embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, are useful to diagnose, prognose, prevent, and/or treat immune complex diseases, including, but not limited to, serum sickness, post streptococcal glomerulonephritis, polyarteritis nodosa, and immune complex-induced vasculitis.

[0520] Polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the invention can be used to treat, detect, and/or prevent infectious agents. For example, by increasing the immune response, particularly increasing the proliferation activation and/or differentiation of B and/or T cells, infectious diseases may be treated, detected, and/or prevented. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may also directly inhibit the infectious agent (refer to section of application listing infectious agents, etc), without necessarily eliciting an immune response.

[0521] In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a vaccine adjuvant that enhances immune responsiveness to an antigen. In a specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance tumor-specific immune responses.

[0522] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-viral immune responses. Anti-viral immune responses that may be enhanced using the compositions of the invention as an adjuvant, include virus and virus associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a virus, disease, or symptom selected from the group consisting of: AIDS, meningitis, Dengue, EBV, and hepatitis (e.g., hepatitis B). In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to a virus, disease, or symptom selected from the group consisting of: HIV/AIDS, respiratory syncytial virus, Dengue, rotavirus, Japanese B encephalitis, influenza A and B, parainfluenza, measles, cytomegalovirus, rabies, Junin, Chikungunya, Rift Valley Fever, herpes simplex, and yellow fever.

[0523] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-bacterial or anti-fungal immune responses. Anti-bacterial or anti-fungal immune responses that may be enhanced using the compositions of the invention as an adjuvant, include bacteria or fungus and bacteria or fungus associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a bacteria or fungus, disease, or symptom selected from the group consisting of: tetanus, Diphtheria, botulism, and meningitis type B.

[0524] In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to a bacteria or fungus, disease, or symptom selected from the group consisting of: Vibrio cholerae, Mycobacterium leprae, Salmonella typhi, Salmonella paratyphi, Meisseria meningitidis, Streptococcus pneumoniae, Group B streptococcus, Shigella spp., Enterotoxigenic Escherichia coli, Enterohemorrhagic E. coli, and Borrelia burgdorferi.

[0525] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-parasitic immune responses. Anti-parasitic immune responses that may be enhanced using the compositions of the invention as an adjuvant, include parasite and parasite associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a parasite. In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to Plasmodium (malaria) or Leishmania.

[0526] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed to treat infectious diseases including silicosis, sarcoidosis, and idiopathic pulmonary fibrosis; for example, by preventing the recruitment and activation of mononuclear phagocytes.

[0527] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an antigen for the generation of antibodies to inhibit or enhance immune mediated responses against polypeptides of the invention.

[0528] In one embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are administered to an animal (e.g., mouse, rat, rabbit, hamster, guinea pig, pigs, micro-pig, chicken, camel, goat, horse, cow, sheep, dog, cat, non-human primate, and human, most preferably human) to boost the immune system to produce increased quantities of one or more antibodies (e.g., IgG, IgA, IgM, and IgE), to induce higher affinity antibody production and immunoglobulin class switching (e.g., IgG, IgA, IgM, and IgE), and/or to increase an immune response.

[0529] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a stimulator of B cell responsiveness to pathogens.

[0530] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an activator of T cells.

[0531] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent that elevates the immune status of an individual prior to their receipt of immunosuppressive therapies.

[0532] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to induce higher affinity antibodies.

[0533] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to increase serum immunoglobulin concentrations.

[0534] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to accelerate recovery of immunocompromised individuals.

[0535] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among aged populations and/or neonates.

[0536] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an immune system enhancer prior to, during, or after bone marrow transplant and/or other transplants (e.g., allogeneic or xenogeneic organ transplantation). With respect to transplantation, compositions of the invention may be administered prior to, concomitant with, and/or after transplantation. In a specific embodiment, compositions of the invention are administered after transplantation, prior to the beginning of recovery of T-cell populations. In another specific embodiment, compositions of the invention are first administered after transplantation after the beginning of recovery of T cell populations, but prior to full recovery of B cell populations.

[0537] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among individuals having an acquired loss of B cell function. Conditions resulting in an acquired loss of B cell function that may be ameliorated or treated by administering the polypeptides, antibodies, polynucleotides and/or agonists or antagonists thereof, include, but are not limited to, HIV Infection, AIDS, bone marrow transplant, and B cell chronic lymphocytic leukemia (CLL).

[0538] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among individuals having a temporary immune deficiency. Conditions resulting in a temporary immune deficiency that may be ameliorated or treated by administering the polypeptides, antibodies, polynucleotides and/or agonists or antagonists thereof, include, but are not limited to, recovery from viral infections (e.g., influenza), conditions associated with malnutrition, recovery from infectious mononucleosis, or conditions associated with stress, recovery from measles, recovery from blood transfusion, and recovery from surgery.

[0539] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a regulator of antigen presentation by monocytes, dendritic cells, and/or B-cells. In one embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention enhance antigen presentation or antagonizes antigen presentation in vitro or in vivo. Moreover, in related embodiments, said enhancement or antagonism of antigen presentation may be useful as an anti-tumor treatment or to modulate the immune system.

[0540] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to direct an individual's immune system towards development of a humoral response (i.e. TH2) as opposed to a TH1 cellular response.

[0541] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means to induce tumor proliferation and thus make it more susceptible to anti-neoplastic agents. For example, multiple myeloma is a slowly dividing disease and is thus refractory to virtually all anti-neoplastic regimens. If these cells were forced to proliferate more rapidly their susceptibility profile would likely change.

[0542] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a stimulator of B cell production in pathologies such as AIDS, chronic lymphocyte disorder and/or Common Variable Immunodificiency.

[0543] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for generation and/or regeneration of lymphoid tissues following surgery, trauma or genetic defect. In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used in the pretreatment of bone marrow samples prior to transplant.

[0544] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a gene-based therapy for genetically inherited disorders resulting in immuno-incompetence/immunodeficiency such as observed among SCID patients.

[0545] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of activating monocytes/macrophages to defend against parasitic diseases that effect monocytes such as Leishmania.

[0546] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of regulating secreted cytokines that are elicited by polypeptides of the invention.

[0547] In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used in one or more of the applications decribed herein, as they may apply to veterinary medicine.

[0548] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of blocking various aspects of immune responses to foreign agents or self. Examples of diseases or conditions in which blocking of certain aspects of immune responses may be desired include autoimmune disorders such as lupus, and arthritis, as well as immunoresponsiveness to skin allergies, inflammation, bowel disease, injury and diseases/disorders associated with pathogens.

[0549] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for preventing the B cell proliferation and Ig secretion associated with autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus and multiple sclerosis.

[0550] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a inhibitor of B and/or T cell migration in endothelial cells. This activity disrupts tissue architecture or cognate responses and is useful, for example in disrupting immune responses, and blocking sepsis.

[0551] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for chronic hypergammaglobulinemia evident in such diseases as monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom's disease, related idiopathic monoclonal gammopathies, and plasmacytomas.

[0552] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed for instance to inhibit polypeptide chemotaxis and activation of macrophages and their precursors, and of neutrophils, basophils, B lymphocytes and some T-cell subsets, e.g., activated and CD8 cytotoxic T cells and natural killer cells, in certain autoimmune and chronic inflammatory and infective diseases. Examples of autoimmune diseases are described herein and include multiple sclerosis, and insulin-dependent diabetes.

[0553] The polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed to treat idiopathic hyper-eosinophilic syndrome by, for example, preventing eosinophil production and migration.

[0554] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used to enhance or inhibit complement mediated cell lysis.

[0555] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used to enhance or inhibit antibody dependent cellular cytotoxicity.

[0556] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed for treating atherosclerosis, for example, by preventing monocyte infiltration in the artery wall.

[0557] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed to treat adult respiratory distress syndrome (ARDS).

[0558] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be useful for stimulating wound and tissue repair, stimulating angiogenesis, and/or stimulating the repair of vascular or lymphatic diseases or disorders. Additionally, agonists and antagonists of the invention may be used to stimulate the regeneration of mucosal surfaces.

[0559] In a specific embodiment, polynucleotides or polypeptides, and/or agonists thereof are used to diagnose, prognose, treat, and/or prevent a disorder characterized by primary or acquired immunodeficiency, deficient serum immunoglobulin production, recurrent infections, and/or immune system dysfunction. Moreover, polynucleotides or polypeptides, and/or agonists thereof may be used to treat or prevent infections of the joints, bones, skin, and/or parotid glands, blood-borne infections (e.g., sepsis, meningitis, septic arthritis, and/or osteomyelitis), autoimmune diseases (e.g., those disclosed herein), inflammatory disorders, and malignancies, and/or any disease or disorder or condition associated with these infections, diseases, disorders and/or malignancies) including, but not limited to, CVID, other primary immune deficiencies, HIV disease, CLL, recurrent bronchitis, sinusitis, otitis media, conjunctivitis, pneumonia, hepatitis, meningitis, herpes zoster (e.g., severe herpes zoster), and/or pneumocystis carnii. Other diseases and disorders that may be prevented, diagnosed, prognosed, and/or treated with polynucleotides or polypeptides, and/or agonists of the present invention include, but are not limited to, HIV infection, HTLV-BLV infection, lymphopenia, phagocyte bactericidal dysfunction anemia, thrombocytopenia, and hemoglobinuria.

[0560] In another embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention are used to treat, and/or diagnose an individual having common variable immunodeficiency disease (“CVID”; also known as “acquired agammaglobulinemia” and “acquired hypogammaglobulinemia”) or a subset of this disease.

[0561] In a specific embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to diagnose, prognose, prevent, and/or treat cancers or neoplasms including immune cell or immune tissue-related cancers or neoplasms. Examples of cancers or neoplasms that may be prevented, diagnosed, or treated by polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic anemia (ALL) Chronic lymphocyte leukemia, plasmacytomas, multiple myeloma, Burkitt's lymphoma, EBV-transformed diseases, and/or diseases and disorders described in the section entitled “Hyperproliferative Disorders” elsewhere herein.

[0562] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for decreasing cellular proliferation of Large B-cell Lymphomas.

[0563] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of decreasing the involvement of B cells and Ig associated with Chronic Myelogenous Leukemia.

[0564] In specific embodiments, the compositions of the invention are used as an agent to boost immunoresponsiveness among B cell immunodeficient individuals, such as, for example, an individual who has undergone a partial or complete splenectomy.

[0565] Antagonists of the invention include, for example, binding and/or inhibitory antibodies, antisense nucleic acids, ribozymes or soluble forms of the polypeptides of the present invention (e.g., Fc fusion protein; see, e.g., Example 9). Agonists of the invention include, for example, binding or stimulatory antibodies, and soluble forms of the polypeptides (e.g., Fc fusion proteins; see, e.g., Example 9). polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed in a composition with a pharmaceutically acceptable carrier, e.g., as described herein.

[0566] In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are administered to an animal (including, but not limited to, those listed above, and also including transgenic animals) incapable of producing functional endogenous antibody molecules or having an otherwise compromised endogenous immune system, but which is capable of producing human immunoglobulin molecules by means of a reconstituted or partially reconstituted immune system from another animal (see, e.g., published PCT Application Nos. WO98/24893, WO/9634096, WO/9633735, and WO/9110741). Administration of polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention to such animals is useful for the generation of monoclonal antibodies against the polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention.

[0567] Blood-Related Disorders

[0568] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate hemostatic (the stopping of bleeding) or thrombolytic (clot dissolving) activity. For example, by increasing hemostatic or thrombolytic activity, polynucleotides or polypeptides, and/or agonists or antagonists of the present invention could be used to treat or prevent blood coagulation diseases, disorders, and/or conditions (e.g., afibrinogenemia, factor deficiencies, hemophilia), blood platelet diseases, disorders, and/or conditions (e.g., thrombocytopenia), or wounds resulting from trauma, surgery, or other causes. Alternatively, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention that can decrease hemostatic or thrombolytic activity could be used to inhibit or dissolve clotting. These molecules could be important in the treatment or prevention of heart attacks (infarction), strokes, or scarring.

[0569] In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to prevent, diagnose, prognose, and/or treat thrombosis, arterial thrombosis, venous thrombosis, thromboembolism, pulmonary embolism, atherosclerosis, myocardial infarction, transient ischemic attack, unstable angina. In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used for the prevention of occulsion of saphenous grafts, for reducing the risk of periprocedural thrombosis as might accompany angioplasty procedures, for reducing the risk of stroke in patients with atrial fibrillation including nonrheumatic atrial fibrillation, for reducing the risk of embolism associated with mechanical heart valves and or mitral valves disease. Other uses for the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention, include, but are not limited to, the prevention of occlusions in extrcorporeal devices (e.g., intravascular canulas, vascular access shunts in hemodialysis patients, hemodialysis machines, and cardiopulmonary bypass machines).

[0570] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to prevent, diagnose, prognose, and/or treat diseases and disorders of the blood and/or blood forming organs associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).

[0571] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate hematopoietic activity (the formation of blood cells). For example, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to increase the quantity of all or subsets of blood cells, such as, for example, erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g., basophils, eosinophils, neutrophils, mast cells, macrophages) and platelets. The ability to decrease the quantity of blood cells or subsets of blood cells may be useful in the prevention, detection, diagnosis and/or treatment of anemias and leukopenias described below. Alternatively, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to decrease the quantity of all or subsets of blood cells, such as, for example, erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g., basophils, eosinophils, neutrophils, mast cells, macrophages) and platelets. The ability to decrease the quantity of blood cells or subsets of blood cells may be useful in the prevention, detection, diagnosis and/or treatment of leukocytoses, such as, for example eosinophilia.

[0572] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to prevent, treat, or diagnose blood dyscrasia.

[0573] Anemias are conditions in which the number of red blood cells or amount of hemoglobin (the protein that carries oxygen) in them is below normal. Anemia may be caused by excessive bleeding, decreased red blood cell production, or increased red blood cell destruction (hemolysis). The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias. Anemias that may be treated prevented or diagnosed by the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include iron deficiency anemia, hypochromic anemia, microcytic anemia, chlorosis, hereditary siderob;astic anemia, idiopathic acquired sideroblastic anemia, red cell aplasia, megaloblastic anemia (e.g., pernicious anemia, (vitamin B12 deficiency) and folic acid deficiency anemia), aplastic anemia, hemolytic anemias (e.g., autoimmune helolytic anemia, microangiopathic hemolytic anemia, and paroxysmal nocturnal hemoglobinuria). The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias associated with diseases including but not limited to, anemias associated with systemic lupus erythematosus, cancers, lymphomas, chronic renal disease, and enlarged spleens. The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias arising from drug treatments such as anemias associated with methyldopa, dapsone, and/or sulfadrugs. Additionally, rhe polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias associated with abnormal red blood cell architecture including but not limited to, hereditary spherocytosis, hereditary elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, and sickle cell anemia.

[0574] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing hemoglobin abnormalities, (e.g., those associated with sickle cell anemia, hemoglobin C disease, hemoglobin S-C disease, and hemoglobin E disease). Additionally, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating thalassemias, including, but not limited to major and minor forms of alpha-thalassemia and beta-thalassemia.

[0575] In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating bleeding disorders including, but not limited to, thrombocytopenia (e.g., idiopathic thrombocytopenic purpura, and thrombotic thrombocytopenic purpura), Von Willebrand's disease, hereditary platelet disorders (e.g., storage pool disease such as Chediak-Higashi and Hermansky-Pudlak syndromes, thromboxane A2 dysfunction, thromboasthenia, and Bemard-Soulier syndrome), hemolytic-uremic syndrome, hemophelias such as hemophelia A or Factor VII deficiency and Christmas disease or Factor IX deficiency, Hereditary Hemorhhagic Telangiectsia, also known as Rendu-Osler-Weber syndrome, allergic purpura (Henoch Schonlein purpura) and disseminated intravascular coagulation.

[0576] The effect of the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention on the clotting time of blood may be monitored using any of the clotting tests known in the art including, but not limited to, whole blood partial thromboplastin time (PTT), the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the recalcified activated clotting time, or the Lee-White Clotting time.

[0577] Several diseases and a variety of drugs can cause platelet dysfunction. Thus, in a specific embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating acquired platelet dysfunction such as platelet dysfunction accompanying kidney failure, leukemia, multiple myeloma, cirrhosis of the liver, and systemic lupus erythematosus as well as platelet dysfunction associated with drug treatments, including treatment with aspirin, ticlopidine, nonsteroidal anti-inflammatory drugs (used for arthritis, pain, and sprains), and penicillin in high doses.

[0578] In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders characterized by or associated with increased or decreased numbers of white blood cells. Leukopenia occurs when the number of white blood cells decreases below normal. Leukopenias include, but are not limited to, neutropenia and lymphocytopenia. An increase in the number of white blood cells compared to normal is known as leukocytosis. The body generates increased numbers of white blood cells during infection. Thus, leukocytosis may simply be a normal physiological parameter that reflects infection. Alternatively, leukocytosis may be an indicator of injury or other disease such as cancer. Leokocytoses, include but are not limited to, eosinophilia, and accumulations of macrophages. In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating leukopenia. In other specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating leukocytosis.

[0579] Leukopenia may be a generalized decreased in all types of white blood cells, or may be a specific depletion of particular types of white blood cells. Thus, in specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating decreases in neutrophil numbers, known as neutropenia. Neutropenias that may be diagnosed, prognosed, prevented, and/or treated by the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, infantile genetic agranulocytosis, familial neutropenia, cyclic neutropenia, neutropenias resulting from or associated with dietary deficiencies (e.g., vitamin B 12 deficiency or folic acid deficiency), neutropenias resulting from or associated with drug treatments (e.g., antibiotic regimens such as penicillin treatment, sulfonamide treatment, anticoagulant treatment, anticonvulsant drugs, anti-thyroid drugs, and cancer chemotherapy), and neutropenias resulting from increased neutrophil destruction that may occur in association with some bacterial or viral infections, allergic disorders, autoimmune diseases, conditions in which an individual has an enlarged spleen (e.g., Felty syndrome, malaria and sarcoidosis), and some drug treatment regimens.

[0580] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating lymphocytopenias (decreased numbers of B and/or T lymphocytes), including, but not limited lymphocytopenias resulting from or associated with stress, drug treatments (e.g., drug treatment with corticosteroids, cancer chemotherapies, and/or radiation therapies), AIDS infection and/or other diseases such as, for example, cancer, rheumatoid arthritis, systemic lupus erythematosus, chronic infections, some viral infections and/or hereditary disorders (e.g., DiGeorge syndrome, Wiskott-Aldrich Syndome, severe combined immunodeficiency, ataxia telangiectsia).

[0581] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders associated with macrophage numbers and/or macrophage function including, but not limited to, Gaucher's disease, Niemann-Pick disease, Letterer-Siwe disease and Hand-Schuller-Christian disease.

[0582] In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders associated with eosinophil numbers and/or eosinophil function including, but not limited to, idiopathic hypereosinophilic syndrome, eosinophilia-myalgia syndrome, and Hand-Schuller-Christian disease.

[0583] In yet another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating leukemias and lymphomas including, but not limited to, acute lymphocytic (lymphpblastic) leukemia (ALL), acute myeloid (myelocytic, myelogenous, myeloblastic, or myelomonocytic) leukemia, chronic lymphocytic leukemia (e.g., B cell leukemias, T cell leukemias, Sezary syndrome, and Hairy cell leukenia), chronic myelocytic (myeloid, myelogenous, or granulocytic) leukemia, Hodgkin's lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, and mycosis fungoides.

[0584] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders of plasma cells including, but not limited to, plasma cell dyscrasias, monoclonal gammaopathies, monoclonal gammopathies of undetermined significance, multiple myeloma, macroglobulinemia, Waldenstrom's macroglobulinemia, cryoglobulinemia, and Raynaud's phenomenon.

[0585] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing myeloproliferative disorders, including but not limited to, polycythemia vera, relative polycythemia, secondary polycythemia, myelofibrosis, acute myelofibrosis, agnogenic myelod metaplasia, thrombocythemia, (including both primary and seconday thrombocythemia) and chronic myelocytic leukemia.

[0586] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as a treatment prior to surgery, to increase blood cell production.

[0587] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to enhance the migration, phagocytosis, superoxide production, antibody dependent cellular cytotoxicity of neutrophils, eosionophils and macrophages.

[0588] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase the number of stem cells in circulation prior to stem cells pheresis. In another specific embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase the number of stem cells in circulation prior to platelet pheresis.

[0589] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase cytokine production.

[0590] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in preventing, diagnosing, and/or treating primary hematopoietic disorders.

[0591] Hyperproliferative Disorders

[0592] In certain embodiments, polynucleotides or polypeptides, or agonists or antagonists of the present invention can be used to treat or detect hyperproliferative disorders, including neoplasms. Polynucleotides or polypeptides, or agonists or antagonists of the present invention may inhibit the proliferation of the disorder through direct or indirect interactions. Alternatively, Polynucleotides or polypeptides, or agonists or antagonists of the present invention may proliferate other cells which can inhibit the hyperproliferative disorder.

[0593] For example, by increasing an immune response, particularly increasing antigenic qualities of the hyperproliferative disorder or by proliferating, differentiating, or mobilizing T-cells, hyperproliferative disorders can be treated. This immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, decreasing an immune response may also be a method of treating hyperproliferative disorders, such as a chemotherapeutic agent.

[0594] Examples of hyperproliferative disorders that can be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention include, but are not limited to neoplasms located in the: colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thorax, and urogenital tract.

[0595] Similarly, other hyperproliferative disorders can also be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention. Examples of such hyperproliferative disorders include, but are not limited to: Acute Childhood Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, Adult (Primary) Hepatocellular Cancer, Adult (Primary) Liver Cancer, Adult Acute Lymphocytic Leukemia, Adult Acute Myeloid Leukemia, Adult Hodgkin's Disease, Adult Hodgkin's Lymphoma, Adult Lymphocytic Leukemia, Adult Non-Hodgkin's Lymphoma, Adult Primary Liver Cancer, Adult Soft Tissue Sarcoma, AIDS-Related Lymphoma, AIDS-Related Malignancies, Anal Cancer, Astrocytoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumors, Breast Cancer, Cancer of the Renal Pelvis and Ureter, Central Nervous System (Primary) Lymphoma, Central Nervous System Lymphoma, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Childhood (Primary) Hepatocellular Cancer, Childhood (Primary) Liver Cancer, Childhood Acute Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Childhood Brain Stem Glioma, Childhood Cerebellar Astrocytoma, Childhood Cerebral Astrocytoma, Childhood Extracranial Germ Cell Tumors, Childhood Hodgkin's Disease, Childhood Hodgkin's Lymphoma, Childhood Hypothalamic and Visual Pathway Glioma, Childhood Lymphoblastic Leukemia, Childhood Medulloblastoma, Childhood Non-Hodgkin's Lymphoma, Childhood Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood Primary Liver Cancer, Childhood Rhabdomyosarcoma, Childhood Soft Tissue Sarcoma, Childhood Visual Pathway and Hypothalamic Glioma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Colon Cancer, Cutaneous T-Cell Lymphoma, Endocrine Pancreas Islet Cell Carcinoma, Endometrial Cancer, Ependymoma, Epithelial Cancer, Esophageal Cancer, Ewing's Sarcoma and Related Tumors, Exocrine Pancreatic Cancer, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Female Breast Cancer, Gaucher's Disease, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Tumors, Germ Cell Tumors, Gestational Trophoblastic Tumor, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular Cancer, Hodgkin's Disease, Hodgkin's Lymphoma, Hypergammaglobulinemia, Hypopharyngeal Cancer, Intestinal Cancers, Intraocular Melanoma, Islet Cell Carcinoma, Islet Cell Pancreatic Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer, Lymphoproliferative Disorders, Macroglobulinemia, Male Breast Cancer, Malignant Mesothelioma, Malignant Thymoma, Medulloblastoma, Melanoma, Mesothelioma, Metastatic Occult Primary Squamous Neck Cancer, Metastatic Primary Squamous Neck Cancer, Metastatic Squamous Neck Cancer, Multiple Myeloma, Multiple Myeloma/Plasma Cell Neoplasm, Myelodysplastic Syndrome, Myelogenous Leukemia, Myeloid Leukemia, Mycloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin's Lymphoma During Pregnancy, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Occult Primary Metastatic Squamous Neck Cancer, Oropharyngeal Cancer, Osteo-/Malignant Fibrous Sarcoma, Osteosarcoma/Malignant Fibrous Histiocytoma, Osteosarcoma/Malignant Fibrous Histiocytoma of Bone, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Paraproteinemias, Purpura, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasmi/Multiple Myeloma, Primary Central Nervous System Lymphoma, Primary Liver Cancer, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis and Ureter Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoidosis Sarcomas, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Neck Cancer, Stomach Cancer, Supratentorial Primitive Neuroectodernal and Pineal Tumors, T-Cell Lymphoma, Testicular Cancer, Thymoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Transitional Renal Pelvis and Ureter Cancer, Trophoblastic Tumors, Ureter and Renal Pelvis Cell Cancer, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma, Vulvar Cancer, Waldenstrom's Macroglobulinemia, Wilms' Tumor, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.

[0596] In another preferred embodiment, polynucleotides or polypeptides, or agonists or antagonists of the present invention are used to diagnose, prognose, prevent, and/or treat premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders described above. Such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W. B. Saunders Co., Philadelphia, pp. 68-79.)

[0597] Hyperplasia is a form of controlled cell proliferation, involving an increase in cell number in a tissue or organ, without significant alteration in structure or function. Hyperplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, angiofollicular mediastinal lymph node hyperplasia, angiolymphoid hyperplasia with eosinophilia, a typical melanocytic hyperplasia, basal cell hyperplasia, benign giant lymph node hyperplasia, cementum hyperplasia, congenital adrenal hyperplasia, congenital sebaceous hyperplasia, cystic hyperplasia, cystic hyperplasia of the breast, denture hyperplasia, ductal hyperplasia, endometrial hyperplasia, fibromuscular hyperplasia, focal epithelial hyperplasia, gingival hyperplasia, inflammatory fibrous hyperplasia, inflammatory papillary hyperplasia, intravascular papillary endothelial hyperplasia, nodular hyperplasia of prostate, nodular regenerative hyperplasia, pseudoepitheliomatous hyperplasia, senile sebaceous hyperplasia, and verrucous hyperplasia.

[0598] Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, agnogenic myeloid metaplasia, apocrine metaplasia, a typical metaplasia, autoparenchymatous metaplasia, connective tissue metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia, metaplastic ossification, metaplastic polyps, myeloid metaplasia, primary myeloid metaplasia, secondary myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion, and symptomatic myeloid metaplasia.

[0599] Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where there exists chronic irritation or inflammation. Dysplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis hemimelia, dysplasia epiphysialis multiplex, dysplasia epiphysialis punctata, epithelial dysplasia, faciodigitogenital dysplasia, familial fibrous dysplasia of jaws, familial white folded dysplasia, fibromuscular dysplasia, fibrous dysplasia of bone, florid osseous dysplasia, hereditary renal-retinal dysplasia, hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary dysplasia, mandibulofacial dysplasia, metaphysial dysplasia, Mondini dysplasia, monostotic fibrous dysplasia, mucoepithelial dysplasia, multiple epiphysial dysplasia, oculoauriculovertebral dysplasia, oculodentodigital dysplasia, oculovertebral dysplasia, odontogenic dysplasia, ophthalmomandibulomelic dysplasia, periapical cemental dysplasia, polyostotic fibrous dysplasia, pseudoachondroplastic spondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia.

[0600] Additional pre-neoplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, benign dysproliferative disorders (e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps, colon polyps, and esophageal dysplasia), leukoplakia, keratoses, Bowen's disease, Farmer's Skin, solar cheilitis, and solar keratosis.

[0601] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognose disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).

[0602] In another embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention conjugated to a toxin or a radioactive isotope, as described herein, may be used to treat cancers and neoplasms, including, but not limited to those described herein. In a further preferred embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention conjugated to a toxin or a radioactive isotope, as described herein, may be used to treat acute myelogenous leukemia.

[0603] Additionally, polynucleotides, polypeptides, and/or agonists or antagonists of the invention may affect apoptosis, and therefore, would be useful in treating a number of diseases associated with increased cell survival or the inhibition of apoptosis. For example, diseases associated with increased cell survival or the inhibition of apoptosis that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include cancers (such as follicular lymphomas, carcinomas with p53 mutations, and hormone-dependent tumors, including, but not limited to colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi's sarcoma and ovarian cancer); autoimmune disorders such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) and viral infections (such as herpes viruses, pox viruses and adenoviruses), inflammation, graft v. host disease, acute graft rejection, and chronic graft rejection.

[0604] In preferred embodiments, polynucleotides, polypeptides, and/or agonists or antagonists of the invention are used to inhibit growth, progression, and/or metastasis of cancers, in particular those listed above.

[0605] Additional diseases or conditions associated with increased cell survival that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, emangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.

[0606] Diseases associated with increased apoptosis that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include AIDS; neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellar degeneration and brain tumor or prior associated disease); autoimmune disorders (such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) myelodysplastic syndromes (such as aplastic anemia), graft v. host disease, ischemic injury (such as that caused by myocardial infarction, stroke and reperfusion injury), liver injury (e.g., hepatitis related liver injury, ischemia/reperfusion injury, cholestosis (bile duct injury) and liver cancer); toxin-induced liver disease (such as that caused by alcohol), septic shock, cachexia and anorexia.

[0607] Hyperproliferative diseases and/or disorders that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include, but are not limited to, neoplasms located in the liver, abdomen, bone, breast, digestive system, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous system (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thorax, and urogenital tract.

[0608] Similarly, other hyperproliferative disorders can also be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention. Examples of such hyperproliferative disorders include, but are not limited to: hypergammaglobulinemia, lymphoproliferative disorders, paraproteinemias, purpura, sarcoidosis, Sezary Syndrome, Waldenstron's macroglobulinemia, Gaucher's Disease, histiocytosis, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.

[0609] Another preferred embodiment utilizes polynucleotides of the present invention to inhibit aberrant cellular division, by gene therapy using the present invention, and/or protein fusions or fragments thereof.

[0610] Thus, the present invention provides a method for treating cell proliferative disorders by inserting into an abnormally proliferating cell a polynucleotide of the present invention, wherein said polynucleotide represses said expression.

[0611] Another embodiment of the present invention provides a method of treating cell-proliferative disorders in individuals comprising administration of one or more active gene copies of the present invention to an abnormally proliferating cell or cells. In a preferred embodiment, polynucleotides of the present invention is a DNA construct comprising a recombinant expression vector effective in expressing a DNA sequence encoding said polynucleotides. In another preferred embodiment of the present invention, the DNA construct encoding the poynucleotides of the present invention is inserted into cells to be treated utilizing a retrovirus, or more preferably an adenoviral vector (See G J. Nabel, et. al., PNAS 1999 96: 324-326, which is hereby incorporated by reference). In a most preferred embodiment, the viral vector is defective and will not transform non-proliferating cells, only proliferating cells. Moreover, in a preferred embodiment, the polynucleotides of the present invention inserted into proliferating cells either alone, or in combination with or fused to other polynucleotides, can then be modulated via an external stimulus (i.e. magnetic, specific small molecule, chemical, or drug administration, etc.), which acts upon the promoter upstream of said polynucleotides to induce expression of the encoded protein product. As such the beneficial therapeutic affect of the present invention may be expressly modulated (i.e. to increase, decrease, or inhibit expression of the present invention) based upon said external stimulus.

[0612] Polynucleotides of the present invention may be useful in repressing expression of oncogenic genes or antigens. By “repressing expression of the oncogenic genes” is intended the suppression of the transcription of the gene, the degradation of the gene transcript (pre-message RNA), the inhibition of splicing, the destruction of the messenger RNA, the prevention of the post-translational modifications of the protein, the destruction of the protein, or the inhibition of the normal function of the protein.

[0613] For local administration to abnormally proliferating cells, polynucleotides of the present invention may be administered by any method known to those of skill in the art including, but not limited to transfection, electroporation, microinjection of cells, or in vehicles such as liposomes, lipofectin, or as naked polynucleotides, or any other method described throughout the specification. The polynucleotide of the present invention may be delivered by known gene delivery systems such as, but not limited to, retroviral vectors (Gilboa, J. Virology 44:845 (1982); Hocke, Nature 320:275 (1986); Wilson, et al., Proc. Natl. Acad. Sci. U.S.A. 85:3014), vaccinia virus system (Chakrabarty et al., Mol. Cell Biol. 5:3403 (1985) or other efficient DNA delivery systems (Yates et al., Nature 313:812 (1985)) known to those skilled in the art. These references are exemplary only and are hereby incorporated by reference. In order to specifically deliver or transfect cells which are abnormally proliferating and spare non-dividing cells, it is preferable to utilize a retrovirus, or adenoviral (as described in the art and elsewhere herein) delivery system known to those of skill in the art. Since host DNA replication is required for retroviral DNA to integrate and the retrovirus will be unable to self replicate due to the lack of the retrovirus genes needed for its life cycle. Utilizing such a retroviral delivery system for polynucleotides of the present invention will target said gene and constructs to abnormally proliferating cells and will spare the non-dividing normal cells.

[0614] The polynucleotides of the present invention may be delivered directly to cell proliferative disorder/disease sites in internal organs, body cavities and the like by use of imaging devices used to guide an injecting needle directly to the disease site. The polynucleotides of the present invention may also be administered to disease sites at the time of surgical intervention.

[0615] By “cell proliferative disease” is meant any human or animal disease or disorder, affecting any one or any combination of organs, cavities, or body parts, which is characterized by single or multiple local abnormal proliferations of cells, groups of cells, or tissues, whether benign or malignant.

[0616] Any amount of the polynucleotides of the present invention may be administered as long as it has a biologically inhibiting effect on the proliferation of the treated cells. Moreover, it is possible to administer more than one of the polynucleotide of the present invention simultaneously to the same site. By “biologically inhibiting” is meant partial or total growth inhibition as well as decreases in the rate of proliferation or growth of the cells. The biologically inhibitory dose may be determined by assessing the effects of the polynucleotides of the present invention on target malignant or abnormally proliferating cell growth in tissue culture, tumor growth in animals and cell cultures, or any other method known to one of ordinary skill in the art.

[0617] The present invention is further directed to antibody-based therapies which involve administering of anti-polypeptides and anti-polynucleotide antibodies to a mammalian, preferably human, patient for treating one or more of the described disorders. Methods for producing anti-polypeptides and anti-polynucleotide antibodies polyclonal and monoclonal antibodies are described in detail elsewhere herein. Such antibodies may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.

[0618] A summary of the ways in which the antibodies of the present invention may be used therapeutically includes binding polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody, e.g. as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the present invention for diagnostic, monitoring or therapeutic purposes without undue experimentation.

[0619] In particular, the antibodies, fragments and derivatives of the present invention are useful for treating a subject having or developing cell proliferative and/or differentiation disorders as described herein. Such treatment comprises administering a single or multiple doses of the antibody, or a fragment, derivative, or a conjugate thereof.

[0620] The antibodies of this invention may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors, for example., which serve to increase the number or activity of effector cells which interact with the antibodies.

[0621] It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for both immunoassays directed to and therapy of disorders related to polynucleotides or polypeptides, including fragements thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides, including fragements thereof Preferred binding affinities include those with a dissociation constant or Kd less than 5×10−6M, 10−6M, 5×10−7M, 10−7M, 5×10−8 M, 10−8M, 5×10−9M, 10−9M, 5×10−10M, 10−10M, 5×10−11M, 10−11M, 5×10−12M, 10−12M, 5×10−13M, 10−13M, 5×10−14M, 10−14M, 5×10−15M, and 10−15M.

[0622] Moreover, polypeptides of the present invention are useful in inhibiting the angiogenesis of proliferative cells or tissues, either alone, as a protein fusion, or in combination with other polypeptides directly or indirectly, as described elsewhere herein. In a most preferred embodiment, said anti-angiogenesis effect may be achieved indirectly, for example, through the inhibition of hematopoietic, tumor-specific cells, such as tumor-associated macrophages (See Joseph I B, et al. J Natl Cancer Inst, 90(21):1648-53 (1998), which is hereby incorporated by reference). Antibodies directed to polypeptides or polynucleotides of the present invention may also result in inhibition of angiogenesis directly, or indirectly (See Witte L, et al., Cancer Metastasis Rev. 17(2):155-61 (1998), which is hereby incorporated by reference)).

[0623] Polypeptides, including protein fusions, of the present invention, or fragments thereof may be useful in inhibiting proliferative cells or tissues through the induction of apoptosis. Said polypeptides may act either directly, or indirectly to induce apoptosis of proliferative cells and tissues, for example in the activation of a death-domain receptor, such as tumor necrosis factor (TNF) receptor-1, CD95 (Fas/APO-1), TNF-receptor-related apoptosis-mediated protein (TRAMP) and TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2 (See Schulze-Osthoff K, et.al., Eur J Biochem 254(3):439-59 (1998), which is hereby incorporated by reference). Moreover, in another preferred embodiment of the present invention, said polypeptides may induce apoptosis through other mechanisms, such as in the activation of other proteins which will activate apoptosis, or through stimulating the expression of said proteins, either alone or in combination with small molecule drugs or adjuviants, such as apoptonin, galectins, thioredoxins, anti-inflammatory proteins (See for example, Mutat Res 400(1-2):447-55 (1998), Med Hypotheses.50(5):423-33 (1998), Chem Biol Interact. Apr 24;111-112:23-34 (1998), J Mol Med.76(6):402-12 (1998), Int J Tissue React;20(1):3-15 (1998), which are all hereby incorporated by reference).

[0624] Polypeptides, including protein fusions to, or fragments thereof, of the present invention are useful in inhibiting the metastasis of proliferative cells or tissues. Inhibition may occur as a direct result of administering polypeptides, or antibodies directed to said polypeptides as described elsewere herein, or indirectly, such as activating the expression of proteins known to inhibit metastasis, for example alpha 4,integrins, (See, e.g., Curr Top Microbiol Immunol 1998;231:125-41, which is hereby incorporated by reference). Such thereapeutic affects of the present invention may be achieved either alone, or in combination with small molecule drugs or adjuvants.

[0625] In another embodiment, the invention provides a method of delivering compositions containing the polypeptides of the invention (e.g., compositions containing polypeptides or polypeptide antibodes associated with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs) to targeted cells expressing the polypeptide of the present invention. Polypeptides or polypeptide antibodes of the invention may be associated with with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalent interactions.

[0626] Polypeptides, protein fusions to, or fragments thereof, of the present invention are useful in enhancing the immunogenicity and/or antigenicity of proliferating cells or tissues, either directly, such as would occur if the polypeptides of the present invention ‘vaccinated’ the immune response to respond to proliferative antigens and immunogens, or indirectly, such as in activating the expression of proteins known to enhance the immune response (e.g. chemokines), to said antigens and immunogens.

[0627] Renal Disorders

[0628] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose disorders of the renal system. Renal disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention include, but are not limited to, kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, electrolyte imbalance, and kidney cancers.

[0629] Kidney diseases which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention include, but are not limited to, acute kidney failure, chronic kidney failure, atheroembolic renal failure, end-stage renal disease, inflammatory diseases of the kidney (e.g., acute glomerulonephritis, postinfectious glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, membranous glomerulonephritis, familial nephrotic syndrome, membranoproliferative glomerulonephritis I and II, mesangial proliferative glomerulonephritis, chronic glomerulonephritis, acute tubulointerstitial nephritis, chronic tubulointerstitial nephritis, acute post-streptococcal glomerulonephritis (PSGN), pyelonephritis, lupus nephritis, chronic nephritis, interstitial nephritis, and post-streptococcal glomerulonephritis), blood vessel disorders of the kidneys (e.g., kidney infarction, atheroembolic kidney disease, cortical necrosis, malignant nephrosclerosis, renal vein thrombosis, renal underperfusion, renal retinopathy, renal ischemia-reperfusion, renal artery embolism, and renal artery stenosis), and kidney disorders resulting form urinary tract disease (e.g., pyelonephritis, hydronephrosis, urolithiasis (renal lithiasis, nephrolithiasis), reflux nephropathy, urinary tract infections, urinary retention, and acute or chronic unilateral obstructive uropathy.)

[0630] In addition, compositions of the invention can be used to diagnose, prognose, prevent, and/or treat metabolic and congenital disorders of the kidney (e.g., uremia, renal amyloidosis, renal osteodystrophy, renal tubular acidosis, renal glycosuria, nephrogenic diabetes insipidus, cystinuria, Fanconi's syndrome, renal fibrocystic osteosis (renal rickets), Hartnup disease, Bartter's syndrome, Liddle's syndrome, polycystic kidney disease, medullary cystic disease, medullary sponge kidney, Alport's syndrome, nail-patella syndrome, congenital nephrotic syndrome, CRUSH syndrome, horseshoe kidney, diabetic nephropathy, nephrogenic diabetes insipidus, analgesic nephropathy, kidney stones, and membranous nephropathy), and autoimmune disorders of the kidney (e.g., systemic lupus erythematosus (SLE), Goodpasture syndrome, IgA nephropathy, and IgM mesangial proliferative glomerulonephritis).

[0631] Compositions of the invention can also be used to diagnose, prognose, prevent, and/or treat sclerotic or necrotic disorders of the kidney (e.g., glomerulosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), necrotizing glomerulonephritis, and renal papillary necrosis), cancers of the kidney (e.g., nephroma, hypemephroma, nephroblastoma, renal cell cancer, transitional cell cancer, renal adenocarcinoma, squamous cell cancer, and Wilm's tumor), and electrolyte imbalances (e.g., nephrocalcinosis, pyuria, edema, hydronephritis, proteinuria, hyponatremia, hypematremia, hypokalernia, hyperkalemia, hypocalcemia, hypercalcemia, hypophosphatemia, and hyperphosphatemia).

[0632] Polypeptides may be administered using any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, biolistic injectors, particle accelerators, gelfoam sponge depots, other commercially available depot materials, osmotic pumps, oral or suppositorial solid pharmaceutical formulations, decanting or topical applications during surgery, aerosol delivery. Such methods are known in the art. Polypeptides may be administered as part of a Therapeutic, described in more detail below. Methods of delivering polynucleotides are described in more detail herein.

[0633] Cardiovascular Disorders

[0634] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose cardiovascular disorders, including, but not limited to, peripheral artery disease, such as limb ischemia.

[0635] Cardiovascular disorders include, but are not limited to, cardiovascular abnormalities, such as arterio-arterial fistula, arterioyenous fistula, cerebral arterioyenous malformations, congenital heart defects, pulmonary atresia, and Scimitar Syndrome. Congenital heart defects include, but are not limited to, aortic coarctation, cor triatriatum, coronary vessel anomalies, crisscross heart, dextrocardia, patent ductus arteriosus, Ebstein's anomaly, Eisenmenger complex, hypoplastic left heart syndrome, levocardia, tetralogy of fallot, transposition of great vessels, double outlet right ventricle, tricuspid atresia, persistent truncus arteriosus, and heart septal defects, such as aortopulmonary septal defect, endocardial cushion defects, Lutembacher's Syndrome, trilogy of Fallot, ventricular heart septal defects.

[0636] Cardiovascular disorders also include, but are not limited to, heart disease, such as arrhythmias, carcinoid heart disease, high cardiac output, low cardiac output, cardiac tamponade, endocarditis (including bacterial), heart aneurysm, cardiac arrest, congestive heart failure, congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, heart hypertrophy, congestive cardiomyopathy, left ventricular hypertrophy, right ventricular hypertrophy, post-infarction heart rupture, ventricular septal rupture, heart valve diseases, myocardial diseases, myocardial ischemia, pericardial effusion, pericarditis (including constrictive and tuberculous), pneumopericardium, postpericardiotomy syndrome, pulmonary heart disease, rheumatic heart disease, ventricular dysfunction, hyperemia, cardiovascular pregnancy complications, Scimitar Syndrome, cardiovascular syphilis, and cardiovascular tuberculosis.

[0637] Arrhythmias include, but are not limited to, sinus arrhythmia, atrial fibrillation, atrial flutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branch block, sinoatrial block, long QT syndrome, parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-excitation syndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome, tachycardias, and ventricular fibrillation. Tachycardias include paroxysmal tachycardia, supraventricular tachycardia, accelerated idioventricular rhythm, atrioventricular nodal reentry tachycardia, ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrial nodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, and ventricular tachycardia.

[0638] Heart valve diseases include, but are not limited to, aortic valve insufficiency, aortic valve stenosis, hear murmurs, aortic valve prolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valve insufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valve insufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspid valve insufficiency, and tricuspid valve stenosis.

[0639] Myocardial diseases include, but are not limited to, alcoholic cardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy, aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis, endomyocardial fibrosis, Kearns Syndrome, myocardial reperfusion injury, and myocarditis.

[0640] Myocardial ischemias include, but are not limited to, coronary disease, such as angina pectoris, coronary aneurysm, coronary arteriosclerosis, coronary thrombosis, coronary vasospasm, myocardial infarction and myocardial stunning.

[0641] Cardiovascular diseases also include vascular diseases such as aneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis, Hippel-Lindau Disease, Klippel-Trenaunay-Weber Syndrome, Sturge-Weber Syndrome, angioneurotic edema, aortic diseases, Takayasu's Arteritis, aortitis, Leriche's Syndrome, arterial occlusive diseases, arteritis, enarteritis, polyarteritis nodosa, cerebrovascular disorders, diabetic angiopathies, diabetic retinopathy, embolisms, thrombosis, erythromelalgia, hemorrhoids, hepatic veno-occlusive disease, hypertension, hypotension, ischemia, peripheral vascular diseases, phlebitis, pulmonary veno-occlusive disease, Raynaud's disease, CREST syndrome, retinal vein occlusion, Scimitar syndrome, superior vena cava syndrome, telangiectasia, atacia telangiectasia, hereditary hemorrhagic telangiectasia, varicocele, varicose veins, varicose ulcer, vasculitis, and venous insufficiency.

[0642] Aneurysms include, but are not limited to, dissecting aneurysms, false aneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms, cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliac aneurysms.

[0643] Arterial occlusive diseases include, but are not limited to, arteriosclerosis, intermittent claudication, carotid stenosis, fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoya disease, renal artery obstruction, retinal artery occlusion, and thromboangiitis obliterans.

[0644] Cerebrovascular disorders include, but are not limited to, carotid artery diseases, cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arterioyenous malformation, cerebral artery diseases, cerebral embolism and thrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg's syndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma, subaraxhnoid hemorrhage, cerebral infarction, cerebral ischemia (including transient), subclavian steal syndrome, periventricular leukomalacia, vascular headache, cluster headache, migraine, and vertebrobasilar insufficiency.

[0645] Embolisms include, but are not limited to, air embolisms, amniotic fluid embolisms, cholesterol embolisms, blue toe syndrome, fat embolisms, pulmonary embolisms, and thromoboembolisms. Thrombosis include, but are not limited to, coronary thrombosis, hepatic vein thrombosis, retinal vein occlusion, carotid artery thrombosis, sinus thrombosis, Wallenberg's syndrome, and thrombophlebitis.

[0646] Ischemic disorders include, but are not limited to, cerebral ischemia, ischemic colitis, compartment syndromes, anterior compartment syndrome, myocardial ischemia, reperfusion injuries, and peripheral limb ischemia. Vasculitis includes, but is not limited to, aortitis, arteritis, Behcet's Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph node syndrome, thromboangiitis obliterans, hypersensitivity vasculitis, Schoenlein-Henoch purpura, allergic cutaneous vasculitis, and Wegener's granulomatosis.

[0647] Polypeptides may be administered using any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, biolistic injectors, particle accelerators, gelfoam sponge depots, other commercially available depot materials, osmotic pumps, oral or suppositorial solid pharmaceutical formulations, decanting or topical applications during surgery, aerosol delivery. Such methods are known in the art. Polypeptides may be administered as part of a Therapeutic, described in more detail below. Methods of delivering polynucleotides are described in more detail herein.

[0648] Respiratory Disorders

[0649] Polynucleotides or polypeptides, or agonists or antagonists of the present invention may be used to treat, prevent, diagnose, and/or prognose diseases and/or disorders of the respiratory system.

[0650] Diseases and disorders of the respiratory system include, but are not limited to, nasal vestibulitis, nonallergic rhinitis (e.g., acute rhinitis, chronic rhinitis, atrophic rhinitis, vasomotor rhinitis), nasal polyps, and sinusitis, juvenile angiofibromas, cancer of the nose and juvenile papillomas, vocal cord polyps, nodules (singer's nodules), contact ulcers, vocal cord paralysis, laryngoceles, pharyngitis (e.g., viral and bacterial), tonsillitis, tonsillar cellulitis, parapharyngeal abscess, laryngitis, laryngoceles, and throat cancers (e.g., cancer of the nasopharynx, tonsil cancer, larynx cancer), lung cancer (e.g., squamous cell carcinoma, small cell (oat cell) carcinoma, large cell carcinoma, and adenocarcinoma), allergic disorders (eosinophilic pneumonia, hypersensitivity pneumonitis (e.g., extrinsic allergic alveolitis, allergic interstitial pneumonitis, organic dust pneumoconiosis, allergic bronchopulmonary aspergillosis, asthma, Wegener's granulomatosis (granulomatous vasculitis), Goodpasture's syndrome)), pneumonia (e.g., bacterial pneumonia (e.g., Streptococcus pneumoniae (pneumoncoccal pneumonia), Staphylococcus aureus (staphylococcal pneumonia), Gram-negative bacterial pneumonia (caused by, e.g., Klebsiella and Pseudomas spp.), Mycoplasma pneumoniae pneumonia, Hemophilus influenzae pneumonia, Legionella pneumophila (Legionnaires' disease), and Chlamydia psittaci (Psittacosis)), and viral pneumonia (e.g., influenza, chickenpox (varicella).

[0651] Additional diseases and disorders of the respiratory system include, but are not limited to bronchiolitis, polio (poliomyelitis), croup, respiratory syncytial viral infection, mumps, erythema infectiosum (fifth disease), roseola infantum, progressive rubella panencephalitis, german measles, and subacute sclerosing panencephalitis), fungal pneumonia (e.g., Histoplasmosis, Coccidioidomycosis, Blastomycosis, fungal infections in people with severely suppressed immune systems (e.g., cryptococcosis, caused by Cryptococcus neoformans; aspergillosis, caused by Aspergillus spp.; candidiasis, caused by Candida; and mucormycosis)), Pneumocystis carinii (pneumocystis pneumonia), a typical pneumonias (e.g., Mycoplasma and Chlamydia spp.), opportunistic infection pneumonia, nosocomial pneumonia, chemical pneumonitis, and aspiration pneumonia, pleural disorders (e.g., pleurisy, pleural effusion, and pneumothorax (e.g., simple spontaneous pneumothorax, complicated spontaneous pneumothorax, tension pneumothorax)), obstructive airway diseases (e.g., asthma, chronic obstructive pulmonary disease (COPD), emphysema, chronic or acute bronchitis), occupational lung diseases (e.g., silicosis, black lung (coal workers' pneumoconiosis), asbestosis, berylliosis, occupational asthsma, byssinosis, and benign pneumoconioses), Infiltrative Lung Disease (e.g., pulmonary fibrosis (e.g., fibrosing alveolitis, usual interstitial pneumonia), idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, histiocytosis X (e.g., Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilic granuloma), idiopathic pulmonary hemosiderosis, sarcoidosis and pulmonary alveolar proteinosis), Acute respiratory distress syndrome (also called, e.g., adult respiratory distress syndrome), edema, pulmonary embolism, bronchitis (e.g., viral, bacterial), bronchiectasis, atelectasis, lung abscess (caused by, e.g., Staphylococcus aureus or Legionella pneumophila), and cystic fibrosis.

[0652] Anti-Angiogenesis Activity

[0653] The naturally occurring balance between endogenous stimulators and inhibitors of angiogenesis is one in which inhibitory influences predominate. Rastinejad et al., Cell 56:345-355 (1989). In those rare instances in which neovascularization occurs under normal physiological conditions, such as wound healing, organ regeneration, embryonic development, and female reproductive processes, angiogenesis is stringently regulated and spatially and temporally delimited. Under conditions of pathological angiogenesis such as that characterizing solid tumor growth, these regulatory controls fail. Unregulated angiogenesis becomes pathologic and sustains progression of many neoplastic and non-neoplastic diseases. A number of serious diseases are dominated by abnormal neovascularization including solid tumor growth and metastases, arthritis, some types of eye disorders, and psoriasis. See, e.g., reviews by Moses et al., Biotech. 9:630-634 (1991); Folkman et al., N. Engl. J. Med., 333:1757-1763 (1995); Auerbach et al., J Microvasc. Res. 29:401-411 (1985); Folkman, Advances in Cancer Research, eds. Klein and Weinhouse, Academic Press, New York, pp. 175-203 (1985); Patz, Am. J. Opthalmol. 94:715-743 (1982); and Folkman et al., Science 221:719-725 (1983). In a number of pathological conditions, the process of angiogenesis contributes to the disease state. For example, significant data have accumulated which suggest that the growth of solid tumors is dependent on angiogenesis. Folkman and Klagsbrun, Science 235:442-447 (1987).

[0654] The present invention provides for treatment of diseases or disorders associated with neovascularization by administration of the polynucleotides and/or polypeptides of the invention, as well as agonists or antagonists of the present invention. Malignant and metastatic conditions which can be treated with the polynucleotides and polypeptides, or agonists or antagonists of the invention include, but are not limited to, malignancies, solid tumors, and cancers described herein and otherwise known in the art (for a review of such disorders, see Fishman et al., Medicine, 2d Ed., J. B. Lippincott Co., Philadelphia (1985)). Thus, the present invention provides a method of treating an angiogenesis-related disease and/or disorder, comprising administering to an individual in need thereof a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist of the invention. For example, polynucleotides, polypeptides, antagonists and/or agonists may be utilized in a variety of additional methods in order to therapeutically treat a cancer or tumor. Cancers which may be treated with polynucleotides, polypeptides, antagonists and/or agonists include, but are not limited to solid tumors, including prostate, lung, breast, ovarian, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, thyroid cancer; primary tumors and metastases; melanomas; glioblastoma; Kaposi's sarcoma; leiomyosarcoma; non-small cell lung cancer; colorectal cancer; advanced malignancies; and blood born tumors such as leukemias. For example, polynucleotides, polypeptides, antagonists and/or agonists may be delivered topically, in order to treat cancers such as skin cancer, head and neck tumors, breast tumors, and Kaposi's sarcoma.

[0655] Within yet other aspects, polynucleotides, polypeptides, antagonists and/or agonists may be utilized to treat superficial forms of bladder cancer by, for example, intravesical administration. Polynucleotides, polypeptides, antagonists and/or agonists may be delivered directly into the tumor, or near the tumor site, via injection or a catheter. Of course, as the artisan of ordinary skill will appreciate, the appropriate mode of administration will vary according to the cancer to be treated. Other modes of delivery are discussed herein.

[0656] Polynucleotides, polypeptides, antagonists and/or agonists may be useful in treating other disorders, besides cancers, which involve angiogenesis. These disorders include, but are not limited to: benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, uvietis and Pterygia (abnormal blood vessel growth) of the eye; rheumatoid arthritis; psoriasis; delayed wound healing; endometriosis; vasculogenesis; granulations; hypertrophic scars (keloids); nonunion fractures; scleroderma; trachoma; vascular adhesions; myocardial angiogenesis; coronary collaterals; cerebral collaterals; arterioyenous malformations; ischemic limb angiogenesis; Osler-Webber Syndrome; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; fibromuscular dysplasia; wound granulation; Crohn's disease; and atherosclerosis.

[0657] For example, within one aspect of the present invention methods are provided for treating hypertrophic scars and keloids, comprising the step of administering a polynucleotide, polypeptide, antagonist and/or agonist of the invention to a hypertrophic scar or keloid.

[0658] Within one embodiment of the present invention polynucleotides, polypeptides, antagonists and/or agonists of the invention are directly injected into a hypertrophic scar or keloid, in order to prevent the progression of these lesions. This therapy is of particular value in the prophylactic treatment of conditions which are known to result in the development of hypertrophic scars and keloids (e.g., bums), and is preferably initiated after the proliferative phase has had time to progress (approximately 14 days after the initial injury), but before hypertrophic scar or keloid development. As noted above, the present invention also provides methods for treating neovascular diseases of the eye, including for example, comeal neovascularization, neovascular glaucoma, proliferative diabetic retinopathy, retrolental fibroplasia and macular degeneration.

[0659] Moreover, Ocular disorders associated with neovascularization which can be treated with the polynucleotides and polypeptides of the present invention (including agonists and/or antagonists) include, but are not limited to: neovascular glaucoma, diabetic retinopathy, retinoblastoma, retrolental fibroplasia, uveitis, retinopathy of prematurity macular degeneration, comeal graft neovascularization, as well as other eye inflammatory diseases, ocular tumors and diseases associated with choroidal or iris neovascularization. See, e.g., reviews by Waltman et al., Am. J. Ophthal. 85:704-710 (1978) and Gartner et al, Surv. Ophthal. 22:291-312 (1978).

[0660] Thus, within one aspect of the present invention methods are provided for treating neovascular diseases of the eye such as corneal neovascularization (including corneal graft neovascularization), comprising the step of administering to a patient a therapeutically effective amount of a compound (as described above) to the cornea, such that the formation of blood vessels is inhibited. Briefly, the cornea is a tissue which normally lacks blood vessels. In certain pathological conditions however, capillaries may extend into the cornea from the pericorneal vascular plexus of the limbus. When the cornea becomes vascularized, it also becomes clouded, resulting in a decline in the patient's visual acuity. Visual loss may become complete if the cornea completely opacitates. A wide variety of disorders can result in corneal neovascularization, including for example, corneal infections (e.g., trachoma, herpes simplex keratitis, leishmaniasis and onchocerciasis), immunological processes (e.g., graft rejection and Stevens-Johnson's syndrome), alkali bums, trauma, inflammation (of any cause), toxic and nutritional deficiency states, and as a complication of wearing contact lenses.

[0661] Within particularly preferred embodiments of the invention, may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form. The solution or suspension may be prepared in its pure form and administered several times daily. Alternatively, anti-angiogenic compositions, prepared as described above, may also be administered directly to the cornea. Within preferred embodiments, the anti-angiogenic composition is prepared with a muco-adhesive polymer which binds to cornea. Within further embodiments, the anti-angiogenic factors or anti-angiogenic compositions may be utilized as an adjunct to conventional steroid therapy. Topical therapy may also be useful prophylactically in corneal lesions which are known to have a high probability of inducing an angiogenic response (such as chemical burns). In these instances the treatment, likely in combination with steroids, may be instituted immediately to help prevent subsequent complications.

[0662] Within other embodiments, the compounds described above may be injected directly into the corneal stroma by an ophthalmologist under microscopic guidance. The preferred site of injection may vary with the morphology of the individual lesion, but the goal of the administration would be to place the composition at the advancing front of the vasculature (i.e., interspersed between the blood vessels and the normal cornea). In most cases this would involve perilimbic corneal injection to “protect” the cornea from the advancing blood vessels. This method may also be utilized shortly after a corneal insult in order to prophylactically prevent corneal neovascularization. In this situation the material could be injected in the perilimbic cornea interspersed between the corneal lesion and its undesired potential limbic blood supply. Such methods may also be utilized in a similar fashion to prevent capillary invasion of transplanted corneas. In a sustained-release form injections might only be required 2-3 times per year. A steroid could also be added to the injection solution to reduce inflammation resulting from the injection itself.

[0663] Within another aspect of the present invention, methods are provided for treating neovascular glaucoma, comprising the step of administering to a patient a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist to the eye, such that the formation of blood vessels is inhibited. In one embodiment, the compound may be administered topically to the eye in order to treat early forms of neovascular glaucoma. Within other embodiments, the compound may be implanted by injection into the region of the anterior chamber angle. Within other embodiments, the compound may also be placed in any location such that the compound is continuously released into the aqueous humor. Within another aspect of the present invention, methods are provided for treating proliferative diabetic retinopathy, comprising the step of administering to a patient a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist to the eyes, such that the formation of blood vessels is inhibited.

[0664] Within particularly preferred embodiments of the invention, proliferative diabetic retinopathy may be treated by injection into the aqueous humor or the vitreous, in order to increase the local concentration of the polynucleotide, polypeptide, antagonist and/or agonist in the retina. Preferably, this treatment should be initiated prior to the acquisition of severe disease requiring photocoagulation.

[0665] Within another aspect of the present invention, methods are provided for treating retrolental fibroplasia, comprising the step of administering to a patient a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist to the eye, such that the formation of blood vessels is inhibited. The compound may be administered topically, via intravitreous injection and/or via intraocular implants.

[0666] Additionally, disorders which can be treated with the polynucleotides, polypeptides, agonists and/or agonists include, but are not limited to, hemangioma, arthritis, psoriasis, angiofibroma, atherosclerotic plaques, delayed wound healing, granulations, hemophilic joints, hypertrophic scars, nonunion fractures, Osler-Weber syndrome, pyogenic granuloma, scleroderma, trachoma, and vascular adhesions.

[0667] Moreover, disorders and/or states, which can be treated, prevented, diagnosed, and/or prognosed with the the polynucleotides, polypeptides, agonists and/or agonists of the invention include, but are not limited to, solid tumors, blood born tumors such as leukemias, tumor metastasis, Kaposi's sarcoma, benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas, rheumatoid arthritis, psoriasis, ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, and uvietis, delayed wound healing, endometriosis, vascluogenesis, granulations, hypertrophic scars (keloids), nonunion fractures, scleroderma, trachoma, vascular adhesions, myocardial angiogenesis, coronary collaterals, cerebral collaterals, arterioyenous malformations, ischemic limb angiogenesis, Osler-Webber Syndrome, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma fibromuscular dysplasia, wound granulation, Crohn's disease, atherosclerosis, birth control agent by preventing vascularization required for embryo implantation controlling menstruation, diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele minalia quintosa), ulcers (Helicobacter pylori), Bartonellosis and bacillary angiomatosis.

[0668] In one aspect of the birth control method, an amount of the compound sufficient to block embryo implantation is administered before or after intercourse and fertilization have occurred, thus providing an effective method of birth control, possibly a “morning after” method. Polynucleotides, polypeptides, agonists and/or agonists may also be used in controlling menstruation or administered as either a peritoneal lavage fluid or for peritoneal implantation in the treatment of endometriosis.

[0669] Polynucleotides, polypeptides, agonists and/or agonists of the present invention may be incorporated into surgical sutures in order to prevent stitch granulomas.

[0670] Polynucleotides, polypeptides, agonists and/or agonists may be utilized in a wide variety of surgical procedures. For example, within one aspect of the present invention a compositions (in the form of, for example, a spray or film) may be utilized to coat or spray an area prior to removal of a tumor, in order to isolate normal surrounding tissues from malignant tissue, and/or to prevent the spread of disease to surrounding tissues. Within other aspects of the present invention, compositions (e.g., in the form of a spray) may be delivered via endoscopic procedures in order to coat tumors, or inhibit angiogenesis in a desired locale. Within yet other aspects of the present invention, surgical meshes which have been coated with anti-angiogenic compositions of the present invention may be utilized in any procedure wherein a surgical mesh might be utilized. For example, within one embodiment of the invention a surgical mesh laden with an anti-angiogenic composition may be utilized during abdominal cancer resection surgery (e.g., subsequent to colon resection) in order to provide support to the structure, and to release an amount of the anti-angiogenic factor.

[0671] Within further aspects of the present invention, methods are provided for treating tumor excision sites, comprising administering a polynucleotide, polypeptide, agonist and/or agonist to the resection margins of a tumor subsequent to excision, such that the local recurrence of cancer and the formation of new blood vessels at the site is inhibited. Within one embodiment of the invention, the anti-angiogenic compound is administered directly to the tumor excision site (e.g., applied by swabbing, brushing or otherwise coating the resection margins of the tumor with the anti-angiogenic compound). Alternatively, the anti-angiogenic compounds may be incorporated into known surgical pastes prior to administration. Within particularly preferred embodiments of the invention, the anti-angiogenic compounds are applied after hepatic resections for malignancy, and after neurosurgical operations.

[0672] Within one aspect of the present invention, polynucleotides, polypeptides, agonists and/or agonists may be administered to the resection margin of a wide variety of tumors, including for example, breast, colon, brain and hepatic tumors. For example, within one embodiment of the invention, anti-angiogenic compounds may be administered to the site of a neurological tumor subsequent to excision, such that the formation of new blood vessels at the site are inhibited.

[0673] The polynucleotides, polypeptides, agonists and/or agonists of the present invention may also be administered along with other anti-angiogenic factors. Representative examples of other anti-angiogenic factors include: Anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel, Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of the lighter “d group” transition metals.

[0674] Lighter “d group” transition metals include, for example, vanadium, molybdenum, tungsten, titanium, niobium, and tantalum species. Such transition metal species may form transition metal complexes. Suitable complexes of the above-mentioned transition metal species include oxo transition metal complexes.

[0675] Representative examples of vanadium complexes include oxo vanadium complexes such as vanadate and vanadyl complexes. Suitable vanadate complexes include metavanadate and orthovanadate complexes such as, for example, ammonium metavanadate, sodium metavanadate, and sodium orthovanadate. Suitable vanadyl complexes include, for example, vanadyl acetylacetonate and vanadyl sulfate including vanadyl sulfate hydrates such as vanadyl sulfate mono- and trihydrates.

[0676] Representative examples of tungsten and molybdenum complexes also include oxo complexes. Suitable oxo tungsten complexes include tungstate and tungsten oxide complexes. Suitable tungstate complexes include ammonium tungstate, calcium tungstate, sodium tungstate dihydrate, and tungstic acid. Suitable tungsten oxides include tungsten (IV) oxide and tungsten (VI) oxide. Suitable oxo molybdenum complexes include molybdate, molybdenum oxide, and molybdenyl complexes. Suitable molybdate complexes include ammonium molybdate and its hydrates, sodium molybdate and its hydrates, and potassium molybdate and its hydrates. Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum (VI) oxide, and molybdic acid. Suitable molybdenyl complexes include, for example, molybdenyl acetylacetonate. Other suitable tungsten and molybdenum complexes include hydroxo derivatives derived from, for example, glycerol, tartaric acid, and sugars.

[0677] A wide variety of other anti-angiogenic factors may also be utilized within the context of the present invention. Representative examples include platelet factor 4; protamine sulphate; sulphated chitin derivatives (prepared from queen crab shells), (Murata et al., Cancer Res. 51:22-26, 1991); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine; modulators of matrix metabolism, including for example, proline analogs, cishydroxyproline, d,L-3,4-dehydroproline, Thiaproline, alpha,alpha-dipyridyl, aminopropionitrile fumarate; 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone; Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326, 1992); Chymostatin (Tomkinson et al., Biochem J. 286:475-480, 1992); Cyclodextrin Tetradecasulfate; Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557, 1990); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin. Invest. 79:1440-1446, 1987); anticollagenase-serum; alpha2-antiplasmin (Holmes et al., J. Biol. Chem. 262(4):1659-1664, 1987); Bisantrene (National Cancer Institute); Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”; Takeuchi et al., Agents Actions 36:312-316, 1992); Thalidomide; Angostatic steroid; AGM-1470; carboxynaminolmidazole; and metalloproteinase inhibitors such as BB94.

[0678] Diseases at the Cellular Level

[0679] Diseases associated with increased cell survival or the inhibition of apoptosis that could be treated, prevented, diagnosed, and/or prognosed using polynucleotides or polypeptides, as well as antagonists or agonists of the present invention, include cancers (such as follicular lymphomas, carcinomas with p53 mutations, and hormone-dependent tumors, including, but not limited to colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi's sarcoma and ovarian cancer); autoimmune disorders (such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) and viral infections (such as herpes viruses, pox viruses and adenoviruses), inflammation, graft v. host disease, acute graft rejection, and chronic graft rejection.

[0680] In preferred embodiments, polynucleotides, polypeptides, and/or antagonists of the invention are used to inhibit growth, progression, and/or metasis of cancers, in particular those listed above.

[0681] Additional diseases or conditions associated with increased cell survival that could be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.

[0682] Diseases associated with increased apoptosis that could be treated, prevented, diagnosed, and/or prognesed using polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, include, but are not limited to, AIDS; neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Retinitis pigmentosa, Cerebellar degeneration and brain tumor or prior associated disease); autoimmune disorders (such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) myelodysplastic syndromes (such as aplastic anemia), graft v. host disease, ischemic injury (such as that caused by myocardial infarction, stroke and reperfusion injury), liver injury (e.g., hepatitis related liver injury, ischemia/reperfusion injury, cholestosis (bile duct injury) and liver cancer); toxin-induced liver disease (such as that caused by alcohol), septic shock, cachexia and anorexia.

[0683] Wound Healing and Epithelial Cell Proliferation

[0684] In accordance with yet a further aspect of the present invention, there is provided a process for utilizing polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, for therapeutic purposes, for example, to stimulate epithelial cell proliferation and basal keratinocytes for the purpose of wound healing, and to stimulate hair follicle production and healing of dermal wounds. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may be clinically useful in stimulating wound healing including surgical wounds, excisional wounds, deep wounds involving damage of the dermis and epidermis, eye tissue wounds, dental tissue wounds, oral cavity wounds, diabetic ulcers, dermal ulcers, cubitus ulcers, arterial ulcers, venous stasis ulcers, burns resulting from heat exposure or chemicals, and other abnormal wound healing conditions such as uremia, malnutrition, vitamin deficiencies and complications associated with systemic treatment with steroids, radiation therapy and antineoplastic drugs and antimetabolites. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to promote dermal reestablishment subsequent to dermal loss

[0685] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to increase the adherence of skin grafts to a wound bed and to stimulate re-epithelialization from the wound bed. The following are types of grafts that polynucleotides or polypeptides, agonists or antagonists of the present invention, could be used to increase adherence to a wound bed: autografts, artificial skin, allografts, autodermic graft, autoepdermic grafts, avacular grafts, Blair-Brown grafts, bone graft, brephoplastic grafts, cutis graft, delayed graft, dermic graft, epidermic graft, fascia graft, full thickness graft, heterologous graft, xenograft, homologous graft, hyperplastic graft, lamellar graft, mesh graft, mucosal graft, Ollier-Thiersch graft, omenpal graft, patch graft, pedicle graft, penetrating graft, split skin graft, thick split graft. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, can be used to promote skin strength and to improve the appearance of aged skin.

[0686] It is believed that polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, will also produce changes in hepatocyte proliferation, and epithelial cell proliferation in the lung, breast, pancreas, stomach, small intestine, and large intestine. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could promote proliferation of epithelial cells such as sebocytes, hair follicles, hepatocytes, type II pneumocytes, mucin-producing goblet cells, and other epithelial cells and their progenitors contained within the skin, lung, liver, and gastrointestinal tract. Polynucleotides or polypeptides, agonists or antagonists of the present invention, may promote proliferation of endothelial cells, keratinocytes, and basal keratinocytes.

[0687] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could also be used to reduce the side effects of gut toxicity that result from radiation, chemotherapy treatments or viral infections. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may have a cytoprotective effect on the small intestine mucosa. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may also stimulate healing of mucositis (mouth ulcers) that result from chemotherapy and viral infections.

[0688] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could further be used in full regeneration of skin in full and partial thickness skin defects, including burns, (i.e., repopulation of hair follicles, sweat glands, and sebaceous glands), treatment of other skin defects such as psoriasis. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to treat epidermolysis bullosa, a defect in adherence of the epidermis to the underlying dermis which results in frequent, open and painful blisters by accelerating reepithelialization of these lesions. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could also be used to treat gastric and doudenal ulcers and help heal by scar formation of the mucosal lining and regeneration of glandular mucosa and duodenal mucosal lining more rapidly. Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, are diseases which result in destruction of the mucosal surface of the small or large intestine, respectively. Thus, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to promote the resurfacing of the mucosal surface to aid more rapid healing and to prevent progression of inflammatory bowel disease. Treatment with polynucleotides or polypeptides, agonists or antagonists of the present invention, is expected to have a significant effect on the production of mucus throughout the gastrointestinal tract and could be used to protect the intestinal mucosa from injurious substances that are ingested or following surgery. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to treat diseases associate with the under expression.

[0689] Moreover, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to prevent and heal damage to the lungs due to various pathological states. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, which could stimulate proliferation and differentiation and promote the repair of alveoli and brochiolar epithelium to prevent or treat acute or chronic lung damage. For example, emphysema, which results in the progressive loss of aveoli, and inhalation injuries, i.e., resulting from smoke inhalation and burns, that cause necrosis of the bronchiolar epithelium and alveoli could be effectively treated using polynucleotides or polypeptides, agonists or antagonists of the present invention. Also, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to stimulate the proliferation of and differentiation of type II pneumocytes, which may help treat or prevent disease such as hyaline membrane diseases, such as infant respiratory distress syndrome and bronchopulmonary displasia, in premature infants.

[0690] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could stimulate the proliferation and differentiation of hepatocytes and, thus, could be used to alleviate or treat liver diseases and pathologies such as fulminant liver failure caused by cirrhosis, liver damage caused by viral hepatitis and toxic substances (i.e., acetaminophen, carbon tetraholoride and other hepatotoxins known in the art).

[0691] In addition, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used treat or prevent the onset of diabetes mellitus. In patients with newly diagnosed Types I and II diabetes, where some islet cell function remains, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to maintain the islet function so as to alleviate, delay or prevent permanent manifestation of the disease. Also, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used as an auxiliary in islet cell transplantation to improve or promote islet cell function.

[0692] Endocrine Disorders

[0693] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose disorders and/or diseases related to hormone imbalance, and/or disorders or diseases of the endocrine system.

[0694] Hormones secreted by the glands of the endocrine system control physical growth, sexual function, metabolism, and other functions. Disorders may be classified in two ways: disturbances in the production of hormones, and the inability of tissues to respond to hormones. The etiology of these hormone imbalance or endocrine system diseases, disorders or conditions may be genetic, somatic, such as cancer and some autoimmune diseases, acquired (e.g., by chemotherapy, injury or toxins), or infectious. Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention can be used as a marker or detector of a particular disease or disorder related to the endocrine system and/or hormone imbalance.

[0695] Endocrine system and/or hormone imbalance and/or diseases encompass disorders of uterine motility including, but not limited to: complications with pregnancy and labor (e.g., pre-term labor, post-term pregnancy, spontaneous abortion, and slow or stopped labor); and disorders and/or diseases of the menstrual cycle (e.g., dysmenorrhea and endometriosis).

[0696] Endocrine system and/or hormone imbalance disorders and/or diseases include disorders and/or diseases of the pancreas, such as, for example, diabetes mellitus, diabetes insipidus, congenital pancreatic agenesis, pheochromocytoma—islet cell tumor syndrome; disorders and/or diseases of the adrenal glands such as, for example, Addison's Disease, corticosteroid deficiency, virilizing disease, hirsutism, Cushing's Syndrome, hyperaldosteronism, pheochromocytoma; disorders and/or diseases of the pituitary gland, such as, for example, hyperpituitarism, hypopituitarism, pituitary dwarfism, pituitary adenoma, panhypopituitarism, acromegaly, gigantism; disorders and/or diseases of the thyroid, including but not limited to, hyperthyroidism, hypothyroidism, Plummer's disease, Graves' disease (toxic diffuse goiter), toxic nodular goiter, thyroiditis (Hashimoto's thyroiditis, subacute granulomatous thyroiditis, and silent lymphocytic thyroiditis), Pendred's syndrome, myxedema, cretinism, thyrotoxicosis, thyroid hormone coupling defect, thymic aplasia, Hurthle cell tumours of the thyroid, thyroid cancer, thyroid carcinoma, Medullary thyroid carcinoma; disorders and/or diseases of the parathyroid, such as, for example, hyperparathyroidism, hypoparathyroidism; disorders and/or diseases of the hypothalamus.

[0697] In addition, endocrine system and/or hormone imbalance disorders and/or diseases may also include disorders and/or diseases of the testes or ovaries, including cancer. Other disorders and/or diseases of the testes or ovaries further include, for example, ovarian cancer, polycystic ovary syndrome, Klinefelter's syndrome, vanishing testes syndrome (bilateral anorchia), congenital absence of Leydig's cells, cryptorchidism, Noonan's syndrome, myotonic dystrophy, capillary haemangioma of the testis (benign), neoplasias of the testis and neo-testis.

[0698] Moreover, endocrine system and/or hormone imbalance disorders and/or diseases may also include disorders and/or diseases such as, for example, polyglandular deficiency syndromes, pheochromocytoma, neuroblastoma, multiple Endocrine neoplasia, and disorders and/or cancers of endocrine tissues.

[0699] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose, prognose, prevent, and/or treat endocrine diseases and/or disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).

[0700] Reproductive System Disorders

[0701] The polynucleotides or polypeptides, or agonists or antagonists of the invention may be used for the diagnosis, treatment, or prevention of diseases and/or disorders of the reproductive system. Reproductive system disorders that can be treated by the compositions of the invention, include, but are not limited to, reproductive system injuries, infections, neoplastic disorders, congenital defects, and diseases or disorders which result in infertility, complications with pregnancy, labor, or parturition, and postpartum difficulties.

[0702] Reproductive system disorders and/or diseases include diseases and/or disorders of the testes, including testicular atrophy, testicular feminization, cryptorchism (unilateral and bilateral), anorchia, ectopic testis, epididymitis and orchitis (typically resulting from infections such as, for example, gonorrhea, mumps, tuberculosis, and syphilis), testicular torsion, vasitis nodosa, germ cell tumors (e.g., seminomas, embryonal cell carcinomas, teratocarcinomas, choriocarcinomas, yolk sac tumors, and teratomas), stromal tumors (e.g., Leydig cell tumors), hydrocele, hematocele, varicocele, spermatocele, inguinal hernia, and disorders of sperm production (e.g., immotile cilia syndrome, aspermia, asthenozoospermia, azoospermia, oligospermia, and teratozoospermia).

[0703] Reproductive system disorders also include disorders of the prostate gland, such as acute non-bacterial prostatitis, chronic non-bacterial prostatitis, acute bacterial prostatitis, chronic bacterial prostatitis, prostatodystonia, prostatosis, granulomatous prostatitis, malacoplakia, benign prostatic hypertrophy or hyperplasia, and prostate neoplastic disorders, including adenocarcinomas, transitional cell carcinomas, ductal carcinomas, and squamous cell carcinomas.

[0704] Additionally, the compositions of the invention may be useful in the diagnosis, treatment, and/or prevention of disorders or diseases of the penis and urethra, including inflammatory disorders, such as balanoposthitis, balanitis xerotica obliterans, phimosis, paraphimosis, syphilis, herpes simplex virus, gonorrhea, non-gonococcal urethritis, chlamydia, mycoplasma, trichomonas, HIV, AIDS, Reiter's syndrome, condyloma acuminatum, condyloma latum, and pearly penile papules; urethral abnormalities, such as hypospadias, epispadias, and phimosis; premalignant lesions, including Erythroplasia of Queyrat, Bowen's disease, Bowenoid paplosis, giant condyloma of Buscke-Lowenstein, and varrucous carcinoma; penile cancers, including squamous cell carcinomas, carcinoma in situ, verrucous carcinoma, and disseminated penile carcinoma; urethral neoplastic disorders, including penile urethral carcinoma, bulbomembranous urethral carcinoma, and prostatic urethral carcinoma; and erectile disorders, such as priapism, Peyronie's disease, erectile dysfunction, and impotence.

[0705] Moreover, diseases and/or disorders of the vas deferens include vasculititis and CBAVD (congenital bilateral absence of the vas deferens); additionally, the polynucleotides, polypeptides, and agonists or antagonists of the present invention may be used in the diagnosis, treatment, and/or prevention of diseases and/or disorders of the seminal vesicles, including hydatid disease, congenital chloride diarrhea, and polycystic kidney disease.

[0706] Other disorders and/or diseases of the male reproductive system include, for example, Klinefelter's syndrome, Young's syndrome, premature ejaculation, diabetes mellitus, cystic fibrosis, Kartagener's syndrome, high fever, multiple sclerosis, and gynecomastia.

[0707] Further, the polynucleotides, polypeptides, and agonists or antagonists of the present invention may be used in the diagnosis, treatment, and/or prevention of diseases and/or disorders of the vagina and vulva, including bacterial vaginosis, candida vaginitis, herpes simplex virus, chancroid, granuloma inguinale, lymphogranuloma venereum, scabies, human papillomavirus, vaginal trauma, vulvar trauma, adenosis, chlamydia vaginitis, gonorrhea, trichomonas vaginitis, condyloma acuminatum, syphilis, molluscum contagiosum, atrophic vaginitis, Paget's disease, lichen sclerosus, lichen planus, vulvodynia, toxic shock syndrome, vaginismus, vulvovaginitis, vulvar vestibulitis, and neoplastic disorders, such as squamous cell hyperplasia, clear cell carcinoma, basal cell carcinoma, melanomas, cancer of Bartholin's gland, and vulvar intraepithelial neoplasia.

[0708] Disorders and/or diseases of the uterus include dysmenorrhea, retroverted uterus, endometriosis, fibroids, adenomyosis, anovulatory bleeding, amenorrhea, Cushing's syndrome, hydatidiform moles, Asherman's syndrome, premature menopause, precocious puberty, uterine polyps, dysfunctional uterine bleeding (e.g., due to aberrant hormonal signals), and neoplastic disorders, such as adenocarcinomas, keiomyosarcomas, and sarcomas. Additionally, the polypeptides, polynucleotides, or agonists or antagonists of the invention may be useful as a marker or detector of, as well as in the diagnosis, treatment, and/or prevention of congenital uterine abnormalities, such as bicornuate uterus, septate uterus, simple unicornuate uterus, unicornuate uterus with a noncavitary rudimentary horn, unicornuate uterus with a non-communicating cavitary rudimentary horn, unicornuate uterus with a communicating cavitary horn, arcuate uterus, uterine didelfus, and T-shaped uterus.

[0709] Ovarian diseases and/or disorders include anovulation, polycystic ovary syndrome (Stein-Leventhal syndrome), ovarian cysts, ovarian hypofunction, ovarian insensitivity to gonadotropins, ovarian overproduction of androgens, right ovarian vein syndrome, amenorrhea, hirutism, and ovarian cancer (including, but not limited to, primary and secondary cancerous growth, Sertoli-Leydig tumors, endometriod carcinoma of the ovary, ovarian papillary serous adenocarcinoma, ovarian mucinous adenocarcinoma, and Ovarian Krukenberg tumors).

[0710] Cervical diseases and/or disorders include cervicitis, chronic cervicitis, mucopurulent cervicitis, cervical dysplasia, cervical polyps, Nabothian cysts, cervical erosion, cervical incompetence, and cervical neoplasms (including, for example, cervical carcinoma, squamous metaplasia, squamous cell carcinoma, adenosquamous cell neoplasia, and columnar cell neoplasia).

[0711] Additionally, diseases and/or disorders of the reproductive system include disorders and/or diseases of pregnancy, including miscarriage and stillbirth, such as early abortion, late abortion, spontaneous abortion, induced abortion, therapeutic abortion, threatened abortion, missed abortion, incomplete abortion, complete abortion, habitual abortion, missed abortion, and septic abortion; ectopic pregnancy, anemia, Rh incompatibility, vaginal bleeding during pregnancy, gestational diabetes, intrauterine growth retardation, polyhydramnios, HELLP syndrome, abruptio placentae, placenta previa, hyperemesis, preeclampsia, eclampsia, herpes gestationis, and urticaria of pregnancy. Additionally, the polynucleotides, polypeptides, and agonists or antagonists of the present invention may be used in the diagnosis, treatment, and/or prevention of diseases that can complicate pregnancy, including heart disease, heart failure, rheumatic heart disease, congenital heart disease, mitral valve prolapse, high blood pressure, anemia, kidney disease, infectious disease (e.g., rubella, cytomegalovirus, toxoplasmosis, infectious hepatitis, chlamydia, HIV, AIDS, and genital herpes), diabetes mellitus, Graves' disease, thyroiditis, hypothyroidism, Hashimoto's thyroiditis, chronic active hepatitis, cirrhosis of the liver, primary biliary cirrhosis, asthma, systemic lupus eryematosis, rheumatoid arthritis, myasthenia gravis, idiopathic thrombocytopenic purpura, appendicitis, ovarian cysts, gallbladder disorders, and obstruction of the intestine.

[0712] Complications associated with labor and parturition include premature rupture of the membranes, pre-term labor, post-tern pregnancy, postmaturity, labor that progresses too slowly, fetal distress (e.g., abnormal heart rate (fetal or maternal), breathing problems, and abnormal fetal position), shoulder dystocia, prolapsed umbilical cord, amniotic fluid embolism, and aberrant uterine bleeding.

[0713] Further, diseases and/or disorders of the postdelivery period, including endometritis, myometritis, parametritis, peritonitis, pelvic thrombophlebitis, pulmonary embolism, endotoxemia, pyelonephritis, saphenous thrombophlebitis, mastitis, cystitis, postpartum hemorrhage, and inverted uterus.

[0714] Other disorders and/or diseases of the female reproductive system that may be diagnosed, treated, and/or prevented by the polynucleotides, polypeptides, and agonists or antagonists of the present invention include, for example, Turner's syndrome, pseudohermaphroditism, premenstrual syndrome, pelvic inflammatory disease, pelvic congestion (vascular engorgement), frigidity, anorgasmia, dyspareunia, ruptured fallopian tube, and Mittelschmerz.

[0715] Infectious Disease

[0716] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention can be used to treat or detect infectious agents. For example, by increasing the immune response, particularly increasing the proliferation and differentiation of B and/or T cells, infectious diseases may be treated. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may also directly inhibit the infectious agent, without necessarily eliciting an immune response.

[0717] Viruses are one example of an infectious agent that can cause disease or symptoms that can be treated or detected by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention. Examples of viruses, include, but are not limited to Examples of viruses, include, but are not limited to the following DNA and RNA viruses and viral families: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Dengue, EBV, HIV, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster), Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Orthomyxoviridae (e.g., Influenza A, Influenza B, and parainfluenza), Papiloma virus, Papovaviridae, Parvoviridae, Picomaviridae, Poxyiridae (such as Smallpox or Vaccinia), Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), and Togaviridae (e.g., Rubivirus). Viruses falling within these families can cause a variety of diseases or symptoms, including, but not limited to: arthritis, bronchiollitis, respiratory syncytial virus, encephalitis, eye infections (e.g., conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active, Delta), Japanese B encephalitis, Junin, Chikungunya, Rift Valley fever, yellow fever, meningitis, opportunistic infections (e.g., AIDS), pneumonia, Burkitt's Lymphoma, chickenpox, hemorrhagic fever, Measles, Mumps, Parainfluenza, Rabies, the common cold, Polio, leukemia, Rubella, sexually transmitted diseases, skin diseases (e.g., Kaposi's, warts), and viremia. polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used to treat or detect any of these symptoms or diseases. In specific embodiments, polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat: meningitis, Dengue, EBV, and/or hepatitis (e.g., hepatitis B). In an additional specific embodiment polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat patients nonresponsive to one or more other commercially available hepatitis vaccines. In a further specific embodiment polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat AIDS.

[0718] Similarly, bacterial and fungal agents that can cause disease or symptoms and that can be treated or detected by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention include, but not limited to, the following Gram-Negative and Gram-positive bacteria, bacterial families, and fungi: Actinomyces (e.g., Norcardia), Acinetobacter, Cryptococcus neoformans, Aspergillus, Bacillaceae (e.g., Bacillus anthrasis), Bacteroides (e.g., Bacteroides fragilis), Blastomycosis, Bordetella, Borrelia (e.g., Borrelia burgdorferi), Brucella, Candidia, Campylobacter, Chlamydia, Clostridium (e.g., Clostridium botulinum, Clostridium dificile, Clostridium perfringens, Clostridium tetani), Coccidioides, Corynebacterium (e.g., Corynebacterium diptheriae), Cryptococcus, Dermatocycoses, E. coli (e.g., Enterotoxigenic E. coli and Enterohemorrhagic E. coli), Enterobacter (e.g. Enterobacter aerogenes), Enterobacteriaceae (Klebsiella, Salmonella (e.g., Salmonella typhi, Salmonella enteritidis, Salmonella typhi), Serratia, Yersinia, Shigella), Erysipelothrix, Haemophilus (e.g., Haemophilus influenza type B), Helicobacter, Legionella (e.g., Legionella pneumophila), Leptospira, Listeria (e.g., Listeria monocytogenes), Mycoplasma, Mycobacterium (e.g., Mycobacterium leprae and Mycobacterium tuberculosis), Vibrio (e.g., Vibrio cholerae), Neisseriaceae (e.g., Neisseria gonorrhea, Neisseria meningitidis), Pasteurellacea, Proteus, Pseudomonas (e.g., Pseudomonas aeruginosa), Rickettsiaceae, Spirochetes (e.g., Treponema spp., Leptospira spp., Borrelia spp.), Shigella spp., Staphylococcus (e.g., Staphylococcus aureus), Meningiococcus, Pneumococcus and Streptococcus (e.g., Streptococcus pneumoniae and Groups A, B, and C Streptococci), and Ureaplasmas. These bacterial, parasitic, and fungal families can cause diseases or symptoms, including, but not limited to: antibiotic-resistant infections, bacteremia, endocarditis, septicemia, eye infections (e.g., conjunctivitis), uveitis, tuberculosis, gingivitis, bacterial diarrhea, opportunistic infections (e.g., AIDS related infections), paronychia, prosthesis-related infections, dental caries, Reiter's Disease, respiratory tract infections, such as Whooping Cough or Empyema, sepsis, Lyme Disease, Cat-Scratch Disease, dysentery, paratyphoid fever, food poisoning, Legionella disease, chronic and acute inflammation, erythema, yeast infections, typhoid, pneumonia, gonorrhea, meningitis (e.g., mengitis types A and B), chlamydia, syphillis, diphtheria, leprosy, brucellosis, peptic ulcers, anthrax, spontaneous abortions, birth defects, pneumonia, lung infections, ear infections, deafness, blindness, lethargy, malaise, vomiting, chronic diarrhea, Crohn's disease, colitis, vaginosis, sterility, pelvic inflammatory diseases, candidiasis, paratuberculosis, tuberculosis, lupus, botulism, gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexually transmitted diseases, skin diseases (e.g., cellulitis, dermatocycoses), toxemia, urinary tract infections, wound infections, noscomial infections. Polynucleotides or polypeptides, agonists or antagonists of the invention, can be used to treat or detect any of these symptoms or diseases. In specific embodiments, polynucleotides, polypeptides, agonists or antagonists of the invention are used to treat: tetanus, diptheria, botulism, and/or meningitis type B.

[0719] Moreover, parasitic agents causing disease or symptoms that can be treated, prevented, and/or diagnosed by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention include, but not limited to, the following families or class: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardias, Helminthiasis, Leishmaniasis, Schistisoma, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas and Sporozoans (e.g., Plasmodium virax, Plasmodium falciparium, Plasmodium malariae and Plasmodium ovale). These parasites can cause a variety of diseases or symptoms, including, but not limited to: Scabies, Trombiculiasis, eye infections, intestinal disease (e.g., dyseritery, giardiasis), liver disease, lung disease, opportunistic infections (e.g., AIDS related), malaria, pregnancy complications, and toxoplasmosis. polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used to treat, prevent, and/or diagnose any of these symptoms or diseases. In specific embodiments, polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat, prevent, and/or diagnose malaria.

[0720] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention of the present invention could either be by administering an effective amount of a polypeptide to the patient, or by removing cells from the patient, supplying the cells with a polynucleotide of the present invention, and returning the engineered cells to the patient (ex vivo therapy). Moreover, the polypeptide or polynucleotide of the present invention can be used as an antigen in a vaccine to raise an immune response against infectious disease.

[0721] Regeneration

[0722] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention can be used to differentiate, proliferate, and attract cells, leading to the regeneration of tissues. (See, Science 276:59-87 (1997)). The regeneration of tissues could be used to repair, replace, or protect tissue damaged by congenital defects, trauma (wounds, bums, incisions, or ulcers), age, disease (e.g. osteoporosis, osteocarthritis, periodontal disease, liver failure), surgery, including cosmetic plastic surgery, fibrosis, reperfusion injury, or systemic cytokine damage.

[0723] Tissues that could be regenerated using the present invention include organs (e.g., pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac), vasculature (including vascular and lymphatics), nervous, hematopoietic, and skeletal (bone, cartilage, tendon, and ligament) tissue. Preferably, regeneration occurs without or decreased scarring. Regeneration also may include angiogenesis.

[0724] Moreover, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may increase regeneration of tissues difficult to heal. For example, increased tendon/ligament regeneration would quicken recovery time after damage. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention could also be used prophylactically in an effort to avoid damage. Specific diseases that could be treated include of tendinitis, carpal tunnel syndrome, and other tendon or ligament defects. A further example of tissue regeneration of non-healing wounds includes pressure ulcers, ulcers associated with vascular insufficiency, surgical, and traumatic wounds.

[0725] Similarly, nerve and brain tissue could also be regenerated by using polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, to proliferate and differentiate nerve cells. Diseases that could be treated using this method include central and peripheral nervous system diseases, neuropathies, or mechanical and traumatic disorders (e.g., spinal cord disorders, head trauma, cerebrovascular disease, and stoke). Specifically, diseases associated with peripheral nerve injuries, peripheral neuropathy (e.g., resulting from chemotherapy or other medical therapies), localized neuropathies, and central nervous system diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome), could all be treated using the polynucleotides or polypeptides, as well as agonists or antagonists of the present invention.

[0726] Gastrointestinal Disorders

[0727] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose gastrointestinal disorders, including inflammatory diseases and/or conditions, infections, cancers (e.g., intestinal neoplasms (carcinoid tumor of the small intestine, non-Hodgkin's lymphoma of the small intestine, small bowl lymphoma)), and ulcers, such as peptic ulcers.

[0728] Gastrointestinal disorders include dysphagia, odynophagia, inflammation of the esophagus, peptic esophagitis, gastric reflux, submucosal fibrosis and stricturing, Mallory-Weiss lesions, leiomyomas, lipomas, epidermal cancers, adeoncarcinomas, gastric retention disorders, gastroenteritis, gastric atrophy, gastric/stomach cancers, polyps of the stomach, autoimmune disorders such as pernicious anemia, pyloric stenosis, gastritis (bacterial, viral, eosinophilic, stress-induced, chronic erosive, atrophic, plasma cell, and Ménétrier's), and peritoneal diseases (e.g., chyloperioneum, hemoperitoneum, mesenteric cyst, mesenteric lymphadenitis, mesenteric vascular occlusion, panniculitis, neoplasms, peritonitis, pneumoperitoneum, bubphrenic abscess,).

[0729] Gastrointestinal disorders also include disorders associated with the small intestine, such as malabsorption syndromes, distension, irritable bowel syndrome, sugar intolerance, celiac disease, duodenal ulcers, duodenitis, tropical sprue, Whipple's disease, intestinal lymphangiectasia, Crohn's disease, appendicitis, obstructions of the ileum, Meckel's diverticulum, multiple diverticula, failure of complete rotation of the small and large intestine, lymphoma, and bacterial and parasitic diseases (such as Traveler's diarrhea, typhoid and paratyphoid, cholera, infection by Roundworms (Ascariasis lumbricoides), Hookworms (Ancylostoma duodenale), Threadworms (Enterobius vermicularis), Tapeworms (Taenia saginata, Echinococcus granulosus, Diphyllobothrium spp., and T. solium).

[0730] Liver diseases and/or disorders include intrahepatic cholestasis (alagille syndrome, biliary liver cirrhosis), fatty liver (alcoholic fatty liver, reye syndrome), hepatic vein thrombosis, hepatolentricular degeneration, hepatomegaly, hepatopulmonary syndrome, hepatorenal syndrome, portal hypertension (esophageal and gastric varices), liver abscess (amebic liver abscess), liver cirrhosis (alcoholic, biliary and experimental), alcoholic liver diseases (fatty liver, hepatitis, cirrhosis), parasitic (hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (hemolytic, hepatocellular, and cholestatic), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (alcoholic hepatitis, animal hepatitis, chronic hepatitis (autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced), toxic hepatitis, viral human hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), Wilson's disease, granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, portal hypertension, varices, hepatic encephalopathy, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (hepatic encephalopathy, acute liver failure), and liver neoplasms (angiomyolipoma, calcified liver metastases, cystic liver metastases, epithelial tumors, fibrolamellar hepatocarcinoma, focal nodular hyperplasia, hepatic adenoma, hepatobiliary cystadenoma, hepatoblastoma, hepatocellular carcinoma, hepatoma, liver cancer, liver hemangioendothelioma, mesenchymal hamartoma, mesenchymal tumors of liver, nodular regenerative hyperplasia, benign liver tumors (Hepatic cysts [Simple cysts, Polycystic liver disease, Hepatobiliary cystadenoma, Choledochal cyst], Mesenchymal tumors [Mesenchymal hamartoma, Infantile hemangioendothelioma, Hemangioma, Peliosis hepatis, Lipomas, Inflammatory pseudotumor, Miscellaneous], Epithelial tumors [Bile duct epithelium (Bile duct hamartoma, Bile duct adenoma), Hepatocyte (Adenoma, Focal nodular hyperplasia, Nodular regenerative hyperplasia)], malignant liver tumors [hepatocellular, hepatoblastoma, hepatocellular carcinoma, cholangiocellular, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi's sarcoma, hemangioendothelioma, other tumors, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma]), peliosis hepatis, erythrohepatic porphyria, hepatic porphyria (acute intermittent porphyria, porphyria cutanea tarda), Zellweger syndrome).

[0731] Pancreatic diseases and/or disorders include acute pancreatitis, chronic pancreatitis (acute necrotizing pancreatitis, alcoholic pancreatitis), neoplasms (adenocarcinoma of the pancreas, cystadenocarcinoma, insulinoma, gastrinoma, and glucagonoma, cystic neoplasms, islet-cell tumors, pancreoblastoma), and other pancreatic diseases (e.g., cystic fibrosis, cyst (pancreatic pseudocyst, pancreatic fistula, insufficiency)).

[0732] Gallbladder diseases include gallstones (cholelithiasis and choledocholithiasis), postcholecystectomy syndrome, diverticulosis of the gallbladder, acute cholecystitis, chronic cholecystitis, bile duct tumors, and mucocele.

[0733] Diseases and/or disorders of the large intestine include antibiotic-associated colitis, diverticulitis, ulcerative colitis, acquired megacolon, abscesses, fungal and bacterial infections, anorectal disorders (e.g., fissures, hemorrhoids), colonic diseases (colitis, colonic neoplasms [colon cancer, adenomatous colon polyps (e.g., villous adenoma), colon carcinoma, colorectal cancer], colonic diverticulitis, colonic diverticulosis, megacolon [Hirschsprung disease, toxic megacolon]; sigmoid diseases [proctocolitis, sigmoin neoplasms]), constipation, Crohn's disease, diarrhea (infantile diarrhea, dysentery), duodenal diseases (duodenal neoplasms, duodenal obstruction, duodenal ulcer, duodenitis), enteritis (enterocolitis), HIV enteropathy, ileal diseases (ileal neoplasms, ileitis), immunoproliferative small intestinal disease, inflammatory bowel disease (ulcerative colitis, Crohn's disease), intestinal atresia, parasitic diseases (anisakiasis, balantidiasis, blastocystis infections, cryptosporidiosis, dientamoebiasis, amebic dysentery, giardiasis), intestinal fistula (rectal fistula), intestinal neoplasms (cecal neoplasms, colonic neoplasms, duodenal neoplasms, ileal neoplasms, intestinal polyps, jejunal neoplasms, rectal neoplasms), intestinal obstruction (afferent loop syndrome, duodenal obstruction, impacted feces, intestinal pseudo-obstruction [cecal volvulus], intussusception), intestinal perforation, intestinal polyps (colonic polyps, gardner syndrome, peutz-jeghers syndrome), jejunal diseases (jejunal neoplasms), malabsorption syndromes (blind loop syndrome, celiac disease, lactose intolerance, short bowl syndrome, tropical sprue, whipple's disease), mesenteric vascular occlusion, pneumatosis cystoides intestinalis, protein-losing enteropathies (intestinal lymphagiectasis), rectal diseases (anus diseases, fecal incontinence, hemorrhoids, proctitis, rectal fistula, rectal prolapse, rectocele), peptic ulcer (duodenal ulcer, peptic esophagitis, hemorrhage, perforation, stomach ulcer, Zollinger-Ellison syndrome), postgastrectomy syndromes (dumping syndrome), stomach diseases (e.g., achlorhydria, duodenogastric reflux (bile reflux), gastric antral vascular ectasia, gastric fistula, gastric outlet obstruction, gastritis (atrophic or hypertrophic), gastroparesis, stomach dilatation, stomach diverticulum, stomach neoplasms (gastric cancer, gastric polyps, gastric adenocarcinoma, hyperplastic gastric polyp), stomach rupture, stomach ulcer, stomach volvulus), tuberculosis, visceroptosis, vomiting (e.g., hematemesis, hyperemesis gravidarum, postoperative nausea and vomiting) and hemorrhagic colitis.

[0734] Further diseases and/or disorders of the gastrointestinal system include biliary tract diseases, such as, gastroschisis, fistula (e.g., biliary fistula, esophageal fistula, gastric fistula, intestinal fistula, pancreatic fistula), neoplasms (e.g., biliary tract neoplasms, esophageal neoplasms, such as adenocarcinoma of the esophagus, esophageal squamous cell carcinoma, gastrointestinal neoplasms, pancreatic neoplasms, such as adenocarcinoma of the pancreas, mucinous cystic neoplasm of the pancreas, pancreatic cystic neoplasms, pancreatoblastoma, and peritoneal neoplasms), esophageal disease (e.g., bullous diseases, candidiasis, glycogenic acanthosis, ulceration, barrett esophagus varices, atresia, cyst, diverticulum (e.g., Zenker's diverticulum), fistula (e.g., tracheoesophageal fistula), motility disorders (e.g., CREST syndrome, deglutition disorders, achalasia, spasm, gastroesophageal reflux), neoplasms, perforation (e.g., Boerhaave syndrome, Mallory-Weiss syndrome), stenosis, esophagitis, diaphragmatic hernia (e.g., hiatal hernia); gastrointestinal diseases, such as, gastroenteritis (e.g., cholera morbus, norwalk virus infection), hemorrhage (e.g., hematemesis, melena, peptic ulcer hemorrhage), stomach neoplasms (gastric cancer, gastric polyps, gastric adenocarcinoma, stomach cancer)), hernia (e.g., congenital diaphragmatic hernia, femoral hernia, inguinal hernia, obturator hernia, umbilical hernia, ventral hernia), and intestinal diseases (e.g., cecal diseases (appendicitis, cecal neoplasms)).

[0735] Chemotaxis

[0736] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may have chemotaxis activity. A chemotaxic molecule attracts or mobilizes cells (e.g., monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells) to a particular site in the body, such as inflammation, infection, or site of hyperproliferation. The mobilized cells can then fight off and/or heal the particular trauma or abnormality.

[0737] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may increase chemotaxic activity of particular cells. These chemotactic molecules can then be used to treat inflammation, infection, hyperproliferative disorders, or any immune system disorder by increasing the number of cells targeted to a particular location in the body. For example, chemotaxic molecules can be used to treat wounds and other trauma to tissues by attracting immune cells to the injured location. Chemotactic molecules of the present invention can also attract fibroblasts, which can be used to treat wounds.

[0738] It is also contemplated that polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may inhibit chemotactic activity. These molecules could also be used to treat disorders. Thus, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention could be used as an inhibitor of chemotaxis.

[0739] Binding Activity

[0740] A polypeptide of the present invention may be used to screen for molecules that bind to the polypeptide or for molecules to which the polypeptide binds. The binding of the polypeptide and the molecule may activate (agonist), increase, inhibit (antagonist), or decrease activity of the polypeptide or the molecule bound. Examples of such molecules include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.

[0741] Preferably, the molecule is closely related to the natural ligand of the polypeptide, e.g., a fragment of the ligand, or a natural substrate, a ligand, a structural or functional mimetic. (See, Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991)). Similarly, the molecule can be closely related to the natural receptor to which the polypeptide binds, or at least, a fragment of the receptor capable of being bound by the polypeptide (e.g., active site). In either case, the molecule can be rationally designed using known techniques.

[0742] Preferably, the screening for these molecules involves producing appropriate cells which express the polypeptide. Preferred cells include cells from mammals, yeast, Drosophila, or E. Coli. Cells expressing the polypeptide (or cell membrane containing the expressed polypeptide) are then preferably contacted with a test compound potentially containing the molecule to observe binding, stimulation, or inhibition of activity of either the polypeptide or the molecule.

[0743] The assay may simply test binding of a candidate compound to the polypeptide, wherein binding is detected by a label, or in an assay involving competition with a labeled competitor. Further, the assay may test whether the candidate compound results in a signal generated by binding to the polypeptide.

[0744] Alternatively, the assay can be carried out using cell-free preparations, polypeptide/molecule affixed to a solid support, chemical libraries, or natural product mixtures. The assay may also simply comprise the steps of mixing a candidate compound with a solution containing a polypeptide, measuring polypeptide/molecule activity or binding, and comparing the polypeptide/molecule activity or binding to a standard.

[0745] Preferably, an ELISA assay can measure polypeptide level or activity in a sample (e.g., biological sample) using a monoclonal or polyclonal antibody. The antibody can measure polypeptide level or activity by either binding, directly or indirectly, to the polypeptide or by competing with the polypeptide for a substrate.

[0746] Additionally, the receptor to which the polypeptide of the present invention binds can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting (Coligan, et al., Current Protocols in Immun., 1(2), Chapter 5, (1991)). For example, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the polypeptides, for example, NIH3T3 cells which are known to contain multiple receptors for the FGF family proteins, and SC-3 cells, and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the polypeptides. Transfected cells which are grown on glass slides are exposed to the polypeptide of the present invention, after they have been labeled. The polypeptides can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase.

[0747] Following fixation and incubation, the slides are subjected to auto-radiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an iterative sub-pooling and re-screening process, eventually yielding a single clones that encodes the putative receptor.

[0748] As an alternative approach for receptor identification, the labeled polypeptides can be photoaffinity linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE analysis and exposed to X-ray film. The labeled complex containing the receptors of the polypeptides can be excised, resolved into peptide fragments, and subjected to protein microsequencing. The amino acid sequence obtained from microsequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the genes encoding the putative receptors.

[0749] Moreover, the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as “DNA shuffling”) may be employed to modulate the activities of the polypeptide of the present invention thereby effectively generating agonists and antagonists of the polypeptide of the present invention. See generally, U.S. Pat. Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458, and Patten, P. A., et al., Curr. Opinion Biotechnol. 8:724-33 (1997); Harayama, S. Trends Biotechnol. 16(2):76-82 (1998); Hansson, L. O., et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo, M. M. and Blasco, R. Biotechniques 24(2):308-13 (1998); each of these patents and publications are hereby incorporated by reference). In one embodiment, alteration of polynucleotides and corresponding polypeptides may be achieved by DNA shuffling. DNA shuffling involves the assembly of two or more DNA segments into a desired molecule by homologous, or site-specific, recombination. In another embodiment, polynucleotides and corresponding polypeptides may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. In another embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of the polypeptide of the present invention may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules. In preferred embodiments, the heterologous molecules are family members. In further preferred embodiments, the heterologous molecule is a growth factor such as, for example, platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I), transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), fibroblast growth factor (FGF), TGF-beta, bone morphogenetic protein (BMP)-2, BMP-4, BMP-5, BMP-6, BMP-7, activins A and B, decapentaplegic(dpp), 60A, OP-2, dorsalin, growth differentiation factors (GDFs), nodal, MIS, inhibin-alpha, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta5, and glial-derived neurotrophic factor (GDNF).

[0750] Other preferred fragments are biologically active fragments of the polypeptide of the present invention. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.

[0751] Additionally, this invention provides a method of screening compounds to identify those which modulate the action of the polypeptide of the present invention. An example of such an assay comprises combining a mammalian fibroblast cell, a the polypeptide of the present invention, the compound to be screened and 3[H] thymidine under cell culture conditions where the fibroblast cell would normally proliferate. A control assay may be performed in the absence of the compound to be screened and compared to the amount of fibroblast proliferation in the presence of the compound to determine if the compound stimulates proliferation by determining the uptake of 3[H] thymidine in each case. The amount of fibroblast cell proliferation is measured by liquid scintillation chromatography which measures the incorporation of 3[H] thymidine. Both agonist and antagonist compounds may be identified by this procedure.

[0752] In another method, a mammalian cell or membrane preparation expressing a receptor for a polypeptide of the present invention is incubated with a labeled polypeptide of the present invention in the presence of the compound. The ability of the compound to enhance or block this interaction could then be measured. Alternatively, the response of a known second messenger system following interaction of a compound to be screened and the receptor is measured and the ability of the compound to bind to the receptor and elicit a second messenger response is measured to determine if the compound is a potential agonist or antagonist. Such second messenger systems include but are not limited to, cAMP guanylate cyclase, ion channels or phosphoinositide hydrolysis.

[0753] All of these above assays can be used as diagnostic or prognostic markers. The molecules discovered using these assays can be used to treat disease or to bring about a particular result in a patient (e.g., blood vessel growth) by activating or inhibiting the polypeptide/molecule. Moreover, the assays can discover agents which may inhibit or enhance the production of the polypeptides of the invention from suitably manipulated cells or tissues.

[0754] Therefore, the invention includes a method of identifying compounds which bind to a polypeptide of the invention comprising the steps of: (a) incubating a candidate binding compound with a polypeptide of the present invention; and (b) determining if binding has occurred. Moreover, the invention includes a method of identifying agonists/antagonists comprising the steps of: (a) incubating a candidate compound with a polypeptide of the present invention, (b) assaying a biological activity, and (b) determining if a biological activity of the polypeptide has been altered.

[0755] Targeted Delivery

[0756] In another embodiment, the invention provides a method of delivering compositions to targeted cells expressing a receptor for a polypeptide of the invention, or cells expressing a cell bound form of a polypeptide of the invention.

[0757] As discussed herein, polypeptides or antibodies of the invention may be associated with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalent interactions. In one embodiment, the invention provides a method for the specific delivery of compositions of the invention to cells by administering polypeptides of the invention (including antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a therapeutic protein into the targeted cell. In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell's genome or replicate episomally and that can be transcribed) into the targeted cell.

[0758] In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention (e.g., polypeptides of the invention or antibodies of the invention) in association with toxins or cytotoxic prodrugs.

[0759] By “toxin” is meant compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. By “cytotoxic prodrug” is meant a non-toxic compound that is converted by an enzyme, normally present in the cell, into a cytotoxic compound. Cytotoxic prodrugs that may be used according to the methods of the invention include, but are not limited to, glutamyl derivatives of benzoic acid mustard alkylating agent, phosphate derivatives of etoposide or mitomycin C, cytosine arabinoside, daunorubisin, and phenoxyacetamide derivatives of doxorubicin.

[0760] Drug Screening

[0761] Further contemplated is the use of the polypeptides of the present invention, or the polynucleotides encoding these polypeptides, to screen for molecules which modify the activities of the polypeptides of the present invention. Such a method would include contacting the polypeptide of the present invention with a selected compound(s) suspected of having antagonist or agonist activity, and assaying the activity of these polypeptides following binding.

[0762] This invention is particularly useful for screening therapeutic compounds by using the polypeptides of the present invention, or binding fragments thereof, in any of a variety of drug screening techniques. The polypeptide or fragment employed in such a test may be affixed to a solid support, expressed on a cell surface, free in solution, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. One may measure, for example, the formulation of complexes between the agent being tested and a polypeptide of the present invention.

[0763] Thus, the present invention provides methods of screening for drugs or any other agents which affect activities mediated by the polypeptides of the present invention. These methods comprise contacting such an agent with a polypeptide of the present invention or a fragment thereof and assaying for the presence of a complex between the agent and the polypeptide or a fragment thereof, by methods well known in the art. In such a competitive binding assay, the agents to screen are typically labeled. Following incubation, free agent is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of a particular agent to bind to the polypeptides of the present invention.

[0764] Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to the polypeptides of the present invention, and is described in great detail in European Patent Application 84/03564, published on Sep. 13, 1984, which is incorporated herein by reference herein. Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The peptide test compounds are reacted with polypeptides of the present invention and washed. Bound polypeptides are then detected by methods well known in the art. Purified polypeptides are coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies may be used to capture the peptide and immobilize it on the solid support.

[0765] This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding polypeptides of the present invention specifically compete with a test compound for binding to the polypeptides or fragments thereof. In this manner, the antibodies are used to detect the presence of any peptide which shares one or more antigenic epitopes with a polypeptide of the invention.

[0766] Antisense and Ribozyme (Antagonists)

[0767] In specific embodiments, antagonists according to the present invention are nucleic acids corresponding to the sequences contained in SEQ ID NO:X, or the complementary strand thereof, and/or to cDNA sequences contained in cDNA Clone ID NO:Z identified for example, in Table 1A. In one embodiment, antisense sequence is generated internally, by the organism, in another embodiment, the antisense sequence is separately administered (see, for example, O'Connor, J., Neurochem. 56:560 (1991). Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Antisense technology can be used to control gene expression through antisense DNA or RNA, or through triple-helix formation. Antisense techniques are discussed for example, in Okano, J., Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Triple helix formation is discussed in, for instance, Lee et al., Nucleic Acids Research 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1300 (1991). The methods are based on binding of a polynucleotide to a complementary DNA or RNA.

[0768] For example, the use of c-myc and c-myb antisense RNA constructs to inhibit the growth of the non-lymphocytic leukemia cell line HL-60 and other cell lines was previously described. (Wickstrom et al. (1988); Anfossi et al. (1989)). These experiments were performed in vitro by incubating cells with the oligoribonucleotide. A similar procedure for in vivo use is described in WO 91/15580. Briefly, a pair of oligonucleotides for a given antisense RNA is produced as follows: A sequence complimentary to the first 15 bases of the open reading frame is flanked by an EcoRI site on the 5 end and a HindIII site on the 3 end. Next, the pair of oligonucleotides is heated at 90° C. for one minute and then annealed in 2× ligation buffer (20 mM TRIS HCl pH 7.5, 10 mM MgCl2, 10MM dithiothreitol (DTT) and 0.2 mM ATP) and then ligated to the EcoRI/Hind III site of the retroviral vector PMV7 (WO 91/15580).

[0769] For example, the 5′ coding portion of a polynucleotide that encodes the polypeptide of the present invention may be used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription thereby preventing transcription and the production of the receptor. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into receptor polypeptide.

[0770] In one embodiment, the antisense nucleic acid of the invention is produced intracellularly by transcription from an exogenous sequence. For example, a vector or a portion thereof, is transcribed, producing an antisense nucleic acid (RNA) of the invention. Such a vector would contain a sequence encoding the antisense nucleic acid. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in vertebrate cells. Expression of the sequence encoding the polypeptide of the present invention or fragments thereof, can be by any promoter known in the art to act in vertebrate, preferably human cells. Such promoters can be inducible or constitutive. Such promoters include, but are not limited to, the SV40 early promoter region (Bernoist and Chambon, Nature 29:304-310 (1981), the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamoto et al., Cell 22:787-797 (1980), the herpes thymidine promoter (Wagner et al., Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445 (1981), the regulatory sequences of the metallothionein gene (Brinster, et al., Nature 296:39-42 (1982)), etc.

[0771] The antisense nucleic acids of the invention comprise a sequence complementary to at least a portion of an RNA transcript of a gene of the present invention. However, absolute complementarity, although preferred, is not required. A sequence “complementary to at least a portion of an RNA,” referred to herein, means a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the larger the hybridizing nucleic acid, the more base mismatches with a RNA it may contain and still form a stable duplex (or triplex as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

[0772] Oligonucleotides that are complementary to the 5′ end of the message, e.g., the 5′ untranslated sequence up to and including the AUG initiation codon, should work most efficiently at inhibiting translation. However, sequences complementary to the 3′ untranslated sequences of mRNAs have been shown to be effective at inhibiting translation of mRNAs as well. See generally, Wagner, R., 1994, Nature 372:333-335. Thus, oligonucleotides complementary to either the 5′- or 3′-non-translated, non-coding regions of polynucleotide sequences described herein could be used in an antisense approach to inhibit translation of endogenous mRNA. Oligonucleotides complementary to the 5′ untranslated region of the mRNA should include the complement of the AUG start codon. Antisense oligonucleotides complementary to mRNA coding regions are less efficient inhibitors of translation but could be used in accordance with the invention. Whether designed to hybridize to the 5′-, 3′- or coding region of mRNA of the present invention, antisense nucleic acids should be at least six nucleotides in length, and are preferably oligonucleotides ranging from 6 to about 50 nucleotides in length. In specific aspects the oligonucleotide is at least 10 nucleotides, at least 17 nucleotides, at least 25 nucleotides or at least 50 nucleotides.

[0773] The polynucleotides of the invention can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, hybridization, etc. The oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors i[vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; PCT Publication No. WO88/09810, published Dec. 15, 1988) or the blood-brain barrier (see, e.g., PCT Publication No. WO89/10134, published Apr. 25, 1988), hybridization-triggered cleavage agents. (See, e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalating agents. (See, e.g., Zon, 1988, Pharm. Res. 5:539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.

[0774] The antisense oligonucleotide may comprise at least one modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.

[0775] The antisense oligonucleotide may also comprise at least one modified sugar moiety selected from the group including, but not limited to, arabinose, 2-fluoroarabinose, xylulose, and hexose.

[0776] In yet another embodiment, the antisense oligonucleotide comprises at least one modified phosphate backbone selected from the group including, but not limited to, a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

[0777] In yet another embodiment, the antisense oligonucleotide is an a-anomeric oligonucleotide. An a-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual b-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a 2′-O-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330).

[0778] Polynucleotides of the invention may be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc.

[0779] While antisense nucleotides complementary to the coding region sequence could be used, those complementary to the transcribed untranslated region are most preferred.

[0780] Potential antagonists according to the invention also include catalytic RNA, or a ribozyme (See, e.g., PCT International Publication WO 90/11364, published Oct. 4, 1990; Sarver et al, Science 247:1222-1225 (1990). While ribozymes that cleave mRNA at site specific recognition sequences can be used to destroy mRNAs, the use of hammerhead ribozymes is preferred. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions that form complementary base pairs with the target mRNA. The sole requirement is that the target mRNA have the following sequence of two bases: 5′-UG-3′. The construction and production of hammerhead ribozymes is well known in the art and is described more fully in Haseloff and Gerlach, Nature 334:585-591 (1988). There are numerous potential hammerhead ribozyme cleavage sites within the nucleotide sequence of SEQ ID NO:X. Preferably, the ribozyme is engineered so that the cleavage recognition site is located near the 5′ end of the mRNA; i.e., to increase efficiency and minimize the intracellular accumulation of non-functional mRNA transcripts.

[0781] As in the antisense approach, the ribozymes of the invention can be composed of modified oligonucleotides (e.g., for improved stability, targeting, etc.) and should be delivered to cells which express in vivo. DNA constructs encoding the ribozyme may be introduced into the cell in the same manner as described above for the introduction of antisense encoding DNA. A preferred method of delivery involves using a DNA construct “encoding” the ribozyme under the control of a strong constitutive promoter, such as, for example, pol III or pol II promoter, so that transfected cells will produce sufficient quantities of the ribozyme to destroy endogenous messages and inhibit translation. Since ribozymes unlike antisense molecules, are catalytic, a lower intracellular concentration is required for efficiency.

[0782] Antagonist/agonist compounds may be employed to inhibit the cell growth and proliferation effects of the polypeptides of the present invention on neoplastic cells and tissues, i.e. stimulation of angiogenesis of tumors, and, therefore, retard or prevent abnormal cellular growth and proliferation, for example, in tumor formation or growth.

[0783] The antagonist/agonist may also be employed to prevent hyper-vascular diseases, and prevent the proliferation of epithelial lens cells after extracapsular cataract surgery. Prevention of the mitogenic activity of the polypeptides of the present invention may also be desirous in cases such as restenosis after balloon angioplasty.

[0784] The antagonist/agonist may also be employed to prevent the growth of scar tissue during wound healing.

[0785] The antagonist/agonist may also be employed to treat the diseases described herein.

[0786] Thus, the invention provides a method of treating disorders or diseases, including but not limited to the disorders or diseases listed throughout this application, associated with overexpression of a polynucleotide of the present invention by administering to a patient (a) an antisense molecule directed to the polynucleotide of the present invention, and/or (b) a ribozyme directed to the polynucleotide of the present invention.

[0787] Binding Peptides and Other Molecules

[0788] The invention also encompasses screening methods for identifying polypeptides and nonpolypeptides that bind polypeptides of the invention, and the binding molecules identified thereby. These binding molecules are useful, for example, as agonists and antagonists of the polypeptides of the invention. Such agonists and antagonists can be used, in accordance with the invention, in the therapeutic embodiments described in detail, below.

[0789] This method comprises the steps of:

[0790] a. contacting polypeptides of the invention with a plurality of molecules; and

[0791] b. identifying a molecule that binds the polypeptides of the invention.

[0792] The step of contacting the polypeptides of the invention with the plurality of molecules may be effected in a number of ways. For example, one may contemplate immobilizing the polypeptides on a solid support and bringing a solution of the plurality of molecules in contact with the immobilized polypeptides. Such a procedure would be akin to an affinity chromatographic process, with the affinity matrix being comprised of the immobilized polypeptides of the invention. The molecules having a selective affinity for the polypeptides can then be purified by affinity selection. The nature of the solid support, process for attachment of the polypeptides to the solid support, solvent, and conditions of the affinity isolation or selection are largely conventional and well known to those of ordinary skill in the art.

[0793] Alternatively, one may also separate a plurality of polypeptides into substantially separate fractions comprising a subset of or individual polypeptides. For instance, one can separate the plurality of polypeptides by gel electrophoresis, column chromatography, or like method known to those of ordinary skill for the separation of polypeptides. The individual polypeptides can also be produced by a transformed host cell in such a way as to be expressed on or about its outer surface (e.g., a recombinant phage). Individual isolates can then be “probed” by the polypeptides of the invention, optionally in the presence of an inducer should one be required for expression, to determine if any selective affinity interaction takes place between the polypeptides and the individual clone. Prior to contacting the polypeptides with each fraction comprising individual polypeptides, the polypeptides could first be transferred to a solid support for additional convenience. Such a solid support may simply be a piece of filter membrane, such as one made of nitrocellulose or nylon. In this manner, positive clones could be identified from a collection of transformed host cells of an expression library, which harbor a DNA construct encoding a polypeptide having a selective affinity for polypeptides of the invention. Furthermore, the amino acid sequence of the polypeptide having a selective affinity for the polypeptides of the invention can be determined directly by conventional means or the coding sequence of the DNA encoding the polypeptide can frequently be determined more conveniently. The primary sequence can then be deduced from the corresponding DNA sequence. If the amino acid sequence is to be determined from the polypeptide itself, one may use microsequencing techniques. The sequencing technique may include mass spectroscopy.

[0794] In certain situations, it may be desirable to wash away any unbound polypeptides from a mixture of the polypeptides of the invention and the plurality of polypeptides prior to attempting to determine or to detect the presence of a selective affinity interaction. Such a wash step may be particularly desirable when the polypeptides of the invention or the plurality of polypeptides are bound to a solid support.

[0795] The plurality of molecules provided according to this method may be provided by way of diversity libraries, such as random or combinatorial peptide or nonpeptide libraries which can be screened for molecules that specifically bind polypeptides of the invention. Many libraries are known in the art that can be used, e.g., chemically synthesized libraries, recombinant (e.g., phage display libraries), and in vitro translation-based libraries. Examples of chemically synthesized libraries are described in Fodor et al., 1991, Science 251:767-773; Houghten et al., 1991, Nature 354:84-86; Lam et al., 1991, Nature 354:82-84; Medynski, 1994, Bio/Technology 12:709-710;Gallop et al., 1994, J. Medicinal Chemistry 37(9):1233-1251; Ohlmeyer et al., 1993, Proc. Natl. Acad. Sci. USA 90:10922-10926; Erb et al., 1994, Proc. Natl. Acad. Sci. USA 91:11422-11426; Houghten et al., 1992, Biotechniques 13:412; Jayawickreme et al., 1994, Proc. Natl. Acad. Sci. USA 91:1614-1618; Salmon et al., 1993, Proc. Natl. Acad. Sci. USA 90:11708-11712; PCT Publication No. WO 93/20242; and Brenner and Lerner, 1992, Proc. Natl. Acad. Sci. USA 89:5381-5383.

[0796] Examples of phage display libraries are described in Scott and Smith, 1990, Science 249:386-390; Devlin et al., 1990, Science, 249:404-406; Christian, R. B., et al., 1992, J. Mol. Biol. 227:711-718); Lenstra, 1992, J. Immunol. Meth. 152:149-157; Kay et al., 1993, Gene 128:59-65; and PCT Publication No. WO 94/18318 dated Aug. 18, 1994. 1746] In vitro translation-based libraries include but are not limited to those described in PCT Publication No. WO 91/05058 dated Apr. 18, 1991; and Mattheakis et al., 1994, Proc. Natl. Acad. Sci. USA 91:9022-9026.

[0797] By way of examples of nonpeptide libraries, a benzodiazepine library (see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712) can be adapted for use. Peptoid libraries (Simon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367-9371) can also be used. Another example of a library that can be used, in which the amide functionalities in peptides have been permethylated to generate a chemically transformed combinatorial library, is described by Ostresh et al. (1994, Proc. Natl. Acad. Sci. USA 91:11138-11142).

[0798] The variety of non-peptide libraries that are useful in the present invention is great. For example, Ecker and Crooke, 1995, Bio/Technology 13:351-360 list benzodiazepines, hydantoins, piperazinediones, biphenyls, sugar analogs, beta-mercaptoketones, arylacetic acids, acylpiperidines, benzopyrans, cubanes, xanthines, aminimides, and oxazolones as among the chemical species that form the basis of various libraries.

[0799] Non-peptide libraries can be classified broadly into two types: decorated monomers and oligomers. Decorated monomer libraries employ a relatively simple scaffold structure upon which a variety functional groups is added. Often the scaffold will be a molecule with a known useful pharmacological activity. For example, the scaffold might be the benzodiazepine structure.

[0800] Non-peptide oligomer libraries utilize a large number of monomers that are assembled together in ways that create new shapes that depend on the order of the monomers. Among the monomer units that have been used are carbamates, pyrrolinones, and morpholinos. Peptoids, peptide-like oligomers in which the side chain is attached to the alpha amino group rather than the alpha carbon, form the basis of another version of non-peptide oligomer libraries. The first non-peptide oligomer libraries utilized a single type of monomer and thus contained a repeating backbone. Recent libraries have utilized more than one monomer, giving the libraries added flexibility.

[0801] Screening the libraries can be accomplished by any of a variety of commonly known methods. See, e.g., the following references, which disclose screening of peptide libraries: Parmley and Smith, 1989, Adv. Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390; Fowlkes et al., 1992; BioTechniques 13:422-427; Oldenburg et al., 1992, Proc. Natl. Acad. Sci. USA 89:5393-5397; Yu et al., 1994, Cell 76:933-945; Staudt et al., 1988, Science 241:577-580; Bock et al., 1992, Nature 355:564-566; Tuerk et al., 1992, Proc. Natl. Acad. Sci. USA 89:6988-6992; Ellington et al., 1992, Nature 355:850-852; U.S. Pat. No. 5,096,815, U.S. Pat. No. 5,223,409, and U.S. Pat. No. 5,198,346, all to Ladner et al.; Rebar and Pabo, 1993, Science 263:671-673; and CT Publication No. WO 94/18318.

[0802] In a specific embodiment, screening to identify a molecule that binds polypeptides of the invention can be carried out by contacting the library members with polypeptides of the invention immobilized on a solid phase and harvesting those library members that bind to the polypeptides of the invention. Examples of such screening methods, termed “panning” techniques are described by way of example in Parmley and Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques 13:422-427; PCT Publication No. WO 94/18318; and in references cited herein.

[0803] In another embodiment, the two-hybrid system for selecting interacting proteins in yeast (Fields and Song, 1989, Nature 340:245-246; Chien et al., 1991, Proc. Natl. Acad. Sci. USA 88:9578-9582) can be used to identify molecules that specifically bind to polypeptides of the invention.

[0804] Where the binding molecule is a polypeptide, the polypeptide can be conveniently selected from any peptide library, including random peptide libraries, combinatorial peptide libraries, or biased peptide libraries. The term “biased” is used herein to mean that the method of generating the library is manipulated so as to restrict one or more parameters that govern the diversity of the resulting collection of molecules, in this case peptides.

[0805] Thus, a truly random peptide library would generate a collection of peptides in which the probability of finding a particular amino acid at a given position of the peptide is the same for all 20 amino acids. A bias can be introduced into the library, however, by specifying, for example, that a lysine occur every fifth amino acid or that positions 4, 8, and 9 of a decapeptide library be fixed to include only arginine. Clearly, many types of biases can be contemplated, and the present invention is not restricted to any particular bias. Furthermore, the present invention contemplates specific types of peptide libraries, such as phage displayed peptide libraries and those that utilize a DNA construct comprising a lambda phage vector with a DNA insert.

[0806] As mentioned above, in the case of a binding molecule that is a polypeptide, the polypeptide may have about 6 to less than about 60 amino acid residues, preferably about 6 to about 10 amino acid residues, and most preferably, about 6 to about 22 amino acids. In another embodiment, a binding polypeptide has in the range of 15-100 amino acids, or 20-50 amino acids.

[0807] The selected binding polypeptide can be obtained by chemical synthesis or recombinant expression.

[0808] Other Activities

[0809] A polypeptide, polynucleotide, agonist, or antagonist of the present invention, as a result of the ability to stimulate vascular endothelial cell growth, may be employed in treatment for stimulating re-vascularization of ischemic tissues due to various disease conditions such as thrombosis, arteriosclerosis, and other cardiovascular conditions. The polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed to stimulate angiogenesis and limb regeneration, as discussed above.

[0810] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for treating wounds due to injuries, burns, post-operative tissue repair, and ulcers since they are mitogenic to various cells of different origins, such as fibroblast cells and skeletal muscle cells, and therefore, facilitate the repair or replacement of damaged or diseased tissue.

[0811] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed stimulate neuronal growth and to treat and prevent neuronal damage which occurs in certain neuronal disorders or neuro-degenerative conditions such as Alzheimer's disease, Parkinson's disease, and AIDS-related complex. A polypeptide, polynucleotide, agonist, or antagonist of the present invention may have the ability to stimulate chondrocyte growth, therefore, they may be employed to enhance bone and periodontal regeneration and aid in tissue transplants or bone grafts.

[0812] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may be also be employed to prevent skin aging due to sunburn by stimulating keratinocyte growth.

[0813] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for preventing hair loss, since FGF family members activate hair-forming cells and promotes melanocyte growth. Along the same lines, a polypeptide, polynucleotide, agonist, or antagonist of the present invention may be employed to stimulate growth and differentiation of hematopoietic cells and bone marrow cells when used in combination with other cytokines.

[0814] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed to maintain organs before transplantation or for supporting cell culture of primary tissues. A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for inducing tissue of mesodermal origin to differentiate in early embryos.

[0815] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also increase or decrease the differentiation or proliferation of embryonic stem cells, besides, as discussed above, hematopoietic lineage.

[0816] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be used to modulate mammalian characteristics, such as body height, weight, hair color, eye color, skin, percentage of adipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery). Similarly, a polypeptide, polynucleotide, agonist, or antagonist of the present invention may be used to modulate mammalian metabolism affecting catabolism, anabolism, processing, utilization, and storage of energy.

[0817] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may be used to change a mammal's mental state or physical state by influencing biorhythms, caricadic rhythms, depression (including depressive disorders), tendency for violence, tolerance for pain, reproductive capabilities (preferably by Activin or Inhibin-like activity), hormonal or endocrine levels, appetite, libido, memory, stress, or other cognitive qualities.

[0818] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be used as a food additive or preservative, such as to increase or decrease storage capabilities, fat content, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional components.

[0819] The above-recited applications have uses in a wide variety of hosts. Such hosts include, but are not limited to, human, murine, rabbit, goat, guinea pig, camel, horse, mouse, rat, hamster, pig, micro-pig, chicken, goat, cow, sheep, dog, cat, non-human primate, and human. In specific embodiments, the host is a mouse, rabbit, goat, guinea pig, chicken, rat, hamster, pig, sheep, dog or cat. In preferred embodiments, the host is a mammal. In most preferred embodiments, the host is a human.

[0820] Other Preferred Embodiments

[0821] Other preferred embodiments of the claimed invention include an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 50 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO:Z.

[0822] Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of the portion of SEQ ID NO:X as defined in column 5, “ORF (From-To)”, in Table 1A.

[0823] Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of the portion of SEQ ID NO:X as defined in columns 8 and 9, “NT From” and “NT To” respectively, in Table 2.

[0824] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 150 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO:Z.

[0825] Further preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 500 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO:Z.

[0826] A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of the portion of SEQ ID NO:X defined in column 5, “ORF (From-To)”, in Table 1A.

[0827] A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of the portion of SEQ ID NO:X defined in columns 8 and 9, “NT From” and “NT To”, respectively, in Table 2.

[0828] A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO:Z.

[0829] Also preferred is an isolated nucleic acid molecule which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO:Z, wherein said nucleic acid molecule which hybridizes does not hybridize under stringent hybridization conditions to a nucleic acid molecule having a nucleotide sequence consisting of only A residues or of only T residues.

[0830] Also preferred is a composition of matter comprising a DNA molecule which comprises the cDNA contained in Clone ID NO:Z.

[0831] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides of the cDNA sequence contained in Clone ID NO:Z.

[0832] Also preferred is an isolated nucleic acid molecule, wherein said sequence of at least 50 contiguous nucleotides is included in the nucleotide sequence of an open reading frame sequence encoded by cDNA contained in Clone ID NO:Z.

[0833] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 150 contiguous nucleotides in the nucleotide sequence encoded by cDNA contained in Clone ID NO:Z.

[0834] A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 500 contiguous nucleotides in the nucleotide sequence encoded by cDNA contained in Clone ID NO:Z.

[0835] A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence encoded by cDNA contained in Clone ID NO:Z.

[0836] A further preferred embodiment is a method for detecting in a biological sample a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence encoded by cDNA contained in Clone ID NO:Z; which method comprises a step of comparing a nucleotide sequence of at least one nucleic acid molecule in said sample with a sequence selected from said group and determining whether the sequence of said nucleic acid molecule in said sample is at least 95% identical to said selected sequence.

[0837] Also preferred is the above method wherein said step of comparing sequences comprises determining the extent of nucleic acid hybridization between nucleic acid molecules in said sample and a nucleic acid molecule comprising said sequence selected from said group. Similarly, also preferred is the above method wherein said step of comparing sequences is performed by comparing the nucleotide sequence determined from a nucleic acid molecule in said sample with said sequence selected from said group. The nucleic acid molecules can comprise DNA molecules or RNA molecules.

[0838] A further preferred embodiment is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting nucleic acid molecules in said sample, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence of the cDNA contained in Clone ID NO:Z.

[0839] The method for identifying the species, tissue or cell type of a biological sample can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.

[0840] Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; or the cDNA contained in Clone ID NO:Z which encodes a protein, wherein the method comprises a step of detecting in a biological sample obtained from said subject nucleic acid molecules, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence of cDNA contained in Clone ID NO:Z.

[0841] The method for diagnosing a pathological condition can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.

[0842] Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence encoded by cDNA contained in Clone ID NO:Z. The nucleic acid molecules can comprise DNA molecules or RNA molecules.

[0843] Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a DNA microarray or “chip” of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 150, 200, 250, 300, 500, 1000, 2000, 3000, or 4000 nucleotide sequences, wherein at least one sequence in said DNA microarray or “chip” is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1A; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA “Clone ID” in Table 1A.

[0844] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO:Z.

[0845] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO:Z.

[0846] Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO:Z.

[0847] Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the complete amino acid sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO:Z.

[0848] Further preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the complete amino acid sequence of a polypeptide encoded by contained in Clone ID NO:Z

[0849] Also preferred is a polypeptide wherein said sequence of contiguous amino acids is included in the amino acid sequence of a portion of said polypeptide encoded by cDNA contained in Clone ID NO:Z; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or the polypeptide sequence of SEQ ID NO:Y.

[0850] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0851] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of a polypeptide encoded by cDNA contained in Clone ID NO:Z.

[0852] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the amino acid sequence of a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0853] Further preferred is an isolated antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0854] Further preferred is a method for detecting in a biological sample a polypeptide comprising an amino acid sequence which is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z; which method comprises a step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group and determining whether the sequence of said polypeptide molecule in said sample is at least 90% identical to said sequence of at least 10 contiguous amino acids.

[0855] Also preferred is the above method wherein said step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group comprises determining the extent of specific binding of polypeptides in said sample to an antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0856] Also preferred is the above method wherein said step of comparing sequences is performed by comparing the amino acid sequence determined from a polypeptide molecule in said sample with said sequence selected from said group.

[0857] Also preferred is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting polypeptide molecules in said sample, if any, comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0858] Also preferred is the above method for identifying the species, tissue or cell type of a biological sample, which method comprises a step of detecting polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the above group.

[0859] Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a nucleic acid sequence identified in Table 1A or Table 2 encoding a polypeptide, which method comprises a step of detecting in a biological sample obtained from said subject polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0860] In any of these methods, the step of detecting said polypeptide molecules includes using an antibody.

[0861] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a nucleotide sequence encoding a polypeptide wherein said polypeptide comprises an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0862] Also preferred is an isolated nucleic acid molecule, wherein said nucleotide sequence encoding a polypeptide has been optimized for expression of said polypeptide in a prokaryotic host.

[0863] Also preferred is a polypeptide molecule, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z.

[0864] Further preferred is a method of making a recombinant vector comprising inserting any of the above isolated nucleic acid molecule into a vector. Also preferred is the recombinant vector produced by this method. Also preferred is a method of making a recombinant host cell comprising introducing the vector into a host cell, as well as the recombinant host cell produced by this method.

[0865] Also preferred is a method of making an isolated polypeptide comprising culturing this recombinant host cell under conditions such that said polypeptide is expressed and recovering said polypeptide. Also preferred is this method of making an isolated polypeptide, wherein said recombinant host cell is a eukaryotic cell and said polypeptide is a human protein comprising an amino acid sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO:Z. The isolated polypeptide produced by this method is also preferred.

[0866] Also preferred is a method of treatment of an individual in need of an increased level of a protein activity, which method comprises administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide, polynucleotide, immunogenic fragment or analogue thereof, binding agent, antibody, or antigen binding fragment of the claimed invention effective to increase the level of said protein activity in said individual.

[0867] Also preferred is a method of treatment of an individual in need of a decreased level of a protein activity, which method comprised administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide, polynucleotide, immunogenic fragment or analogue thereof, binding agent, antibody, or antigen binding fragment of the claimed invention effective to decrease the level of said protein activity in said individual.

[0868] Also preferred is a method of treatment of an individual in need of a specific delivery of toxic compositions to diseased cells (e.g., tumors, leukemias or lymphomas), which method comprises administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide of the invention, including, but not limited to a binding agent, or antibody of the claimed invention that are associated with toxin or cytotoxic prodrugs.

[0869] Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting.

TABLE 6
ATCC Deposits	Deposit Date	ATCC Designation Number
LP01, LP02, LP03,	May-20-97	209059, 209060, 209061,
LP04, LP05, LP06,		209062, 209063, 209064,
LP07, LP08, LP09,		209065, 209066, 209067,
LP10, LP11,		209068, 209069
LP12	Jan-12-98	209579
LP13	Jan-12-98	209578
LP14	Jul-16-98	203067
LP15	Jul-16-98	203068
LP16	Feb-1-99	203609
LP17	Feb-1-99	203610
LP20	Nov-17-98	203485
LP21	Jun-18-99	PTA-252
LP22	Jun-18-99	PTA-253
LP23	Dec-22-99	PTA-1081

EXAMPLES

Example 1

Isolation of a Selected cDNA Clone from the Deposited Sample

[0870] Each Clone ID NO:Z is contained in a plasmid vector. Table 7 identifies the vectors used to construct the cDNA library from which each clone was isolated. In many cases, the vector used to construct the library is a phage vector from which a plasmid has been excised. The following correlates the related plasmid for each phage vector used in constructing the cDNA library. For example, where a particular clone is identified in Table 7 as being isolated in the vector “Lambda Zap,” the corresponding deposited clone is in “pBluescript.”

Vector Used to Construct Library Corresponding Deposited Plasmid
Lambda Zap                       pBluescript (pBS)
Uni-Zap XR                       pBluescript (pBS)
Zap Express                      pBK
lafmid BA                        plafMid BA
pSport1                          pSport1
pCMVSport 2.0                    pCMVSport 2.0
pCMVSport 3.0                    pCMVSport 3.0
pCR ® 2.1                        pCR ® 2.1

[0871] Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Both can be transformed into E. coli strain XL-1 Blue, also available from Stratagene. pBS comes in 4 forms SK+, SK−, KS+ and KS. The S and K refers to the orientation of the polylinker to the T7 and T3 primer sequences which flank the polylinker region (“S” is for SacI and “K” is for KpnI which are the first sites on each respective end of the linker). “+” or “−” refer to the orientation of the fl origin of replication (“ori”), such that in one orientation, single stranded rescue initiated from the fl ori generates sense strand DNA and in the other, antisense.

[0872] Vectors pSport1, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. (See, for instance, Gruber, C. E., et al., Focus 15:59 (1993)). Vector lafmid BA (Bento Soares, Columbia University, NY) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR®2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. (See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991)). Preferably, a polynucleotide of the present invention does not comprise the phage vector sequences identified for the particular clone in Table 7, as well as the corresponding plasmid vector sequences designated above.

[0873] The deposited material in the sample assigned the ATCC Deposit Number cited by reference to Tables 1, 2, 6 and 7 for any given cDNA clone also may contain one or more additional plasmids, each comprising a cDNA clone different from that given clone. Thus, deposits sharing the same ATCC Deposit Number contain at least a plasmid for each Clone ID NO:Z.

TABLE 7
			ATCC
Libraries owned by Catalog	Catalog Description	Vector	Deposit
HUKA HUKB HUKC HUKD HUKE	Human Uterine Cancer	Lambda ZAP II	LP01
HUKF HUKG
HCNA HCNB	Human Colon	Lambda Zap II	LP01
HFFA	Human Fetal Brain, random primed	Lambda Zap II	LP01
HTWA	Resting T-Cell	Lambda ZAP II	LP01
HBQA	Early Stage Human Brain, random	Lambda ZAP II	LP01
	primed
HLMB HLMF HLMG HLMH HLMI	breast lymph node CDNA library	Lambda ZAP II	LP01
HLMJ HLMM HLMN
HCQA HCQB	human colon cancer	Lamda ZAP II	LP01
HMEA HMEC HMED HMEE HMEF	Human Microvascular Endothelial	Lambda ZAP II	LP01
HMEG HMEI HMEJ HMEK HMEL	Cells, fract. A
HUSA HUSC	Human Umbilical Vein Endothelial	Lambda ZAP II	LP01
	Cells, fract. A
HLQA HLQB	Hepatocellular Tumor	Lambda ZAP II	LP01
HHGA HHGB HHGC HHGD	Hemangiopericytoma	Lambda ZAP II	LP01
HSDM	Human Striatum Depression, re-	Lambda ZAP II	LP01
	rescue
HUSH	H Umbilical Vein Endothelial Cells,	Lambda ZAP II	LP01
	frac A, re-excision
HSGS	Salivary gland, subtracted	Lambda ZAP II	LP01
HFXA HFXB HFXC HFXD HFXE	Brain frontal cortex	Lambda ZAP II	LP01
HFXF HFXG HFXH
HPQA HPQB HPQC	PERM TF274	Lambda ZAP II	LP01
HFXJ HFXK	Brain Frontal Cortex, re-excision	Lambda ZAP II	LP01
HCWA HCWB HCWC HCWD HCWE	CD34 positive cells (Cord Blood)	ZAP Express	LP02
HCWF HCWG HCWH HCWI HCWJ
HCWK
HCUA HCUB HCUC	CD34 depleted Buffy Coat (Cord	ZAP Express	LP02
	Blood)
HRSM	A-14 cell line	ZAP Express	LP02
HRSA	A1-CELL LINE	ZAP Express	LP02
HCUD HCUE HCUF HCUG HCUH	CD34 depleted Buffy Coat (Cord	ZAP Express	LP02
HCUI	Blood), re-excision
HBXE HBXF HBXG	H. Whole Brain #2, re-excision	ZAP Express	LP02
HRLM	L8 cell line	ZAP Express	LP02
HBXA HBXB HBXC HBXD	Human Whole Brain #2 - Oligo dT >	ZAP Express	LP02
	1.5 Kb
HUDA HUDB HUDC	Testes	ZAP Express	LP02
HHTM HHTN HHTO	H. hypothalamus, frac A, re-excision	ZAP Express	LP02
HHTL	H. hypothalamus, frac A	ZAP Express	LP02
HASA HASD	Human Adult Spleen	Uni-ZAP XR	LP03
HFKC HFKD HFKE HFKF HFKG	Human Fetal Kidney	Uni-ZAP XR	LP03
HE8A HE8B HE8C HE8D HE8E HE8F	Human 8 Week Whole Embryo	Uni-ZAP XR	LP03
HE8M HE8N
HGBA HGBD HGBE HGBF HGBG	Human Gall Bladder	Uni-ZAP XR	LP03
HGBH HGBI
HLHA HLHB HLHC HLHD HLHE	Human Fetal Lung III	Uni-ZAP XR	LP03
HLHF HLHG HLHH HLHQ
HPMA HPMB HPMC HPMD HPME	Human Placenta	Uni-ZAP XR	LP03
HPMF HPMG HPMH
HPRA HPRB HPRC HPRD	Human Prostate	Uni-ZAP XR	LP03
HSIA HSIC HSID HSIE	Human Adult Small Intestine	Uni-ZAP XR	LP03
HTEA HTEB HTEC HTED HTEE	Human Testes	Uni-ZAP XR	LP03
HTEF HTEG HTEH HTEI HTEJ HTEK
HTPA HTPB HTPC HTPD HTPE	Human Pancreas Tumor	Uni-ZAP XR	LP03
HTTA HTTB HTTC HTTD HTTE	Human Testes Tumor	Uni-ZAP XR	LP03
HTTF
HAPA HAPB HAPC HAPM	Human Adult Pulmonary	Uni-ZAP XR	LP03
HETA HETB HETC HETD HETE	Human Endometrial Tumor	Uni-ZAP XR	LP03
HETF HETG HETH HETI
HHFB HHFC HHFD HHFE HHFF	Human Fetal Heart	Uni-ZAP XR	LP03
HHFG HHFH HHFI
HHPB HHPC HHPD HHPE HHPF	Human Hippocampus	Uni-ZAP XR	LP03
HHPG HHPH
HCE1 HCE2 HCE3 HCE4 HCE5 HCEB	Human Cerebellum	Uni-ZAP XR	LP03
HCEC HCED HCEE HCEF HCEG
HUVB HUVC HUVD HUVE	Human Umbilical Vein, Endo.	Uni-ZAP XR	LP03
	remake
HSTA HSTB HSTC HSTD	Human Skin Tumor	Uni-ZAP XR	LP03
HTAA HTAB HTAC HTAD HTAE	Human Activated T-Cells	Uni-ZAP XR	LP03
HFEA HFEB HFEC	Human Fetal Epithelium (Skin)	Uni-ZAP XR	LP03
HJPA HJPB HJPC HJPD	HUMAN JURKAT MEMBRANE	Uni-ZAP XR	LP03
	BOUND POLYSOMES
HESA	Human epithelioid sarcoma	Uni-Zap XR	LP03
HLTA HLTB HLTC HLTD HLTE	Human T-Cell Lymphoma	Uni-ZAP XR	LP03
HLTF
HFTA HFTB HFTC HFTD	Human Fetal Dura Mater	Uni-ZAP XR	LP03
HRDA HRDB HRDC HRDD HRDE	Human Rhabdomyosarcoma	Uni-ZAP XR	LP03
HRDF
HCAA HCAB HCAC	Cem cells cyclohexamide treated	Uni-ZAP XR	LP03
HRGA HRGB HRGC HRGD	Raji Cells, cyclohexamide treated	Uni-ZAP XR	LP03
HSUA HSUB HSUC HSUM	Supt Cells, cyclohexamide treated	Uni-ZAP XR	LP03
HT4A HT4C HT4D	Activated T-Cells, 12 hrs.	Uni-ZAP XR	LP03
HE9A HE9B HE9C HE9D HE9E HE9F	Nine Week Old Early Stage Human	Uni-ZAP XR	LP03
HE9G HE9H HE9M HE9N
HATA HATB HATC HATD HATE	Human Adrenal Gland Tumor	Uni-ZAP XR	LP03
HT5A	Activated T-Cells, 24 hrs.	Uni-ZAP XR	LP03
HFGA HFGM	Human Fetal Brain	Uni-ZAP XR	LP03
HNEA HNEB HNEC HNED HNEE	Human Neutrophil	Uni-ZAP XR	LP03
HBGB HBGD	Human Primary Breast Cancer	Uni-ZAP XR	LP03
HBNA HBNB	Human Normal Breast	Uni-ZAP XR	LP03
HCAS	Cem Cells, cyclohexamide treated,	Uni-ZAP XR	LP03
	subtra
HHPS	Human Hippocampus, subtracted	pBS	LP03
HKCS HKCU	Human Colon Cancer, subtracted	pBS	LP03
HRGS	Raji cells, cyclohexamide treated,	pBS	LP03
	subtracted
HSUT	Supt cells, cyclohexamide treated,	pBS	LP03
	differentially expressed
HT4S	Activated T-Cells, 12 hrs, subtracted	Uni-ZAP XR	LP03
HCDA HCDB HCDC HCDD HCDE	Human Chondrosarcoma	Uni-ZAP XR	LP03
HOAA HOAB HOAC	Human Osteosarcoma	Uni-ZAP XR	LP03
HTLA HTLB HTLC HTLD HTLE	Human adult testis, large inserts	Uni-ZAP XR	LP03
HTLF
HLMA HLMC HLMD	Breast Lymph node cDNA library	Uni-ZAP XR	LP03
H6EA H6EB H6EC	HL-60, PMA 4H	Uni-ZAP XR	LP03
HTXA HTXB HTXC HTXD HTXE	Activated T-Cell (12 hs)/Thiouridine	Uni-ZAP XR	LP03
HTXF HTXG HTXH	labelledEco
HNFA HNFB HNFC HNFD HNFE	Human Neutrophil, Activated	Uni-ZAP XR	LP03
HNFF HNFG HNFH HNFJ
HTOB HTOC	HUMAN TONSILS, FRACTION 2	Uni-ZAP XR	LP03
HMGB	Human OB MG63 control fraction I	Uni-ZAP XR	LP03
HOPB	Human OB HOS control fraction I	Uni-ZAP XR	LP03
HORB	Human OB HOS treated (10 nM E2)	Uni-ZAP XR	LP03
	fraction I
HSVA HSVB HSVC	Human Chronic Synovitis	Uni-ZAP XR	LP03
HROA	HUMAN STOMACH	Uni-ZAP XR	LP03
HBJA HBJB HBJC HBJD HBJE HBJF	HUMAN B CELL LYMPHOMA	Uni-ZAP XR	LP03
HBJG HBJH HBJI HBJJ HBJK
HCRA HCRB HCRC	human corpus colosum	Uni-ZAP XR	LP03
HODA HODB HODC HODD	human ovarian cancer	Uni-ZAP XR	LP03
HDSA	Dermatofibrosarcoma Protuberance	Uni-ZAP XR	LP03
HMWA HMWB HMWC HMWD	Bone Marrow Cell Line (RS4, 11)	Uni-ZAP XR	LP03
HMWE HMWF HMWG HMWH
HMWI HMWJ
HSOA	stomach cancer (human)	Uni-ZAP XR	LP03
HERA	SKIN	Uni-ZAP XR	LP03
HMDA	Brain-medulloblastoma	Uni-ZAP XR	LP03
HGLA HGLB HGLD	Glioblastoma	Uni-ZAP XR	LP03
HEAA	H. Atrophic Endometrium	Uni-ZAP XR	LP03
HBCA HBCB	H. Lymph node breast Cancer	Uni-ZAP XR	LP03
HPWT	Human Prostate BPH, re-excision	Uni-ZAP XR	LP03
HFVG HFVH HFVI	Fetal Liver, subtraction II	pBS	LP03
HNFI	Human Neutrophils, Activated, re-	pBS	LP03
	excision
HBMB HBMC HBMD	Human Bone Marrow, re-excision	pBS	LP03
HKML HKMM HKMN	H. Kidney Medulla, re-excision	pBS	LP03
HKIX HKIY	H. Kidney Cortex, subtracted	pBS	LP03
HADT	H. Amygdala Depression, subtracted	pBS	LP03
H6AS	HI-60, untreated, subtracted	Uni-ZAP XR	LP03
H6ES	HL-60, PMA 4 H, subtracted	Uni-ZAP XR	LP03
H6BS	HL-60, RA 4 h, Subtracted	Uni-ZAP XR	LP03
H6CS	HL-60, PMA 1d, subtracted	Uni-ZAP XR	LP03
HTXJ HTXK	Activated T-cell(12 h)/Thiouridine-re-	Uni-ZAP XR	LP03
	excision
HMSA HMSB HMSC HMSD HMSE	Monocyte activated	Uni-ZAP XR	LP03
HMSF HMSG HMSH HMSI HMSJ
HMSK
HAGA HAGB HAGC HAGD HAGE	Human Amygdala	Uni-ZAP XR	LP03
HAGF
HSRA HSRB HSRE	STROMAL-OSTEOCLASTOMA	Uni-ZAP XR	LP03
HSRD HSRF HSRG HSRH	Human Osteoclastoma Stromal Cells -	Uni-ZAP XR	LP03
	unamplified
HSQA HSQB HSQC HSQD HSQE	Stromal cell TF274	Uni-ZAP XR	LP03
HSQF HSQG
HSKA HSKB HSKC HSKD HSKE	Smooth muscle, serum treated	Uni-ZAP XR	LP03
HSKF HSKZ
HSLA HSLB HSLC HSLD HSLE HSLF	Smooth muscle, control	Uni-ZAP XR	LP03
HSLG
HSDA HSDD HSDE HSDF HSDG	Spinal cord	Uni-ZAP XR	LP03
HSDH
HPWS	Prostate-BPH subtracted II	pBS	LP03
HSKW HSKX HSKY	Smooth Muscle-HASTE normalized	pBS	LP03
HFPB HFPC HFPD	H. Frontal cortex, epileptic; re-excision	Uni-ZAP XR	LP03
HSDI HSDJ HSDK	Spinal Cord, re-excision	Uni-ZAP XR	LP03
HSKN HSKO	Smooth Muscle Serum Treated, Norm	pBS	LP03
HSKG HSKH HSKI	Smooth muscle, serum induced, re-exc	pBS	LP03
HFCA HFCB HFCC HFCD HFCE	Human Fetal Brain	Uni-ZAP XR	LP04
HFCF
HPTA HPTB HPTD	Human Pituitary	Uni-ZAP XR	LP04
HTHB HTHC HTHD	Human Thymus	Uni-ZAP XR	LP04
HE6B HE6C HE6D HE6E HE6F HE6G	Human Whole Six Week Old Embryo	Uni-ZAP XR	LP04
HE6S
HSSA HSSB HSSC HSSD HSSE HSSF	Human Synovial Sarcoma	Uni-ZAP XR	LP04
HSSG HSSH HSSI HSSJ HSSK
HE7T	7 Week Old Early Stage Human,	Uni-ZAP XR	LP04
	subtracted
HEPA HEPB HEPC	Human Epididymus	Uni-ZAP XR	LP04
HSNA HSNB HSNC HSNM HSNN	Human Synovium	Uni-ZAP XR	LP04
HPFB HPFC HPFD HPFE	Human Prostate Cancer, Stage C	Uni-ZAP XR	LP04
	fraction
HE2A HE2D HE2E HE2H HE2I HE2M	12 Week Old Early Stage Human	Uni-ZAP XR	LP04
HE2N HE2O
HE2B HE2C HE2F HE2G HE2P HE2Q	12 Week Old Early Stage Human, II	Uni-ZAP XR	LP04
HPTS HPTT HPTU	Human Pituitary, subtracted	Uni-ZAP XR	LP04
HAUA HAUB HAUC	Amniotic Cells - TNF induced	Uni-ZAP XR	LP04
HAQA HAQB HAQC HAQD	Amniotic Cells - Primary Culture	Uni-ZAP XR	LP04
HWTA HWTB HWTC	wilm's tumor	Uni-ZAP XR	LP04
HBSD	Bone Cancer, re-excision	Uni-ZAP XR	LP04
HSGB	Salivary gland, re-excision	Uni-ZAP XR	LP04
HSJA HSJB HSJC	Smooth muscle-ILb induced	Uni-ZAP XR	LP04
HSXA HSXB HSXC HSXD	Human Substantia Nigra	Uni-ZAP XR	LP04
HSHA HSHB HSHC	Smooth muscle, IL1b induced	Uni-ZAP XR	LP04
HOUA HOUB HOUC HOUD HOUE	Adipocytes	Uni-ZAP XR	LP04
HPWA HPWB HPWC HPWD HPWE	Prostate BPH	Uni-ZAP XR	LP04
HELA HELB HELC HELD HELE	Endothelial cells-control	Uni-ZAP XR	LP04
HELF HELG HELH
HEMA HEMB HEMC HEMD HEME	Endothelial-induced	Uni-ZAP XR	LP04
HEMF HEMG HEMH
HBIA HBIB HBIC	Human Brain, Striatum	Uni-ZAP XR	LP04
HHSA HHSB HHSC HHSD HHSE	Human Hypothalmus, Schizophrenia	Uni-ZAP XR	LP04
HNGA HNGB HNGC HNGD HNGE	neutrophils control	Uni-ZAP XR	LP04
HNGF HNGG HNGH HNGI HNGJ
HNHA HNHB HNHC HNHD HNHE	Neutrophils IL-1 and LPS induced	Uni-ZAP XR	LP04
HNHF HNHG HNHH HNHI HNHJ
HSDB HSDC	STRIATUM DEPRESSION	Uni-ZAP XR	LP04
HHPT	Hypothalamus	Uni-ZAP XR	LP04
HSAT HSAU HSAV HSAW HSAX	Anergic T-cell	Uni-ZAP XR	LP04
HSAY HSAZ
HBMS HBMT HBMU HBMV HBMW	Bone marrow	Uni-ZAP XR	LP04
HBMX
HOEA HOEB HOEC HOED HOEE	Osteoblasts	Uni-ZAP XR	LP04
HOEF HOEJ
HAIA HAIB HAIC HAID HAIE HAIF	Epithelial-TNFa and INF induced	Uni-ZAP XR	LP04
HTGA HTGB HTGC HTGD	Apoptotic T-cell	Uni-ZAP XR	LP04
HMCA HMCB HMCC HMCD HMCE	Macrophage-oxLDL	Uni-ZAP XR	LP04
HMAA HMAB HMAC HMAD HMAE	Macrophage (GM-CSF treated)	Uni-ZAP XR	LP04
HMAF HMAG
HPHA	Normal Prostate	Uni-ZAP XR	LP04
HPIA HPIB HPIC	LNCAP prostate cell line	Uni-ZAP XR	LP04
HPJA HPJB HPJC	PC3 Prostate cell line	Uni-ZAP XR	LP04
HOSE HOSF HOSG	Human Osteoclastoma, re-excision	Uni-ZAP XR	LP04
HTGE HTGF	Apoptotic T-cell, re-excision	Uni-ZAP XR	LP04
HMAJ HMAK	H Macrophage (GM-CSF treated), re-	Uni-ZAP XR	LP04
	excision
HACB HACC HACD	Human Adipose Tissue, re-excision	Uni-ZAP XR	LP04
HFPA	H. Frontal Cortex, Epileptic	Uni-ZAP XR	LP04
HFAA HFAB HFAC HFAD HFAE	Alzheimer's, spongy change	Uni-ZAP XR	LP04
HFAM	Frontal Lobe, Dementia	Uni-ZAP XR	LP04
HMIA HMIB HMIC	Human Manic Depression Tissue	Uni-ZAP XR	LP04
HTSA HTSE HTSF HTSG HTSH	Human Thymus	pBS	LP05
HPBA HPBB HPBC HPBD HPBE	Human Pineal Gland	pBS	LP05
HSAA HSAB HSAC	HSA 172 Cells	pBS	LP05
HSBA HSBB HSBC HSBM	HSC172 cells	pBS	LP05
HJAA HJAB HJAC HJAD	Jurkat T-cell G1 phase	pBS	LP05
HJBA HJBB HJBC HJBD	Jurkat T-Cell, S phase	pBS	LP05
HAFA HAFB	Aorta endothelial cells + TNF-a	pBS	LP05
HAWA HAWB HAWC	Human White Adipose	pBS	LP05
HTNA HTNB	Human Thyroid	pBS	LP05
HONA	Normal Ovary, Premenopausal	pBS	LP05
HARA HARB	Human Adult Retina	pBS	LP05
HLJA HLJB	Human Lung	pCMVSport 1	LP06
HOFM HOFN HOFO	H. Ovarian Tumor, II, OV5232	pCMVSport 2.0	LP07
HOGA HOGB HOGC	OV 10-3-95	pCMVSport 2.0	LP07
HCGL	CD34+cells, II	pCMVSport 2.0	LP07
HDLA	Hodgkin's Lymphoma I	pCMVSport 2.0	LP07
HDTA HDTB HDTC HDTD HDTE	Hodgkin's Lymphoma II	pCMVSport 2.0	LP07
HKAA HKAB HKAC HKAD HKAE	Keratinocyte	pCMVSport 2.0	LP07
HKAF HKAG HKAH
HCIM	CAPFINDER, Crohn's Disease, lib 2	pCMVSport 2.0	LP07
HKAL	Keratinocyte, lib 2	pCMVSport 2.0	LP07
HKAT	Keratinocyte, lib 3	pCMVSport 2.0	LP07
HNDA	Nasal polyps	pCMVSport 2.0	LP07
HDRA	H. Primary Dendritic Cells, lib 3	pCMVSport 2.0	LP07
HOHA HOHB HOHC	Human Osteoblasts II	pCMVSport 2.0	LP07
HLDA HLDB HLDC	Liver, Hepatoma	pCMVSport 3.0	LP08
HLDN HLDO HLDP	Human Liver, normal	pCMVSport 3.0	LP08
HMTA	pBMC stimulated w/poly I/C	pCMVSport 3.0	LP08
HNTA	NTERA2, control	pCMVSport 3.0	LP08
HDPA HDPB HDPC HDPD HDPF	Primary Dendritic Cells, lib 1	pCMVSport 3.0	LP08
HDPG HDPH HDPI HDPJ HDPK
HDPM HDPN HDPO HDPP	Primary Dendritic cells, frac 2	pCMVSport 3.0	LP08
HMUA HMUB HMUC	Myoloid Progenitor Cell Line	pCMVSport 3.0	LP08
HHEA HHEB HHEC HHED	T Cell helper I	pCMVSport 3.0	LP08
HHEM HHEN HHEO HHEP	T cell helper II	pCMVSport 3.0	LP08
HEQA HEQB HEQC	Human endometrial stromal cells	pCMVSport 3.0	LP08
HJMA HJMB	Human endometrial stromal cells-	pCMVSport 3.0	LP08
	treated with progesterone
HSWA HSWB HSWC	Human endometrial stromal cells-	pCMVSport 3.0	LP08
	treated with estradiol
HSYA HSYB HSYC	Human Thymus Stromal Cells	pCMVSport 3.0	LP08
HLWA HLWB HLWC	Human Placenta	pCMVSport 3.0	LP08
HRAA HRAB HRAC	Rejected Kidney, lib 4	pCMVSport 3.0	LP08
HMTM	PCR, pBMC I/C treated	PCRII	LP09
HMJA	H. Meniingima, M6	pSport 1	LP10
HMKA HMKB HMKC HMKD HMKE	H Meningima, M1	pSport 1	LP10
HUSG HUSI	Human umbilical vein endothelial	pSport 1	LP10
	cells, IL-4 induced
HUSX HUSY	Human Umbilical Vein Endothelial	pSport 1	LP10
	Cells, uninduced
HOFA	Ovarian Tumor I, OV5232	pSport 1	LP10
HCFA HCFB HCFC HCFD	T-Cell PHA 16 hrs	pSport 1	LP10
HCFL HCFM HCFN HCFO	T-Cell PHA 24 hrs	pSport 1	LP10
HADA HADC HADD HADE HADF	Human Adipose	pSport 1	LP10
HADG
HOVA HOVB HOVC	Human Ovary	pSport 1	LP10
HTWB HTWC HTWD HTWE HTWF	Resting T-Cell Library, II	pSport 1	LP10
HMMA	Spleen metastic melanoma	pSport 1	LP10
HLYA HLYB HLYC HLYD HLYE	Spleen, Chronic lymphocytic	pSport 1	LP10
	leukemia
HCGA	CD34+cell, I	pSport 1	LP10
HEOM HEON	Human Eosinophils	pSport 1	LP10
HTDA	Human Tonsil, Lib 3	pSport 1	LP10
HSPA	Salivary Gland, Lib 2	pSport 1	LP10
HCHA HCHB HCHC	Breast Cancer cell line, MDA 36	pSport 1	LP10
HCHM HCHN	Breast Cancer Cell line, angiogenic	pSport 1	LP10
HCIA	Crohn's Disease	pSport 1	LP10
HDAA HDAB HDAC	HEL cell line	pSport 1	LP10
HABA	Human Astrocyte	pSport 1	LP10
HUFA HUFB HUFC	Ulcerative Colitis	pSport 1	LP10
HNTM	NTERA2 + retinoic acid, 14 days	pSport 1	LP10
HDQA	Primary Dendritic cells, CapFinder2,	pSport 1	LP10
	frac 1
HDQM	Primary Dendritic Cells, CapFinder,	pSport 1	LP10
	frac 2
HLDX	Human Liver, normal, CapFinder	pSport 1	LP10
HULA HULB HULC	Human Dermal Endothelial	pSport 1	LP10
	Cells, untreated
HUMA	Human Dermal Endothelial	pSport 1	LP10
	cells, treated
HCJA	Human Stromal Endometrial	pSport 1	LP10
	fibroblasts, untreated
HCJM	Human Stromal endometrial	pSport 1	LP10
	fibroblasts, treated w/estradiol
HEDA	Human Stromal endometrial	pSport 1	LP10
	fibroblasts, treated with progesterone
HFNA	Human ovary tumor cell OV350721	pSport 1	LP10
HKGA HKGB HKGC HKGD	Merkel Cells	pSport 1	LP10
HISA HISB HISC	Pancreas Islet Cell Tumor	pSport 1	LP10
HLSA	Skin, burned	pSport 1	LP10
HBZA	Prostate, BPH, Lib 2	pSport 1	LP10
HBZS	Prostate BPH, Lib 2, subtracted	pSport 1	LP10
HFIA HFIB HFIC	Synovial Fibroblasts (control)	pSport 1	LP10
HFIH HFII HFIJ	Synovial hypoxia	pSport 1	LP10
HFIT HFIU HFIV	Synovial IL-1/TNF stimulated	pSport 1	LP10
HGCA	Messangial cell, frac 1	pSport 1	LP10
HMVA HMVB HMVC	Bone Marrow Stromal Cell, untreated	pSport 1	LP10
HFIX HFIY HFIZ	Synovial Fibroblasts (III/TNF), subt	pSport 1	LP10
HFOX HFOY HFOZ	Synovial hypoxia-RSF subtracted	pSport 1	LP10
HMQA HMQB HMQC HMQD	Human Activated Monocytes	Uni-ZAP XR	LP11
HLIA HLIB HLIC	Human Liver	pCMVSport 1	LP012
HHBA HHBB HHBC HHBD HHBE	Human Heart	pCMVSport 1	LP012
HBBA HBBB	Human Brain	pCMVSport 1	LP012
HLJA HLJB HLJC HLJD HLJE	Human Lung	pCMVSport 1	LP012
HOGA HOGB HOGC	Ovarian Tumor	pCMVSport 2.0	LP012
HTJM	Human Tonsils, Lib 2	pCMVSport 2.0	LP012
HAMF HAMG	KMH2	pCMVSport 3.0	LP012
HAJA HAJB HAJC	L428	pCMVSport 3.0	LP012
HWBA HWBB HWBC HWBD HWBE	Dendritic cells, pooled	pCMVSport 3.0	LP012
HWAA HWAB HWAC HWAD HWAE	Human Bone Marrow, treated	pCMVSport 3.0	LP012
HYAA HYAB HYAC	B Cell lymphoma	pCMVSport 3.0	LP012
HWHG HWHH HWHI	Healing groin wound, 6.5 hours post	pCMVSport 3.0	LP012
	incision
HWHP HWHQ HWHR	Healing groin wound, 7.5 hours post	pCMVSport 3.0	LP012
	incision
HARM	Healing groin wound - zero hr post-	pCMVSport 3.0	LP012
	incision (control)
HBIM	Olfactory epithelium, nasalcavity	pCMVSport 3.0	LP012
HWDA	Healing Abdomen wound; 70&90	pCMVSport 3.0	LP012
	min post incision
HWEA	Healing Abdomen Wound; 15 days	pCMVSport 3.0	LP012
	post incision
HWJA	Healing Abdomen Wound; 21&29	pCMVSport 3.0	LP012
	days
HNAL	Human Tongue, frac 2	pSport 1	LP012
HMJA	H. Meniingima, M6	pSport 1	LP012
HMKA HMKB HMKC HMKD HMKE	H. Meningima, M1	pSport 1	LP012
HOFA	Ovarian Tumor I, OV5232	pSport 1	LP012
HCFA HCFB HCFC HCFD	T-Cell PHA 16 hrs	pSport 1	LP012
HCFL HCFM HCFN HCFO	T-Cell PHA 24 hrs	pSport 1	LP012
HMMA HMMB HMMC	Spleen metastic melanoma	pSport 1	LP012
HTDA	Human Tonsil, Lib 3	pSport 1	LP012
HDBA	Human Fetal Thymus	pSport 1	LP012
HDUA	Pericardium	pSport 1	LP012
HBZA	Prostate, BPH, Lib 2	pSport 1	LP012
HWCA	Larynx tumor	pSport 1	LP012
HWKA	Normal lung	pSport 1	LP012
HSMB	Bone marrow stroma, treated	pSport 1	LP012
HBHM	Normal trachea	pSport 1	LP012
HLFC	Human Larynx	pSport 1	LP012
HLRB	Siebben Polyposis	pSport 1	LP012
HNIA	Mammary Gland	pSport 1	LP012
HNJB	Palate carcinoma	pSport 1	LP012
HNKA	Palate normal	pSport 1	LP012
HMZA	Pharynx carcinoma	pSport 1	LP012
HABG	Cheek Carcinoma	pSport 1	LP012
HMZM	Pharynx Carcinoma	pSport 1	LP012
HDRM	Larynx Carcinoma	pSport 1	LP012
HVAA	Pancreas normal PCA4 No	pSport 1	LP012
HICA	Tongue carcinoma	pSport 1	LP012
HUKA HUKB HUKC HUKD HUKE	Human Uterine Cancer	Lambda ZAP II	LP013
HFFA	Human Fetal Brain, random primed	Lambda ZAP II	LP013
HTUA	Activated T-cell labeled with 4-	Lambda ZAP II	LP013
	thioluri
HBQA	Early Stage Human Brain, random	Lambda ZAP II	LP013
	primed
HMEB	Human microvascular Endothelial	Lambda ZAP II	LP013
	cells, fract. B
HUSH	Human Umbilical Vein Endothelial	Lambda ZAP II	LP013
	cells, fract. A, re-excision
HLQC HLQD	Hepatocellular tumor, re-excision	Lambda ZAP II	LP013
HTWJ HTWK HTWL	Resting T-cell, re-excision	Lambda ZAP II	LP013
HF6S	Human Whole 6 week Old Embryo	pBluescript	LP013
	(II), subt
HHPS	Human Hippocampus, subtracted	pBluescript	LP013
HLIS	LNCAP, differential expression	pBluescript	LP013
HLHS HLHT	Early Stage Human Lung, Subtracted	pBluescript	LP013
HSUS	Supt cells, cyclohexamide treated,	pBluescript	LP013
	subtracted
HSUT	Supt cells, cyclohexamide treated,	pBluescript	LP013
	differentially expressed
HSDS	H. Striatum Depression, subtracted	pBluescript	LP013
HPTZ	Human Pituitary, Subtracted VII	pBluescript	LP013
HSDX	H. Striatum Depression, subt II	pBluescript	LP013
HSDZ	H. Striatum Depression, subt	pBluescript	LP013
HPBA HPBB HPBC HPBD HPBE	Human Pineal Gland	pBluescript SK-	LP013
HRTA	Colorectal Tumor	pBluescript SK-	LP013
HSBA HSBB HSBC HSBM	HSC172 cells	pBluescript SK-	LP013
HJAA HJAB HJAC HJAD	Jurkat T-cell G1 phase	pBluescript SK-	LP013
HJBA HJBB HJBC HJBD	Jurkat T-cell, S1 phase	pBluescript SK-	LP013
HTNA HTNB	Human Thyroid	pBluescript SK-	LP013
HAHA HAHB	Human Adult Heart	Uni-ZAP XR	LP013
HE6A	Whole 6 week Old Embryo	Uni-ZAP XR	LP013
HFCA HFCB HFCC HFCD HFCE	Human Fetal Brain	Uni-ZAP XR	LP013
HFKC HFKD HFKE HFKF HFKG	Human Fetal Kidney	Uni-ZAP XR	LP013
HGBA HGBD HGBE HGBF HGBG	Human Gall Bladder	Uni-ZAP XR	LP013
HPRA HPRB HPRC HPRD	Human Prostate	Uni-ZAP XR	LP013
HTEA HTEB HTEC HTED HTEE	Human Testes	Uni-ZAP XR	LP013
HTTA HTTB HTTC HTTD HTTE	Human Testes Tumor	Uni-ZAP XR	LP013
HYBA HYBB	Human Fetal Bone	Uni-ZAP XR	LP013
HFLA	Human Fetal Liver	Uni-ZAP XR	LP013
HHFB HHFC HHFD HHFE HHFF	Human Fetal Heart	Uni-ZAP XR	LP013
HUVB HUVC HUVD HUVE	Human Umbilical Vein, End. remake	Uni-ZAP XR	LP013
HTHB HTHC HTHD	Human Thymus	Uni-ZAP XR	LP013
HSTA HSTB HSTC HSTD	Human Skin Tumor	Uni-ZAP XR	LP013
HTAA HTAB HTAC HTAD HTAE	Human Activated T-cells	Uni-ZAP XR	LP013
HFEA HFEB HFEC	Human Fetal Epithelium (skin)	Uni-ZAP XR	LP013
HJPA HJPB HJPC HJPD	Human Jurkat Membrane Bound	Uni-ZAP XR	LP013
	Polysomes
HESA	Human Epithelioid Sarcoma	Uni-ZAP XR	LP013
HALS	Human Adult Liver, Subtracted	Uni-ZAP XR	LP013
HFTA HFTB HFTC HFTD	Human Fetal Dura Mater	Uni-ZAP XR	LP013
HCAA HCAB HCAC	Cem cells, cyclohexamide treated	Uni-ZAP XR	LP013
HRGA HRGB HRGC HRGD	Raji Cells, cyclohexamide treated	Uni-ZAP XR	LP013
HE9A HE9B HE9C HE9D HE9E	Nine Week Old Early Stage Human	Uni-ZAP XR	LP013
HSFA	Human Fibrosarcoma	Uni-ZAP XR	LP013
HATA HATB HATC HATD HATE	Human Adrenal Gland Tumor	Uni-ZAP XR	LP013
HTRA	Human Trachea Tumor	Uni-ZAP XR	LP013
HE2A HE2D HE2E HE2H HE2I	12 Week Old Early Stage Human	Uni-ZAP XR	LP013
HE2B HE2C HE2F HE2G HE2P	12 Week Old Early Stage Human, II	Uni-ZAP XR	LP013
HNEA HNEB HNEC HNED HNEE	Human Neutrophil	Uni-ZAP XR	LP013
HBGA	Human Primary Breast Cancer	Uni-ZAP XR	LP013
HPTS HPTT HPTU	Human Pituitary, subtracted	Uni-ZAP XR	LP013
HMQA HMQB HMQC HMQD	Human Activated Monocytes	Uni-ZAP XR	LP013
HOAA HOAB HOAC	Human Osteosarcoma	Uni-ZAP XR	LP013
HTOA HTOD HTOE HTOF HTOG	human tonsils	Uni-ZAP XR	LP013
HMGB	Human OB MG63 control fraction I	Uni-ZAP XR	LP013
HOPB	Human OB HOS control fraction I	Uni-ZAP XR	LP013
HOQB	Human OB HOS treated (1 nM E2)	Uni-ZAP XR	LP013
	fraction I
HAUA HAUB HAUC	Amniotic Cells - TNF induced	Uni-ZAP XR	LP013
HAQA HAQB HAQC HAQD	Amniotic Cells - Primary Culture	Uni-ZAP XR	LP013
HROA HROC	HUMAN STOMACH	Uni-ZAP XR	LP013
HBJA HBJB HBJC HBJD HBJE	HUMAN B CELL LYMPHOMA	Uni-ZAP XR	LP013
HODA HODB HODC HODD	human ovarian cancer	Uni-ZAP XR	LP013
HCPA	Corpus Callosum	Uni-ZAP XR	LP013
HSOA	stomach cancer (human)	Uni-ZAP XR	LP013
HERA	SKIN	Uni-ZAP XR	LP013
HMDA	Brain-medulloblastoma	Uni-ZAP XR	LP013
HGLA HGLB HGLD	Glioblastoma	Uni-ZAP XR	LP013
HWTA HWTB HWTC	wilm's tumor	Uni-ZAP XR	LP013
HEAA	H. Atrophic Endometrium	Uni-ZAP XR	LP013
HAPN HAPO HAPP HAPQ HAPR	Human Adult Pulmonary; re-excision	Uni-ZAP XR	LP013
HLTG HLTH	Human T-cell lymphoma; re-excision	Uni-ZAP XR	LP013
HAHC HAHD HAHE	Human Adult Heart; re-excision	Uni-ZAP XR	LP013
HAGA HAGB HAGC HAGD HAGE	Human Amygdala	Uni-ZAP XR	LP013
HSJA HSJB HSJC	Smooth muscle-ILb induced	Uni-ZAP XR	LP013
HSHA HSHB HSHC	Smooth muscle, IL1b induced	Uni-ZAP XR	LP013
HPWA HPWB HPWC HPWD HPWE	Prostate BPH	Uni-ZAP XR	LP013
HPIA HPIB HPIC	LNCAP prostate cell line	Uni-ZAP XR	LP013
HPJA HPJB HPJC	PC3 Prostate cell line	Uni-ZAP XR	LP013
HBTA	Bone Marrow Stroma, TNF&LPS ind	Uni-ZAP XR	LP013
HMCF HMCG HMCH HMCI HMCJ	Macrophage-oxLDL; re-excision	Uni-ZAP XR	LP013
HAGG HAGH HAGI	Human Amygdala; re-excision	Uni-ZAP XR	LP013
HACA	H Adipose Tissue	Uni-ZAP XR	LP013
HKFB	K562 + PMA (36 hrs), re-excision	ZAP Express	LP013
HCWT HCWU HCWV	CD34 positive cells (cord blood), re-	ZAP Express	LP013
	ex
HBWA	Whole brain	ZAP Express	LP013
HBXA HBXB HBXC HBXD	Human Whole Brain #2 - Oligo dT >	ZAP Express	LP013
	1.5 Kb
HAVM	Temporal cortex-Alzheizmer	pT-Adv	LP014
HAVT	Hippocampus, Alzheimer Subtracted	pT-Adv	LP014
HHAS	CHME Cell Line	Uni-ZAP XR	LP014
HAJR	Larynx normal	pSport 1	LP014
HWLE HWLF HWLG HWLH	Colon Normal	pSport 1	LP014
HCRM HCRN HCRO	Colon Carcinoma	pSport 1	LP014
HWLI HWLJ HWLK	Colon Normal	pSport 1	LP014
HWLQ HWLR HWLS HWLT	Colon Tumor	pSport 1	LP014
HBFM	Gastrocnemius Muscle	pSport 1	LP014
HBOD HBOE	Quadriceps Muscle	pSport 1	LP014
HBKD HBKE	Soleus Muscle	pSport 1	LP014
HCCM	Pancreatic Langerhans	pSport 1	LP014
HWGA	Larynx carcinoma	pSport 1	LP014
HWGM HWGN	Larynx carcinoma	pSport 1	LP014
HWLA HWLB HWLC	Normal colon	pSport 1	LP014
HWLM HWLN	Colon Tumor	pSport 1	LP014
HVAM HVAN HVAO	Pancreas Tumor	pSport 1	LP014
HWGQ	Larynx carcinoma	pSport 1	LP014
HAQM HAQN	Salivary Gland	pSport 1	LP014
HASM	Stomach; normal	pSport 1	LP014
HBCM	Uterus; normal	pSport 1	LP014
HCDM	Testis, normal	pSport 1	LP014
HDJM	Brain; normal	pSport 1	LP014
HEFM	Adrenal Gland, normal	pSport 1	LP014
HBAA	Rectum normal	pSport 1	LP014
HFDM	Rectum tumor	pSport 1	LP014
HGAM	Colon, normal	pSport 1	LP014
HHMM	Colon, tumor	pSport 1	LP014
HCLB HCLC	Human Lung Cancer	Lambda Zap II	LP015
HRLA	L1 Cell line	ZAP Express	LP015
HHAM	Hypothalamus, Alzheimer's	pCMVSport 3.0	LP015
HKBA	Ku 812F Basophils Line	pSport 1	LP015
HS2S	Saos2, Dexamethosome Treated	pSport 1	LP016
HA5A	Lung Carcinoma A549 TNF alpha	pSport 1	LP016
	activated
HTFM	TF-1 Cell Line GM-CSF Treated	pSport 1	LP016
HYAS	Thyroid Tumor	pSport 1	LP016
HUTS	Larynx Normal	pSport 1	LP016
HXOA	Larynx Tumor	pSport 1	LP016
HEAH	Ea.hy.926 cell line	pSport 1	LP016
HINA	Adenocarcinoma Human	pSport 1	LP016
HRMA	Lung Mesothelium	pSport 1	LP016
HLCL	Human Pre-Differentiated Adipocytes	Uni-Zap XR	LP017
HS2A	Saos2 Cells	pSport 1	LP020
HS2I	Saos2 Cells; Vitamin D3 Treated	pSport 1	LP020
HUCM	CHME Cell Line, untreated	pSport 1	LP020
HEPN	Aryepiglottis Normal	pSport 1	LP020
HPSN	Sinus Piniformis Tumor	pSport 1	LP020
HNSA	Stomach Normal	pSport 1	LP020
HNSM	Stomach Tumor	pSport 1	LP020
HNLA	Liver Normal Met5No	pSport 1	LP020
HUTA	Liver Tumor Met 5 Tu	pSport 1	LP020
HOCN	Colon Normal	pSport 1	LP020
HOCT	Colon Tumor	pSport 1	LP020
HTNT	Tongue Tumour	pSport 1	LP020
HLXN	Larynx Normal	pSport 1	LP020
HLXT	Larynx Tumour	pSport 1	LP020
HTYN	Thymus	pSport 1	LP020
HPLN	Placenta	pSport 1	LP020
HTNG	Tongue Normal	pSport 1	LP020
HZAA	Thyroid Normal (SDCA2 No)	pSport 1	LP020
HWES	Thyroid Thyroiditis	pSport 1	LP020
HFHD	Ficolled Human Stromal Cells, 5Fu	pTrip1Ex2	LP021
	treated
HFHM, HFHN	Ficolled Human Stromal Cells,	pTrip1Ex2	LP021
	Untreated
HPCI	Hep G2 Cells, lambda library	lambda Zap-CMV XR	LP021
HBCA, HBCB, HBCC	H. Lymph node breast Cancer	Uni-ZAP XR	LP021
HCOK	Chondrocytes	pSPORT1	LP022
HDCA, HDCB, HDCC	Dendritic Cells From CD34 Cells	pSPORT1	LP022
HDMA, HDMB	CD40 activated monocyte dendritic	pSPORT1	LP022
	cells
HDDM, HDDN, HDDO	LPS activated derived dendritic cells	pSPORT1	LP022
HPCR	Hep G2 Cells, PCR library	lambda Zap-CMV XR	LP022
HAAA, HAAB, HAAC	Lung, Cancer (4005313A3): Invasive	pSPORT1	LP022
	Poorly Differentiated Lung
	Adenocarcinoma
HIPA, HIPB, HIPC	Lung, Cancer (4005163 B7):	pSPORT1	LP022
	Invasive, Poorly Diff
	Adenocarcinoma, Metastatic
HOOH, HOOI	Ovary, Cancer (4004562 B6)	pSPORT1	LP022
	Papillary Serous Cystic Neoplasm,
	Low Malignant Pot
HIDA	Lung, Normal: (4005313 B1)	pSPORT1	LP022
HUJA, HUJB, HUJC, HUJD, HUJE	B-Cells	pCMVSport 3.0	LP022
HNOA, HNOB, HNOC, HNOD	Ovary, Normal: (9805C040R)	pSPORT1	LP022
HNLM	Lung, Normal: (4005313 B1)	pSPORT1	LP022
HSCL	Stromal Cells	pSPORT1	LP022
HAAX	Lung, Cancer: (4005313 A3) Invasive	pSPORT1	LP022
	Poorly-differentiated Metastatic lung
	adenocarcinoma
HUUA, HUUB, HUUC, HUUD	B-cells (unstimulated)	pTrip1Ex2	LP022
HWWA, HWWB, HWWC, HWWD, HWWE,	B-cells (stimulated)	pSPORT1	LP022
HWWF, HWWG
HCCC	Colon, Cancer: (9808C064R)	pCMVSport 3.0	LP023
HPDO HPDP HPDQ HPDR HPD	Ovary, Cancer (9809C332): Poorly	pSport 1	LP023
	differentiated adenocarcinoma
HPCO HPCP HPCQ HPCT	Ovary, Cancer (15395A1F): Grade II	pSport 1	LP023
	Papillary Carcinoma
HOCM HOCO HOCP HOCQ	Ovary, Cancer: (15799A1F) Poorly	pSport 1	LP023
	differentiated carcinoma
HCBM HCBN HCBO	Breast, Cancer: (4004943 A5)	pSport 1	LP023
HNBT HNBU HNBV	Breast, Normal: (4005522B2)	pSport 1	LP023
HBCP HBCQ	Breast, Cancer: (4005522 A2)	pSport 1	LP023
HBCJ	Breast, Cancer: (9806C012R)	pSport 1	LP023
HSAM HSAN	Stromal cells 3.88	pSport 1	LP023
HVCA HVCB HVCC HVCD	Ovary, Cancer: (4004332 A2)	pSport 1	LP023
HSCK HSEN HSEO	Stromal cells (HBM3 18)	pSport 1	LP023
HSCP HSCQ	stromal cell clone 2.5	pSport 1	LP023
HUXA	Breast Cancer: (4005385 A2)	pSport 1	LP023
HCOM HCON HCOO HCOP HCOQ	Ovary, Cancer (4004650 A3): Well-	pSport 1	LP023
	Differentiated Micropapillary Serous
	Carcinoma
HBNM	Breast, Cancer: (9802C020E)	pSport 1	LP023
HVVA HVVB HVVC HVVD HVVE	Human Bone Marrow, treated	pSport 1	LP023

[0874] Two nonlimiting examples are provided below for isolating a particular clone from the deposited sample of plasmid cDNAs cited for that clone in Table 7. First, a plasmid is directly isolated by screening the clones using a polynucleotide probe corresponding to the nucleotide sequence of SEQ ID NO:X.

[0875] Particularly, a specific polynucleotide with 30-40 nucleotides is synthesized using an Applied Biosystems DNA synthesizer according to the sequence reported. The oligonucleotide is labeled, for instance, with 32P-γ-ATP using T4 polynucleotide kinase and purified according to routine methods. (E.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring, N.Y. (1982)). The plasmid mixture is transformed into a suitable host, as indicated above (such as XL-1 Blue (Stratagene)) using techniques known to those of skill in the art, such as those provided by the vector supplier or in related publications or patents cited above. The transformants are plated on 1.5% agar plates (containing the appropriate selection agent, e.g., ampicillin) to a density of about 150 transformants (colonies) per plate. These plates are screened using Nylon membranes according to routine methods for bacterial colony screening (e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Edit., (1989), Cold Spring Harbor Laboratory Press, pages 1.93 to 1.104), or other techniques known to those of skill in the art.

[0876] Alternatively, two primers of 17-20 nucleotides derived from both ends of the nucleotide sequence of SEQ ID NO:X are synthesized and used to amplify the desired cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 l of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM MgCl2, 0.01% (w/v) gelatin, 20 μM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturation at 94° C. for 1 min; annealing at 55° C. for 1 min; elongation at 72° C. for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis and the DNA band with expected molecular weight is excised and purified. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product.

[0877] Several methods are available for the identification of the 5′ or 3′ non-coding portions of a gene which may not be present in the deposited clone. These methods include but are not limited to, filter probing, clone enrichment using specific probes, and protocols similar or identical to 5′ and 3′ “RACE” protocols which are well known in the art. For instance, a method similar to 5′ RACE is available for generating the missing 5′ end of a desired full-length transcript. (Fromont-Racine et al., Nucleic Acids Res. 21(7):1683-1684 (1993)).

[0878] Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of a population of RNA presumably containing full-length gene RNA transcripts. A primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest is used to PCR amplify the 5′ portion of the desired full-length gene. This amplified product may then be sequenced and used to generate the full length gene.

[0879] This above method starts with total RNA isolated from the desired source, although poly-A+ RNA can be used. The RNA preparation can then be treated with phosphatase if necessary to eliminate 5′ phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase should then be inactivated and the RNA treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5′ ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the 5′ end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase.

[0880] This modified RNA preparation is used as a template for first strand cDNA synthesis using a gene specific oligonucleotide. The first strand synthesis reaction is used as a template for PCR amplification of the desired 5′ end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5′ end sequence belongs to the desired gene.

Example 2

Isolation of Genomic Clones Corresponding to a Polynucleotide

[0881] A human genomic P1 library (Genomic Systems, Inc.) is screened by PCR using primers selected for the sequence corresponding to SEQ ID NO:X according to the method described in Example 1. (See also, Sambrook.)

Example 3

Tissue Specific Expression Analysis

[0882] The Human Genome Sciences, Inc. (HGS) database is derived from sequencing tissue and/or disease specific cDNA libraries. Libraries generated from a particular tissue are selected and the specific tissue expression pattern of EST groups or assembled contigs within these libraries is determined by comparison of the expression patterns of those groups or contigs within the entire database. ESTs and assembled contigs which show tissue specific expression are selected.

[0883] The original clone from which the specific EST sequence was generated, or in the case of an assembled contig, the clone from which the 5′ most EST sequence was generated, is obtained from the catalogued library of clones and the insert amplified by PCR using methods known in the art. The PCR product is denatured and then transferred in 96 or 384 well format to a nylon membrane (Schleicher and Scheull) generating an array filter of tissue specific clones. Housekeeping genes, maize genes, and known tissue specific genes are included on the filters. These targets can be used in signal normalization and to validate assay sensitivity. Additional targets are included to monitor probe length and specificity of hybridization.

[0884] Radioactively labeled hybridization probes are generated by first strand cDNA synthesis per the manufacturer's instructions (Life Technologies) from mRNA/RNA samples prepared from the specific tissue being analyzed (e.g., prostate, prostate cancer, ovarian, ovarian cancer, etc.). The hybridization probes are purified by gel exclusion chromatography, quantitated, and hybridized with the array filters in hybridization bottles at 65° C. overnight. The filters are washed under stringent conditions and signals are captured using a Fuji phosphorimager.

[0885] Data is extracted using AIS software and following background subtraction, signal normalization is performed. This includes a normalization of filter-wide expression levels between different experimental runs. Genes that are differentially expressed in the tissue of interest are identified.

Example 4

Chromosomal Mapping of the Polynucleotides

[0886] An oligonucleotide primer set is designed according to the sequence at the 5′ end of SEQ ID NO:X. This primer preferably spans about 100 nucleotides. This primer set is then used in a polymerase chain reaction under the following set of conditions: 30 seconds, 95° C.; 1 minute, 56° C.; 1 minute, 70° C. This cycle is repeated 32 times followed by one 5 minute cycle at 70° C. Human, mouse, and hamster DNA is used as template in addition to a somatic cell hybrid panel containing individual chromosomes or chromosome fragments (Bios, Inc). The reactions are analyzed on either 8% polyacrylamide gels or 3.5% agarose gels. Chromosome mapping is determined by the presence of an approximately 100 bp PCR fragment in the particular somatic cell hybrid.

Example 5

Bacterial Expression of a Polypeptide

[0887] A polynucleotide encoding a polypeptide of the present invention is amplified using PCR oligonucleotide primers corresponding to the 5′ and 3′ ends of the DNA sequence, as outlined in Example 1, to synthesize insertion fragments. The primers used to amplify the cDNA insert should preferably contain restriction sites, such as BamHI and XbaI, at the 5′ end of the primers in order to clone the amplified product into the expression vector. For example, BamHI and XbaI correspond to the restriction enzyme sites on the bacterial expression vector pQE-9. (Qiagen, Inc., Chatsworth, Calif.). This plasmid vector encodes antibiotic resistance (Ampr), a bacterial origin of replication (ori), an IPTG-regulatable promoter/operator (P/O), a ribosome binding site (RBS), a 6-histidine tag (6-His), and restriction enzyme cloning sites.

[0888] The pQE-9 vector is digested with BamHI and XbaI and the amplified fragment is ligated into the pQE-9 vector maintaining the reading frame initiated at the bacterial RBS. The ligation mixture is then used to transform the E. coli strain M15/rep4 (Qiagen, Inc.) which contains multiple copies of the plasmid pREP4, which expresses the lad repressor and also confers kanamycin resistance (Kanr). Transformants are identified by their ability to grow on LB plates and ampicillin/kanamycin resistant colonies are selected. Plasmid DNA is isolated and confirmed by restriction analysis.

[0889] Clones containing the desired constructs are grown overnight (O/N) in liquid culture in LB media supplemented with both Amp (100 ug/ml) and Kan (25 ug/ml). The O/N culture is used to inoculate a large culture at a ratio of 1:100 to 1:250. The cells are grown to an optical density 600 (O.D.600) of between 0.4 and 0.6. IPTG (Isopropyl-B-D-thiogalacto pyranoside) is then added to a final concentration of 1 mM. IPTG induces by inactivating the lacI repressor, clearing the P/O leading to increased gene expression.

[0890] Cells are grown for an extra 3 to 4 hours. Cells are then harvested by centrifugation (20 mins at 6000×g). The cell pellet is solubilized in the chaotropic agent 6 Molar Guanidine HCl by stirring for 3-4 hours at 4° C. The cell debris is removed by centrifugation, and the supernatant containing the polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid (“Ni-NTA”) affinity resin column (available from QIAGEN, Inc., supra). Proteins with a 6×His tag bind to the Ni-NTA resin with high affinity and can be purified in a simple one-step procedure (for details see: The QIAexpressionist (1995) QIAGEN, Inc., supra).

[0891] Briefly, the supernatant is loaded onto the column in 6 M guanidine-HCl, pH 8. The column is first washed with 10 volumes of 6 M guanidine-HCl, pH 8, then washed with 10 volumes of 6 M guanidine-HCl pH 6, and finally the polypeptide is eluted with 6 M guanidine-HCl, pH 5.

[0892] The purified protein is then renatured by dialyzing it against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus 200 mM NaCl. Alternatively, the protein can be successfully refolded while immobilized on the Ni-NTA column. The recommended conditions are as follows: renature using a linear 6M-1M urea gradient in 500 mM NaCl, 20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors. The renaturation should be performed over a period of 1.5 hours or more. After renaturation the proteins are eluted by the addition of 250 mM immidazole. Immidazole is removed by a final dialyzing step against PBS or 50 mM sodium acetate pH 6 buffer plus 200 mM NaCl. The purified protein is stored at 4° C. or frozen at −80° C.

[0893] In addition to the above expression vector, the present invention further includes an expression vector, called pHE4a (ATCC Accession Number 209645, deposited on Feb. 25, 1998) which contains phage operator and promoter elements operatively linked to a polynucleotide of the present invention, called pHE4a. (ATCC Accession Number 209645, deposited on Feb. 25, 1998.) This vector contains: 1) a neomycinphosphotransferase gene as a selection marker, 2) an E. coli origin of replication, 3) a T5 phage promoter sequence, 4) two lac operator sequences, 5) a Shine-Delgarno sequence, and 6) the lactose operon repressor gene (lacIq). The origin of replication (oriC) is derived from pUC19 (LTI, Gaithersburg, Md.). The promoter and operator sequences are made synthetically.

[0894] DNA can be inserted into the pHE4a by restricting the vector with NdeI and XbaI, BamHI, XhoI, or Asp718, running the restricted product on a gel, and isolating the larger fragment (the stuffer fragment should be about 310 base pairs). The DNA insert is generated according to the PCR protocol described in Example 1, using PCR primers having restriction sites for NdeI (5′ primer) and XbaI, BamHI, XhoI, or Asp718 (3′ primer). The PCR insert is gel purified and restricted with compatible enzymes. The insert and vector are ligated according to standard protocols.

[0895] The engineered vector could easily be substituted in the above protocol to express protein in a bacterial system.

Example 6

Purification of a Polypeptide from an Inclusion Body

[0896] The following alternative method can be used to purify a polypeptide expressed in E coli when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10° C.

[0897] Upon completion of the production phase of the E. coli fermentation, the cell culture is cooled to 4-10° C. and the cells harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of the expected yield of protein per unit weight of cell paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.

[0898] The cells are then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCl solution to a final concentration of 0.5 M NaCl, followed by centrifugation at 7000×g for 15 min. The resultant pellet is washed again using 0.5M NaCl, 100 mM Tris, 50 mM EDTA, pH 7.4.

[0899] The resulting washed inclusion bodies are solubilized with 1.5 M guanidine hydrochloride (GuHCl) for 2-4 hours. After 7000×g centrifugation for 15 min., the pellet is discarded and the polypeptide containing supernatant is incubated at 4° C. overnight to allow further GuHCl extraction.

[0900] Following high speed centrifugation (30,000×g) to remove insoluble particles, the GuHCl solubilized protein is refolded by quickly mixing the GuHCl extract with 20 volumes of buffer containing 50 mM sodium, pH 4.5, 150 mM NaCl, 2 mM EDTA by vigorous stirring. The refolded diluted protein solution is kept at 4° C. without mixing for 12 hours prior to further purification steps.

[0901] To clarify the refolded polypeptide solution, a previously prepared tangential filtration unit equipped with 0.16 μm membrane filter with appropriate surface area (e.g., Filtron), equilibrated with 40 mM sodium acetate, pH 6.0 is employed. The filtered sample is loaded onto a cation exchange resin (e.g., Poros HS-50, Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCl in the same buffer, in a stepwise manner. The absorbance at 280 nm of the effluent is continuously monitored. Fractions are collected and further analyzed by SDS-PAGE.

[0902] Fractions containing the polypeptide are then pooled and mixed with 4 volumes of water. The diluted sample is then loaded onto a previously prepared set of tandem columns of strong anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros CM-20, Perseptive Biosystems) exchange resins. The columns are equilibrated with 40 mM sodium acetate, pH 6.0. Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaCl. The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCl, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCl, 50 mM sodium acetate, pH 6.5. Fractions are collected under constant A280 monitoring of the effluent. Fractions containing the polypeptide (determined, for instance, by 16% SDS-PAGE) are then pooled.

[0903] The resultant polypeptide should exhibit greater than 95% purity after the above refolding and purification steps. No major contaminant bands should be observed from Commassie blue stained 16% SDS-PAGE gel when 5 μg of purified protein is loaded. The purified protein can also be tested for endotoxin/LPS contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL assays.

Example 7

Cloning and Expression of a Polypeptide in a Baculovirus Expression System

[0904] In this example, the plasmid shuttle vector pA2 is used to insert a polynucleotide into a baculovirus to express a polypeptide. This expression vector contains the strong polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus (AcMNPV) followed by convenient restriction sites such as BamHI, Xba I and Asp718. The polyadenylation site of the simian virus 40 (“SV40”) is used for efficient polyadenylation. For easy selection of recombinant virus, the plasmid contains the beta-galactosidase gene from E. coli under control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences for cell-mediated homologous recombination with wild-type viral DNA to generate a viable virus that express the cloned polynucleotide.

[0905] Many other baculovirus vectors can be used in place of the vector above, such as pAc373, pVL941, and pAcIM1, as one skilled in the art would readily appreciate, as long as the construct provides appropriately located signals for transcription, translation, secretion and the like, including a signal peptide and an in-frame AUG as required. Such vectors are described, for instance, in Luckow et al., Virology 170:31-39 (1989).

[0906] Specifically, the cDNA sequence contained in the deposited clone, including the AUG initiation codon, is amplified using the PCR protocol described in Example 1. If a naturally occurring signal sequence is used to produce the polypeptide of the present invention, the pA2 vector does not need a second signal peptide. Alternatively, the vector can be modified (pA2 GP) to include a baculovirus leader sequence, using the standard methods described in Summers et al., “A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures,” Texas Agricultural Experimental Station Bulletin No. 1555 (1987).

[0907] The amplified fragment is isolated from a 1% agarose gel using a commercially available kit (“Geneclean,” BIO 101 Inc., La Jolla, Calif.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.

[0908] The plasmid is digested with the corresponding restriction enzymes and optionally, can be dephosphorylated using calf intestinal phosphatase, using routine procedures known in the art. The DNA is then isolated from a 1% agarose gel using a commercially available kit (“Geneclean” BIO 101 Inc., La Jolla, Calif.).

[0909] The fragment and the dephosphorylated plasmid are ligated together with T4 DNA ligase. E. coli HB101 or other suitable E. coli hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla, Calif.) cells are transformed with the ligation mixture and spread on culture plates. Bacteria containing the plasmid are identified by digesting DNA from individual colonies and analyzing the digestion product by gel electrophoresis. The sequence of the cloned fragment is confirmed by DNA sequencing.

[0910] Five μg of a plasmid containing the polynucleotide is co-transfected with 1.0 μg of a commercially available linearized baculovirus DNA (“BaculoGold™ baculovirus DNA, Pharmingen, San Diego, Calif.), using the lipofection method described by Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417 (1987). One μg of BaculoGold™ virus DNA and 5 μg of the plasmid are mixed in a sterile well of a microtiter plate containing 50 μl of serum-free Grace's medium (Life Technologies Inc., Gaithersburg, Md.). Afterwards, 10 μl Lipofectin plus 90 μl Grace's medium are added, mixed and incubated for 15 minutes at room temperature. Then the transfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL 1711) seeded in a 35 mm tissue culture plate with 1 ml Grace's medium without serum. The plate is then incubated for 5 hours at 27° C. The transfection solution is then removed from the plate and 1 ml of Grace's insect medium supplemented with 10% fetal calf serum is added. Cultivation is then continued at 27° C. for four days.

[0911] After four days the supernatant is collected and a plaque assay is performed, as described by Summers and Smith, supra. An agarose gel with “Blue Gal” (Life Technologies Inc., Gaithersburg) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plaques. (A detailed description of a “plaque assay” of this type can also be found in the user's guide for insect cell culture and baculovirology distributed by Life Technologies Inc., Gaithersburg, page 9-10.) After appropriate incubation, blue stained plaques are picked with the tip of a micropipettor (e.g., Eppendorf). The agar containing the recombinant viruses is then resuspended in a microcentrifuge tube containing 200 μl of Grace's medium and the suspension containing the recombinant baculovirus is used to infect Sf9 cells seeded in 35 mm dishes. Four days later the supernatants of these culture dishes are harvested and then they are stored at 4° C.

[0912] To verify the expression of the polypeptide, Sf9 cells are grown in Grace's medium supplemented with 10% heat-inactivated FBS. The cells are infected with the recombinant baculovirus containing the polynucleotide at a multiplicity of infection (“MOI”) of about 2. If radiolabeled proteins are desired, 6 hours later the medium is removed and is replaced with SF900 II medium minus methionine and cysteine (available from Life Technologies Inc., Rockville, Md.). After 42 hours, 5 μCi of 35S-methionine and 5 μCi 35S-cysteine (available from Amersham) are added. The cells are further incubated for 16 hours and then are harvested by centrifugation. The proteins in the supernatant as well as the intracellular proteins are analyzed by SDS-PAGE followed by autoradiography (if radiolabeled).

[0913] Microsequencing of the amino acid sequence of the amino terminus of purified protein may be used to determine the amino terminal sequence of the produced protein.

Example 8

Expression of a Polypeptide in Mammalian Cells

[0914] The polypeptide of the present invention can be expressed in a mammalian cell. A typical mammalian expression vector contains a promoter element, which mediates the initiation of transcription of mRNA, a protein coding sequence, and signals required for the termination of transcription and polyadenylation of the transcript. Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription is achieved with the early and late promoters from SV40, the long terminal repeats (LTRs) from Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the cytomegalovirus (CMV). However, cellular elements can also be used (e.g., the human actin promoter).

[0915] Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pSVL and pMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146), pBC12MI (ATCC 67109), pCMVSport 2.0, and pCMVSport 3.0. Mammalian host cells that could be used include, human Hela, 293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7 and CV1, quail QC1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells.

[0916] Alternatively, the polypeptide can be expressed in stable cell lines containing the polynucleotide integrated into a chromosome. The co-transfection with a selectable marker such as DHFR, gpt, neomycin, or hygromycin allows the identification and isolation of the transfected cells.

[0917] The transfected gene can also be amplified to express large amounts of the encoded protein. The DHFR (dihydrofolate reductase) marker is useful in developing cell lines that carry several hundred or even several thousand copies of the gene of interest. (See, e.g., Alt, F. W., et al., J. Biol. Chem. 253:1357-1370 (1978); Hamlin, J. L. and Ma, C., Biochem. et Biophys. Acta, 1097:107-143 (1990); Page, M. J. and Sydenham, M. A., Biotechnology 9:64-68 (1991)). Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279 (1991); Bebbington et al., Bio/Technology 10:169-175 (1992). Using these markers, the mammalian cells are grown in selective medium and the cells with the highest resistance are selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of proteins.

[0918] Derivatives of the plasmid pSV2-dhfr (ATCC Accession No. 37146), the expression vectors pC4 (ATCC Accession No. 209646) and pC6 (ATCC Accession No.209647) contain the strong promoter (LTR) of the Rous Sarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438-447 (March, 1985)) plus a fragment of the CMV-enhancer (Boshart et al., Cell 41:521-530 (1985)). Multiple cloning sites, e.g., with the restriction enzyme cleavage sites BamHI, XbaI and Asp718, facilitate the cloning of the gene of interest. The vectors also contain the 3′ intron, the polyadenylation and termination signal of the rat preproinsulin gene, and the mouse DHFR gene under control of the SV40 early promoter.

[0919] Specifically, the plasmid pC6, for example, is digested with appropriate restriction enzymes and then dephosphorylated using calf intestinal phosphates by procedures known in the art. The vector is then isolated from a 1% agarose gel.

[0920] A polynucleotide of the present invention is amplified according to the protocol outlined in Example 1. If a naturally occurring signal sequence is used to produce the polypeptide of the present invention, the vector does not need a second signal peptide. Alternatively, if a naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., International Publication No. WO 96/34891.)

[0921] The amplified fragment is isolated from a 1% agarose gel using a commercially available kit (“Geneclean,” BIO 101 Inc., La Jolla, Calif.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.

[0922] The amplified fragment is then digested with the same restriction enzyme and purified on a 1% agarose gel. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC6 using, for instance, restriction enzyme analysis.

[0923] Chinese hamster ovary cells lacking an active DHFR gene is used for transfection. Five μg of the expression plasmid pC6 or pC4 is cotransfected with 0.5 μg of the plasmid pSVneo using lipofectin (Felgner et al., supra). The plasmid pSV2-neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G418. The cells are seeded in alpha minus MEM supplemented with 1 mg/ml G418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/ml of methotrexate plus 1 mg/ml G418. After about 10-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate (1 μM, 2 μM, 5 μM, 10 mM, 20 mM). The same procedure is repeated until clones are obtained which grow at a concentration of 100-200 μM. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis.

Example 9

Protein Fusions

[0924] The polypeptides of the present invention are preferably fused to other proteins. These fusion proteins can be used for a variety of applications. For example, fusion of the present polypeptides to His-tag, HA-tag, protein A, IgG domains, and maltose binding protein facilitates purification. (See Example 5; see also EP A 394,827; Traunecker, et al., Nature 331:84-86 (1988)). Similarly, fusion to IgG-1, IgG-3, and albumin increases the halflife time in vivo. Nuclear localization signals fused to the polypeptides of the present invention can target the protein to a specific subcellular localization, while covalent heterodimer or homodimers can increase or decrease the activity of a fusion protein. Fusion proteins can also create chimeric molecules having more than one function. Finally, fusion proteins can increase solubility and/or stability of the fused protein compared to the non-fused protein. All of the types of fusion proteins described above can be made by modifying the following protocol, which outlines the fusion of a polypeptide to an IgG molecule, or the protocol described in Example 5.

[0925] Briefly, the human Fc portion of the IgG molecule can be PCR amplified, using primers that span the 5′ and 3′ ends of the sequence described below. These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a mammalian expression vector.

[0926] For example, if pC4 (ATCC Accession No. 209646) is used, the human Fc portion can be ligated into the BamHI cloning site. Note that the 3′ BamHI site should be destroyed. Next, the vector containing the human Fc portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example 1, is ligated into this BamHI site. Note that the polynucleotide is cloned without a stop codon, otherwise a fusion protein will not be produced.

[0927] If the naturally occurring signal sequence is used to produce the polypeptide of the present invention, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., International Publication No. WO 96/34891.)

Human IgG Fc region
(SEQ ID NO: 1)
GGGATCCGGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGC
CCAGCACCTGAATTCGAGGGTGCACCGTCAGTCTTCCTCTTCCCCCCAAA
ACCCAAGGACACCCTCATGATCTCCCGGACTCCTGAGGTCACATGCGTGG
TGGTGGACGTAAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTG
GACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTA
CAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT
GGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCA
ACCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACC
ACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGG
TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGTG
GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC
CGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGG
ACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCAT
GAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGG
TAAATGAGTGCGACGGCCGCGACTCTAGAGGAT

Example 10

Production of an Antibody from a Polypeptide

[0928] a) Hybridoma Technology

[0929] The antibodies of the present invention can be prepared by a variety of methods. (See, Current Protocols, Chapter 2.) As one example of such methods, cells expressing a polypeptide of the present invention are administered to an animal to induce the production of sera containing polyclonal antibodies. In a preferred method, a preparation of a a polypeptide of the present invention is prepared and purified to render it substantially free of natural contaminants. Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity.

[0930] Monoclonal antibodies specific for a polypeptide of the present invention are prepared using hybridoma technology (Kohler et al., Nature 256:495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Kohler et al., Eur. J. Immunol. 6:292 (1976); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981)). In general, an animal (preferably a mouse) is immunized with a polypeptide of the present invention or, more preferably, with a secreted polypeptide of the present invention-expressing cell. Such polypeptide-expressing cells are cultured in any suitable tissue culture medium, preferably in Earle's modified Eagle's medium supplemented with 10% fetal bovine serum (inactivated at about 56° C.), and supplemented with about 10 g/l of nonessential amino acids, about 1,000 U/ml of penicillin, and about 100 μg/ml of streptomycin.

[0931] The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferable to employ the parent myeloma cell line (SP20), available from the ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (Gastroenterology 80:225-232 (1981)). The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the polypeptide of the present invention.

[0932] Alternatively, additional antibodies capable of binding to polypeptide of the present invention can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the polypeptide of the present invention-specific antibody can be blocked by polypeptide of the present invention. Such antibodies comprise anti-idiotypic antibodies to the polypeptide of the present invention-specific antibody and are used to immunize an animal to induce formation of further polypeptide of the present invention-specific antibodies.

[0933] For in vivo use of antibodies in humans, an antibody is “humanized”. Such antibodies can be produced using genetic constructs derived from hybridoma cells producing the monoclonal antibodies described above. Methods for producing chimeric and humanized antibodies are known in the art and are discussed herein. (See, for review, Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., International Publication No. WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985)).

[0934] b) Isolation of Antibody Fragments Directed Against Polypeptide of the Present Invention from a Library of scFvs

[0935] Naturally occurring V-genes isolated from human PBLs are constructed into a library of antibody fragments which contain reactivities against polypeptide of the present invention to which the donor may or may not have been exposed (see e.g., U.S. Pat. No. 5,885,793 incorporated herein by reference in its entirety).

[0936] Rescue of the Library. A library of scFvs is constructed from the RNA of human PBLs as described in International Publication No. WO 92/01047. To rescue phage displaying antibody fragments, approximately 109 E. coli harboring the phagemid are used to inoculate 50 ml of 2×TY containing 1% glucose and 100 μg/ml of ampicillin (2×TY-AMP-GLU) and grown to an O.D. of 0.8 with shaking. Five ml of this culture is used to inoculate 50 ml of 2×TY-AMP-GLU, 2×108 TU of delta gene 3 helper (M13 delta gene III, see International Publication No. WO 92/01047) are added and the culture incubated at 37° C. for 45 minutes without shaking and then at 37° C. for 45 minutes with shaking. The culture is centrifuged at 4000 r.p.m. for 10 min. and the pellet resuspended in 2 liters of 2×TY containing 100 μg/ml ampicillin and 50 ug/ml kanamycin and grown overnight. Phage are prepared as described in International Publication No. WO 92/01047.

[0937] M13 delta gene III is prepared as follows: M13 delta gene III helper phage does not encode gene III protein, hence the phage(mid) displaying antibody fragments have a greater avidity of binding to antigen. Infectious M13 delta gene III particles are made by growing the helper phage in cells harboring a pUC19 derivative supplying the wild type gene III protein during phage morphogenesis. The culture is incubated for 1 hour at 37° C. without shaking and then for a further hour at 37° C. with shaking. Cells are spun down (IEC-Centra 8,400 r.p.m. for 10 min), resuspended in 300 ml 2×TY broth containing 100 μg ampicillin/ml and 25 μg kanamycin/ml (2×TY-AMP-KAN) and grown overnight, shaking at 37° C. Phage particles are purified and concentrated from the culture medium by two PEG-precipitations (Sambrook et al., 1990), resuspended in 2 ml PBS and passed through a 0.45 μm filter (Minisart NML; Sartorius) to give a final concentration of approximately 1013 transducing units/ml (ampicillin-resistant clones).

[0938] Panning of the Library. Immunotubes (Nunc) are coated overnight in PBS with 4 ml of either 100 μg/ml or 10 μg/ml of a polypeptide of the present invention. Tubes are blocked with 2% Marvel-PBS for 2 hours at 37° C. and then washed 3 times in PBS. Approximately 1013 TU of phage is applied to the tube and incubated for 30 minutes at room temperature tumbling on an over and under turntable and then left to stand for another 1.5 hours. Tubes are washed 10 times with PBS 0.1% Tween-20 and 10 times with PBS. Phage are eluted by adding 1 ml of 100 mM triethylamine and rotating 15 minutes on an under and over turntable after which the solution is immediately neutralized with 0.5 ml of 1.0M Tris-HCl, pH 7.4. Phage are then used to infect 10 ml of mid-log E. coli TG1 by incubating eluted phage with bacteria for 30 minutes at 37° C. The E. coli are then plated on TYE plates containing 1% glucose and 100 μg/ml ampicillin. The resulting bacterial library is then rescued with delta gene 3 helper phage as described above to prepare phage for a subsequent round of selection. This process is then repeated for a total of 4 rounds of affinity purification with tube-washing increased to 20 times with PBS, 0.1% Tween-20 and 20 times with PBS for rounds 3 and 4.

[0939] Characterization of Binders. Eluted phage from the 3rd and 4th rounds of selection are used to infect E. coli HB 2151 and soluble scFv is produced (Marks, et al., 1991) from single colonies for assay. ELISAs are performed with microtitre plates coated with either 10 pg/ml of the polypeptide of the present invention in 50 mM bicarbonate pH 9.6. Clones positive in ELISA are further characterized by PCR fingerprinting (see, e.g., International Publication No. WO 92/01047) and then by sequencing. These ELISA positive clones may also be further characterized by techniques known in the art, such as, for example, epitope mapping, binding affinity, receptor signal transduction, ability to block or competitively inhibit antibody/antigen binding, and competitive agonistic or antagonistic activity.

Example 11

Method of Determining Alterations in a Gene Corresponding to a Polynucleotide

[0940] RNA isolated from entire families or individual patients presenting with a phenotype of interest (such as a disease) is isolated. cDNA is then generated from these RNA samples using protocols known in the art. (See, Sambrook.) The cDNA is then used as a template for PCR, employing primers surrounding regions of interest in SEQ ID NO:X; and/or the nucleotide sequence of the cDNA contained in Clone ID NO:Z. Suggested PCR conditions consist of 35 cycles at 95 degrees C. for 30 seconds; 60-120 seconds at 52-58 degrees C.; and 60-120 seconds at 70 degrees C., using buffer solutions described in Sidransky et al., Science 252:706 (1991).

[0941] PCR products are then sequenced using primers labeled at their 5′ end with T4 polynucleotide kinase, employing SequiTherm Polymerase (Epicentre Technologies). The intron-exon boundaries of selected exons is also determined and genomic PCR products analyzed to confirm the results. PCR products harboring suspected mutations are then cloned and sequenced to validate the results of the direct sequencing.

[0942] PCR products are cloned into T-tailed vectors as described in Holton et al., Nucleic Acids Research, 19:1156 (1991) and sequenced with T7 polymerase (United States Biochemical). Affected individuals are identified by mutations not present in unaffected individuals.

[0943] Genomic rearrangements are also observed as a method of determining alterations in a gene corresponding to a polynucleotide. Genomic clones isolated according to Example 2 are nick-translated with digoxigenindeoxy-uridine 5′-triphosphate (Boehringer Manheim), and FISH performed as described in Johnson et al., Methods Cell Biol. 35:73-99 (1991). Hybridization with the labeled probe is carried out using a vast excess of human cot-1 DNA for specific hybridization to the corresponding genomic locus.

[0944] Chromosomes are counterstained with 4,6-diamino-2-phenylidole and propidium iodide, producing a combination of C- and R-bands. Aligned images for precise mapping are obtained using a triple-band filter set (Chroma Technology, Brattleboro, Vt.) in combination with a cooled charge-coupled device camera (Photometrics, Tucson, Ariz.) and variable excitation wavelength filters. (Johnson et al., Genet. Anal. Tech. Appl., 8:75 (1991)). Image collection, analysis and chromosomal fractional length measurements are performed using the ISee Graphical Program System. (Inovision Corporation, Durham, N.C.) Chromosome alterations of the genomic region hybridized by the probe are identified as insertions, deletions, and translocations. These alterations are used as a diagnostic marker for an associated disease.

Example 12

Method of Detecting Abnormal Levels of a Polypeptide in a Biological Sample

[0945] A polypeptide of the present invention can be detected in a biological sample, and if an increased or decreased level of the polypeptide is detected, this polypeptide is a marker for a particular phenotype. Methods of detection are numerous, and thus, it is understood that one skilled in the art can modify the following assay to fit their particular needs.

[0946] For example, antibody-sandwich ELISAs are used to detect polypeptides in a sample, preferably a biological sample. Wells of a microtiter plate are coated with specific antibodies, at a final concentration of 0.2 to 10 ug/ml. The antibodies are either monoclonal or polyclonal and are produced by the method described in Example 10. The wells are blocked so that non-specific binding of the polypeptide to the well is reduced.

[0947] The coated wells are then incubated for >2 hours at RT with a sample containing the polypeptide. Preferably, serial dilutions of the sample should be used to validate results. The plates are then washed three times with deionized or distilled water to remove unbound polypeptide.

[0948] Next, 50 ul of specific antibody-alkaline phosphatase conjugate, at a concentration of 25-400 ng, is added and incubated for 2 hours at room temperature. The plates are again washed three times with deionized or distilled water to remove unbound conjugate.

[0949] Add 75 ul of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenyl phosphate (NPP) substrate solution to each well and incubate 1 hour at room temperature. Measure the reaction by a microtiter plate reader. Prepare a standard curve, using serial dilutions of a control sample, and plot polypeptide concentration on the X-axis (log scale) and fluorescence or absorbance of the Y-axis (linear scale). Interpolate the concentration of the polypeptide in the sample using the standard curve.

Example 13

Formulation

[0950] The invention also provides methods of treatment and/or prevention of diseases or disorders (such as, for example, any one or more of the diseases or disorders disclosed herein) by administration to a subject of an effective amount of a Therapeutic. By therapeutic is meant polynucleotides or polypeptides of the invention (including fragments and variants), agonists or antagonists thereof, and/or antibodies thereto, in combination with a pharmaceutically acceptable carrier type (e.g., a sterile carrier).

[0951] The Therapeutic will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the Therapeutic alone), the site of delivery, the method of administration, the scheduling of administration, and other factors known to practitioners. The “effective amount” for purposes herein is thus determined by such considerations.

[0952] As a general proposition, the total pharmaceutically effective amount of the Therapeutic administered parenterally per dose will be in the range of about 1 ug/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone. If given continuously, the Therapeutic is typically administered at a dose rate of about 1 ug/kg/hour to about 50 ug/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect.

[0953] Therapeutics can be are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.

[0954] Therapeutics of the invention are also suitably administered by sustained-release systems. Suitable examples of sustained-release Therapeutics are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.

[0955] Therapeutics of the invention are also suitably administered by sustained-release systems. Suitable examples of sustained-release Therapeutics include suitable polymeric materials (such as, for example, semi-permeable polymer matrices in the form of shaped articles, e.g., films, or mirocapsules), suitable hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, and sparingly soluble derivatives (such as, for example, a sparingly soluble salt).

[0956] Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547-556 (1983)), poly (2-hydroxyethyl methacrylate) (Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981), and Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (Langer et al., Id.) or poly-D-(−)-3-hydroxybutyric acid (EP 133,988).

[0957] Sustained-release Therapeutics also include liposomally entrapped Therapeutics of the invention (see generally, Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 317-327 and 353-365 (1989)). Liposomes containing the Therapeutic are prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci.(USA) 77:4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal Therapeutic.

[0958] In yet an additional embodiment, the Therapeutics of the invention are delivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).

[0959] Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).

[0960] For parenteral administration, in one embodiment, the Therapeutic is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to the Therapeutic.

[0961] Generally, the formulations are prepared by contacting the Therapeutic uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.

[0962] The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.

[0963] The Therapeutic is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, at a pH of about 3 to 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of polypeptide salts.

[0964] Any pharmaceutical used for therapeutic administration can be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutics generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0965] Therapeutics ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous Therapeutic solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized Therapeutic using bacteriostatic Water-for-Injection.

[0966] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the Therapeutics of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. In addition, the Therapeutics may be employed in conjunction with other therapeutic compounds.

[0967] The Therapeutics of the invention may be administered alone or in combination with adjuvants. Adjuvants that may be administered with the Therapeutics of the invention include, but are not limited to, alum, alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genentech, Inc.), BCG (e.g., THERACYS®), MPL and nonviable prepartions of Corynebacterium parvum. In a specific embodiment, Therapeutics of the invention are administered in combination with alum. In another specific embodiment, Therapeutics of the invention are administered in combination with QS-21. Further adjuvants that may be administered with the Therapeutics of the invention include, but are not limited to, Monophosphoryl lipid immunomodulator, AdjuVax lOa, QS-21, QS-18, CRL1005, Aluminum salts, MF-59, and Virosomal adjuvant technology. Vaccines that may be administered with the Therapeutics of the invention include, but are not limited to, vaccines directed toward protection against MMR (measles, mumps, rubella), polio, varicella, tetanus/diptheria, hepatitis A, hepatitis B, haemophilus influenzae B, whooping cough, pneumonia, influenza, Lyme's Disease, rotavirus, cholera, yellow fever, Japanese encephalitis, poliomyelitis, rabies, typhoid fever, and pertussis. Combinations may be administered either concomitantly, e.g., as an admixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also procedures in which the combined agents are administered separately but simultaneously, e.g., as through separate intravenous lines into the same individual. Administration “in combination” further includes the separate administration of one of the compounds or agents given first, followed by the second.

[0968] The Therapeutics of the invention may be administered alone or in combination with other therapeutic agents. Therapeutic agents that may be administered in combination with the Therapeutics of the invention, include but are not limited to psychotherapeutic agents (e.g., antipsychotic agents, antimanic agents, antidepressants, antianxiety agents, and stimulants), anti-epileptics, antiparkinsonian agents, ALS therapeutics, steroidal and non-steroidal anti-inflammatory agents, anticaogulation and thrombolytic agents, chemotherapeutic agents, cytokines and/or growth factors, antiviral agents, members of the TNF family, antibiotics, and/or conventional immunotherapeutic agents. Combinations may be administered either concomitantly, e.g., as an admixture, separately but simultaneously or concurrently; or sequetially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also procedures in which the combined agents are administered separately but simultaneously, e.g., as through separate intravenous lines into the same individual. Administration “in combination” further includes the separate administration of one of the compounds or agents given first, followed by the second.

[0969] In one embodiment, the Therapeutics of the invention are administered in combination with an anticoagulant. Anticoagulants that may be administered with the compositions of the invention include, but are not limited to, heparin, low molecular weight heparin, warfarin sodium (e.g., COUMADIN®), dicumarol, 4-hydroxycoumarin, anisindione (e.g., MIRADON™), acenocoumarol (e.g., nicoumalone, SINTHROME™), indan-1,3-dione, phenprocoumon (e.g., MARCUMAR™), ethyl biscoumacetate (e.g., TROMEXAN™), and aspirin. In a specific embodiment, compositions of the invention are administered in combination with heparin and/or warfarin. In another specific embodiment, compositions of the invention are administered in combination with warfarin. In another specific embodiment, compositions of the invention are administered in combination with warfarin and aspirin. In another specific embodiment, compositions of the invention are administered in combination with heparin. In another specific embodiment, compositions of the invention are administered in combination with heparin and aspirin.

[0970] In another embodiment, the Therapeutics of the invention are administered in combination with thrombolytic drugs. Thrombolytic drugs that may be administered with the compositions of the invention include, but are not limited to, plasminogen, lys-plasminogen, alpha2-antiplasmin, streptokinae (e.g., KABIKINASE™), antiresplace (e.g., EMINASE™), tissue plasminogen activator (t-PA, altevase, ACTIVASE™), urokinase (e.g., ABBOKINASE™), sauruplase, (Prourokinase, single chain urokinase), and aminocaproic acid (e.g., AMICAR™). In a specific embodiment, compositions of the invention are administered in combination with tissue plasminogen activator and aspirin.

[0971] In another embodiment, the Therapeutics of the invention are administered in combination with antiplatelet drugs. Antiplatelet drugs that may be administered with the compositions of the invention include, but are not limited to, aspirin, dipyridamole (e.g., PERSANTINE™), and ticlopidine (e.g., TICLID™).

[0972] In specific embodiments, the use of anti-coagulants, thrombolytic and/or antiplatelet drugs in combination with Therapeutics of the invention is contemplated for the prevention, diagnosis, and/or treatment of thrombosis, arterial thrombosis, venous thrombosis, thromboembolism, pulmonary embolism, atherosclerosis, myocardial infarction, transient ischemic attack, unstable angina. In specific embodiments, the use of anticoagulants, thrombolytic drugs and/or antiplatelet drugs in combination with Therapeutics of the invention is contemplated for the prevention of occulsion of saphenous grafts, for reducing the risk of periprocedural thrombosis as might accompany angioplasty procedures, for reducing the risk of stroke in patients with atrial fibrillation including nonrheumatic atrial fibrillation, for reducing the risk of embolism associated with mechanical heart valves and or mitral valves disease. Other uses for the therapeutics of the invention, alone or in combination with antiplatelet, anticoagulant, and/or thrombolytic drugs, include, but are not limited to, the prevention of occlusions in extracorporeal devices (e.g., intravascular canulas, vascular access shunts in hemodialysis patients, hemodialysis machines, and cardiopulmonary bypass machines).

[0973] In certain embodiments, Therapeutics of the invention are administered in combination with antiretroviral agents, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and/or protease inhibitors (PIs). NRTIs that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, RETROVIR™ (zidovudine/AZT), VIDEX™ (didanosine/ddI), HIVID™ (zalcitabine/ddC), ZERIT™ (stavudine/d4T), EPIVIR™ (lamivudine/3TC), and COMBIVIR™ (zidovudine/lamivudine). NNRTIs that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, VIRAMUNE™ (nevirapine), RESCRIPTOR™ (delavirdine), and SUSTIVA™ (efavirenz). Protease inhibitors that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, CRIXIVAN™ (indinavir), NORVIR™ (ritonavir), INVIRASE™ (saquinavir), and VIRACEPT™ (nelfinavir). In a specific embodiment, antiretroviral agents, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and/or protease inhibitors may be used in any combination with Therapeutics of the invention to treat AIDS and/or to prevent or treat HIV infection.

[0974] Additional NRTIs include LODENOSINE™ (F-ddA; an acid-stable adenosine NRTI; Triangle/Abbott; COVIRACIL™ (emtricitabine/FTC; structurally related to lamivudine (3TC) but with 3- to 10-fold greater activity in vitro; Triangle/Abbott); dOTC (BCH-10652, also structurally related to lamivudine but retains activity against a substantial proportion of lamivudine-resistant isolates; Biochem Pharma); Adefovir (refused approval for anti-HIV therapy by FDA; Gilead Sciences); PREVEON® (Adefovir Dipivoxil, the active prodrug of adefovir; its active form is PMEA-pp); TENOFOVIR™ (bis-POC PMPA, a PMPA prodrug; Gilead); DAPD/DXG (active metabolite of DAPD; Triangle/Abbott); D-D4FC (related to 3TC, with activity against AZT/3TC-resistant virus); GW420867X (Glaxo Wellcome); ZIAGEN™ (abacavir/159U89; Glaxo Wellcome Inc.); CS-87 (3′azido-2′,3′-dideoxyuridine; WO 99/66936); and S-acyl-2-thioethyl (SATE)-bearing prodrug forms of β-L-FD4C and β-L-FddC (WO 98/17281).

[0975] Additional NNRTIs include COACTINON™ (Emivirine/MKC-442, potent NNRTI of the HEPT class; Triangle/Abbott); CAPRAVIRINE™ (AG-1549/S-1153, a next generation NNRTI with activity against viruses containing the K103N mutation; Agouron); PNU-142721 (has 20- to 50-fold greater activity than its predecessor delavirdine and is active against K103N mutants; Pharmacia & Upjohn); DPC-961 and DPC-963 (second-generation derivatives of efavirenz, designed to be active against viruses with the K103N mutation; DuPont); GW-420867×(has 25-fold greater activity than HBY097 and is active against K103N mutants; Glaxo Wellcome); CALANOLIDE A (naturally occurring agent from the latex tree; active against viruses containing either or both the Y181 C and K103N mutations); and Propolis (WO 99/49830).

[0976] Additional protease inhibitors include LOPINAVIR™ (ABT378/r; Abbott Laboratories); BMS-232632 (an azapeptide; Bristol-Myres Squibb); TIPRANAVIR™ (PNU-140690, a non-peptic dihydropyrone; Pharmacia & Upjohn); PD-178390 (a nonpeptidic dihydropyrone; Parke-Davis); BMS 232632 (an azapeptide; Bristol-Myers Squibb); L-756,423 (an indinavir analog; Merck); DMP-450 (a cyclic urea compound; Avid & DuPont); AG-1776 (a peptidomimetic with in vitro activity against protease inhibitor-resistant viruses; Agouron); VX-175/GW-433908 (phosphate prodrug of amprenavir; Vertex & Glaxo Welcome); CGP61755 (Ciba); and AGENERASE™ (amprenavir; Glaxo Wellcome Inc.).

[0977] Additional antiretroviral agents include fusion inhibitors/gp41 binders. Fusion inhibitors/gp41 binders include T-20 (a peptide from residues 643-678 of the HIV gp41 transmembrane protein ectodomain which binds to gp41 in its resting state and prevents transformation to the fusogenic state; Trimeris) and T-1249 (a second-generation fusion inhibitor; Trimeris).

[0978] Additional antiretroviral agents include fusion inhibitors/chemokine receptor antagonists. Fusion inhibitors/chemokine receptor antagonists include CXCR4 antagonists such as AMD 3100 (a bicyclam), SDF-1 and its analogs, and ALX40-4C (a cationic peptide), T22 (an 18 amino acid peptide; Trimeris) and the T22 analogs T134 and T140; CCR5 antagonists such as RANTES (9-68), AOP-RANTES, NNY-RANTES, and TAK-779; and CCR5/CXCR4 antagonists such as NSC 651016 (a distamycin analog). Also included are CCR2B, CCR3, and CCR6 antagonists. Chemokine recpetor agonists such as RANTES, SDF-1, MIP-1α, MIP-1β, etc., may also inhibit fusion.

[0979] Additional antiretroviral agents include integrase inhibitors. Integrase inhibitors include dicaffeoylquinic (DFQA) acids; L-chicoric acid (a dicaffeoyltartaric (DCTA) acid); quinalizarin (QLC) and related anthraquinones; ZINTEVIR™ (AR 177, an oligonucleotide that probably acts at cell surface rather than being a true integrase inhibitor; Arondex); and naphthols such as those disclosed in WO 98150347.

[0980] Additional antiretroviral agents include hydroxyurea-like compunds such as BCX-34 (a purine nucleoside phosphorylase inhibitor; Biocryst); ribonucleotide reductase inhibitors such as DIDOX™ (Molecules for Health); inosine monophosphate dehydrogenase (IMPDH) inhibitors sucha as VX-497 (Vertex); and mycopholic acids such as CellCept (mycophenolate mofetil; Roche).

[0981] Additional antiretroviral agents include inhibitors of viral integrase, inhibitors of viral genome nuclear translocation such as arylene bis(methylketone) compounds; inhibitors of HIV entry such as AOP-RANTES, NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES and glycosaminoglycans (GAG), and AMD-3100; nucleocapsid zinc finger inhibitors such as dithiane compounds; targets of HIV Tat and Rev; and pharmacoenhancers such as ABT-378.

[0982] Other antiretroviral therapies and adjunct therapies include cytokines and lymphokines such as MIP-1α, MIP-1β, SDF-1α, IL-2, PROLEUKIN™ (aldesleukin/L2-7001; Chiron), IL-4, IL-10, IL-12, and IL-13; interferons such as IFN-α2a; antagonists of TNFs, NFκB, GM-CSF, M-CSF, and IL-10; agents that modulate immune activation such as cyclosporin and prednisone; vaccines such as Remune™ (HIV Immunogen), APL 400-003 (Apollon), recombinant gp120 and fragments, bivalent (B/E) recombinant envelope glycoprotein, rgp120CM235, MN rgp120, SF-2 rgp120, gp120/soluble CD4 complex, Delta JR-FL protein, branched synthetic peptide derived from discontinuous gp120 C3/C4 domain, fusion-competent immunogens, and Gag, Pol, Nef, and Tat vaccines; gene-based therapies such as genetic suppressor elements (GSEs; WO 98/54366), and intrakines (genetically modified CC chemokines targetted to the ER to block surface expression of newly synthesized CCR5 (Yang et al., PNAS 94:11567-72 (1997); Chen et al., Nat. Med. 3:1110-16 (1997)); antibodies such as the anti-CXCR4 antibody 12G5, the anti-CCR5 antibodies 2D7, 5C7, PA8, PA9, PA10, PA11, PA12, and PA14, the anti-CD4 antibodies Q4120 and RPA-T4, the anti-CCR3 antibody 7B11, the anti-gp120 antibodies 17b, 48d, 447-52D, 257-D, 268-D and 50.1, anti-Tat antibodies, anti-TNF-α antibodies, and monoclonal antibody 33A; aryl hydrocarbon (AH) receptor agonists and antagonists such as TCDD, 3,3′,4,4′,5-pentachlorobiphenyl, 3,3′,4,4′-tetrachlorobiphenyl, and α-naphthoflavone (WO 98/30213); and antioxidants such as γ-L-glutamyl-L-cysteine ethyl ester (γ-GCE; WO 99/56764).

[0983] In a further embodiment, the Therapeutics of the invention are administered in combination with an antiviral agent. Antiviral agents that may be administered with the Therapeutics of the invention include, but are not limited to, acyclovir, ribavirin, amantadine, and remantidine.

[0984] In other embodiments, Therapeutics of the invention may be administered in combination with anti-opportunistic infection agents. Anti-opportunistic agents that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, ATOVAQUONE™, ISONIAZID™ RIFAMPIN™, PYRAZINAMIDE™, ETHAMBUTOL™, RIFABUTIN™, CLARITHROMYCIN™, AZITHROMYCIN™, GANCICLOVIR™, FOSCARNET™, CIDOFOVIR™, FLUCONAZOLE™, ITRACONAZOLE™, KETOCONAZOLE™, ACYCLOVIR™, FAMCICOLVIR™, PYRIMETHAMINE™, LEUCOVORIN™, NEUPOGEN™ (filgrastim/G-CSF), and LEUKINE™ (sargramostim/GM-CSF). In a specific embodiment, Therapeutics of the invention are used in any combination with TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, and/or ATOVAQUONE™ to prophylactically treat or prevent an opportunistic Pneumocystis carinii pneumonia infection. In another specific embodiment, Therapeutics of the invention are used in any combination with ISONLAZID™, RIFAMPIN™, PYRAZINAMIDE™, and/or ETHAMBUTOL™ to prophylactically treat or prevent an opportunistic Mycobacterium avium complex infection. In another specific embodiment, Therapeutics of the invention are used in any combination with RIFABUTIN™, CLARITHROMYCIN™, and/or AZITHROMYCIN™ to prophylactically treat or prevent an opportunistic Mycobacterium tuberculosis infection. In another specific embodiment, Therapeutics of the invention are used in any combination with GANCICLOVIR™, FOSCARNET™, and/or CIDOFOVIR™ to prophylactically treat or prevent an opportunistic cytomegalovirus infection. In another specific embodiment, Therapeutics of the invention are used in any combination with FLUCONAZOLE™, ITRACONAZOLE™, and/or KETOCONAZOLE™ to prophylactically treat or prevent an opportunistic fungal infection. In another specific embodiment, Therapeutics of the invention are used in any combination with ACYCLOVIR™ and/or FAMCICOLVIR™ to prophylactically treat or prevent an opportunistic herpes simplex virus type I and/or type II infection. In another specific embodiment, Therapeutics of the invention are used in any combination with PYRIMETHAMINE™ and/or LEUCOVORIN™ to prophylactically treat or prevent an opportunistic Toxoplasma gondii infection. In another specific embodiment, Therapeutics of the invention are used in any combination with LEUCOVORIN™ and/or NEUPOGEN™ to prophylactically treat or prevent an opportunistic bacterial infection.

[0985] In a further embodiment, the Therapeutics of the invention are administered in combination with an antibiotic agent. Antibiotic agents that may be administered with the Therapeutics of the invention include, but are not limited to, amoxicillin, beta-lactamases, aminoglycosides, beta-lactam (glycopeptide), beta-lactamases, Clindamycin, chloramphenicol, cephalosporins, ciprofloxacin, erythromycin, fluoroquinolones, macrolides, metronidazole, penicillins, quinolones, rapamycin, rifampin, streptomycin, sulfonamide, tetracyclines, trimethoprim, trimethoprim-sulfamethoxazole, and vancomycin.

[0986] In other embodiments, the Therapeutics of the invention are administered in combination with immunestimulants. Immunostimulants that may be administered in combination with the Therapeutics of the invention include, but are not limited to, levamisole (e.g., ERGAMISOL™), isoprinosine (e.g. INOSIPLEX™), interferons (e.g. interferon alpha), and interleukins (e.g., IL-2).

[0987] In other embodiments, Therapeutics of the invention are administered in combination with immunosuppressive agents. Immunosuppressive agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to, steroids, cyclosporine, cyclosporine analogs, cyclophosphamide methylprednisone, prednisone, azathioprine, FK-506, 15-deoxyspergualin, and other immunosuppressive agents that act by suppressing the function of responding T cells. Other immunosuppressive agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to, prednisolone, methotrexate, thalidomide, methoxsalen, rapamycin, leflunomide, mizoribine (BREDININ™), brequinar, deoxyspergualin, and azaspirane (SKF 105685), ORTHOCLONE OKT® 3 (muromonab-CD3), SANDIMMUNE™, NEORAL™, SANGDYA™ (cyclosporine), PROGRAF® (FK506, tacrolimus), CELLCEPT® (mycophenolate motefil, of which the active metabolite is mycophenolic acid), IMURAN™ (azathioprine), glucocorticosteroids, adrenocortical steroids such as DELTASONE™ (prednisone) and HYDELTRASOL™ (prednisolone), FOLEX™ and MEXATE™ (methotrxate), OXSORALEN-ULTRA™ (methoxsalen) and RAPAMUNE™ (sirolimus). In a specific embodiment, immunosuppressants may be used to prevent rejection of organ or bone marrow transplantation.

[0988] In an additional embodiment, Therapeutics of the invention are administered alone or in combination with one or more intravenous immune globulin preparations. Intravenous immune globulin preparations that may be administered with the Therapeutics of the invention include, but not limited to, GAMMAR™, IVEEGAM™, SANDOGLOBULIN™, GAMMAGARD S/D™, ATGAM™ (antithymocyte glubulin), and GAMIMUNE™. In a specific embodiment, Therapeutics of the invention are administered in combination with intravenous immune globulin preparations in transplantation therapy (e.g., bone marrow transplant).

[0989] In certain embodiments, the Therapeutics of the invention are administered alone or in combination with an anti-inflammatory agent. Anti-inflammatory agents that may be administered with the Therapeutics of the invention include, but are not limited to, corticosteroids (e.g. betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone), nonsteroidal anti-inflammatory drugs (e.g., diclofenac, diflunisal, etodolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tenoxicam, tiaprofenic acid, and tolmetin.), as well as antihistamines, aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, and tenidap.

[0990] In an additional embodiment, the compositions of the invention are administered alone or in combination with an anti-angiogenic agent. Anti-angiogenic agents that may be administered with the compositions of the invention include, but are not limited to, Angiostatin (Entremed, Rockville, Md.), Troponin-1 (Boston Life Sciences, Boston, Mass.), anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel (Taxol), Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, VEGI, Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of the lighter “d group” transition metals.

[0991] Lighter “d group” transition metals include, for example, vanadium, molybdenum, tungsten, titanium, niobium, and tantalum species. Such transition metal species may form transition metal complexes. Suitable complexes of the above-mentioned transition metal species include oxo transition metal complexes.

[0992] Representative examples of vanadium complexes include oxo vanadium complexes such as vanadate and vanadyl complexes. Suitable vanadate complexes include metavanadate and orthovanadate complexes such as, for example, ammonium metavanadate, sodium metavanadate, and sodium orthovanadate. Suitable vanadyl complexes include, for example, vanadyl acetylacetonate and vanadyl sulfate including vanadyl sulfate hydrates such as vanadyl sulfate mono- and trihydrates.

[0993] Representative examples of tungsten and molybdenum complexes also include oxo complexes. Suitable oxo tungsten complexes include tungstate and tungsten oxide complexes. Suitable tungstate complexes include ammonium tungstate, calcium tungstate, sodium tungstate dihydrate, and tungstic acid. Suitable tungsten oxides include tungsten (IV) oxide and tungsten (VI) oxide. Suitable oxo molybdenum complexes include molybdate, molybdenum oxide, and molybdenyl complexes. Suitable molybdate complexes include ammonium molybdate and its hydrates, sodium molybdate and its hydrates, and potassium molybdate and its hydrates. Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum (VI) oxide, and molybdic acid. Suitable molybdenyl complexes include, for example, molybdenyl acetylacetonate. Other suitable tungsten and molybdenum complexes include hydroxo derivatives derived from, for example, glycerol, tartaric acid, and sugars.

[0994] A wide variety of other anti-angiogenic factors may also be utilized within the context of the present invention. Representative examples include, but are not limited to, platelet factor 4; protamine sulphate; sulphated chitin derivatives (prepared from queen crab shells), (Murata et al., Cancer Res. 51:22-26, (1991)); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine; modulators of matrix metabolism, including for example, proline analogs, cishydroxyproline, d,L-3,4-dehydroproline, Thiaproline, alpha,alpha-dipyridyl, aminopropionitrile fumarate; 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone; Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326, (1992)); Chymostatin (Tomkinson et al., Biochem J. 286:475-480, (1992)); Cyclodextrin Tetradecasulfate; Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557, (1990)); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin. Invest. 79:1440-1446, (1987)); anticollagenase-serum; alpha2-antiplasmin (Holmes et al., J. Biol. Chem. 262(4):1659-1664, (1987)); Bisantrene (National Cancer Institute); Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”; (Takeuchi et al., Agents Actions 36:312-316, (1992)); and metalloproteinase inhibitors such as BB94.

[0995] Additional anti-angiogenic factors that may also be utilized within the context of the present invention include Thalidomide, (Celgene, Warren, N.J.); Angiostatic steroid; AGM-1470 (H. Brem and J. Folkman J Pediatr. Surg. 28:445-51 (1993)); an integrin alpha v beta 3 antagonist (C. Storgard et al., J. Clin. Invest. 103:47-54 (1999)); carboxynaminolmidazole; Carboxyamidotriazole (CAI) (National Cancer Institute, Bethesda, Md.); Conbretastatin A-4 (CA4P) (OXiGENE, Boston, Mass.); Squalamine (Magainin Pharmaceuticals, Plymouth Meeting, Pa.); TNP-470, (Tap Pharmaceuticals, Deerfield, Ill.); ZD-0101 AstraZeneca (London, UK); APRA (CT2584); Benefin, Byrostatin-1 (SC339555); CGP-41251 (PKC 412); CM101; Dexrazoxane (ICRF187); DMXAA; Endostatin; Flavopridiol; Genestein; GTE; lInmTher; Iressa (ZD1839); Octreotide (Somatostatin); Panretin; Penacillamine; Photopoint; PI-88; Prinomastat (AG-3340) Purlytin; Suradista (FCE26644); Tamoxifen (Nolvadex); Tazarotene; Tetrathiomolybdate; Xeloda (Capecitabine); and 5-Fluorouracil.

[0996] Anti-angiogenic agents that may be administed in combination with the compounds of the invention may work through a variety of mechanisms including, but not limited to, inhibiting proteolysis of the extracellular matrix, blocking the function of endothelial cell-extracellular matrix adhesion molecules, by antagonizing the function of angiogenesis inducers such as growth factors, and inhibiting integrin receptors expressed on proliferating endothelial cells. Examples of anti-angiogenic inhibitors that interfere with extracellular matrix proteolysis and which may be administered in combination with the compositons of the invention include, but are not lmited to, AG-3340 (Agouron, La Jolla, Calif.), BAY-12-9566 (Bayer, West Haven, Conn.), BMS-275291 (Bristol Myers Squibb, Princeton, N.J.), CGS-27032A (Novartis, East Hanover, N.J.), Marimastat (British Biotech, Oxford, UK), and Metastat (Aeterna, St-Foy, Quebec). Examples of anti-angiogenic inhibitors that act by blocking the function of endothelial cell-extracellular matrix adhesion molecules and which may be administered in combination with the compositons of the invention include, but are not Imited to, EMD-121974 (Merck KcgaA Darmstadt, Germany) and Vitaxin (Ixsys, La Jolla, Calif./Medimmune, Gaithersburg, Md.). Examples of anti-angiogenic agents that act by directly antagonizing or inhibiting angiogenesis inducers and which may be administered in combination with the compositons of the invention include, but are not lmited to, Angiozyme (Ribozyme, Boulder, Colo.), Anti-VEGF antibody (Genentech, S. San Francisco, Calif.), PTK-787/ZK-225846 (Novartis, Basel, Switzerland), SU-101 (Sugen, S. San Francisco, Calif.), SU-5416 (Sugen/Pharmacia Upjohn, Bridgewater, N.J.), and SU-6668 (Sugen). Other anti-angiogenic agents act to indirectly inhibit angiogenesis. Examples of indirect inhibitors of angiogenesis which may be administered in combination with the compositons of the invention include, but are not limited to, IM-862 (Cytran, Kirkland, Wash.), Interferon-alpha, IL-12 (Roche, Nutley, N.J.), and Pentosan polysulfate (Georgetown University, Washington, D.C.).

[0997] In particular embodiments, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of an autoimmune disease, such as for example, an autoimmune disease described herein.

[0998] In a particular embodiment, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of arthritis. In a more particular embodiment, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of rheumatoid arthritis.

[0999] In another embodiment, the polynucleotides encoding a polypeptide of the present invention are administered in combination with an angiogenic protein, or polynucleotides encoding an angiogenic protein. Examples of angiogenic proteins that may be administered with the compositions of the invention include, but are not limited to, acidic and basic fibroblast growth factors, VEGF-1, VEGF-2, VEGF-3, epidermal growth factor alpha and beta, platelet-derived endothelial cell growth factor, platelet-derived growth factor, tumor necrosis factor alpha, hepatocyte growth factor, insulin-like growth factor, colony stimulating factor, macrophage colony stimulating factor, granulocyte/macrophage colony stimulating factor, and nitric oxide synthase.

[1000] In additional embodiments, compositions of the invention are administered in combination with a chemotherapeutic agent. Chemotherapeutic agents that may be administered with the Therapeutics of the invention include, but are not limited to alkylating agents such as nitrogen mustards (for example, Mechlorethamine, cyclophosphamide, Cyclophosphamide Ifosfamide, Melphalan (L-sarcolysin), and Chlorambucil), ethylenimines and methylmelamines (for example, Hexamethylmelamine and Thiotepa), alkyl sulfonates (for example, Busulfan), nitrosoureas (for example, Carmustine (BCNU), Lomustine (CCNU), Semustine (methyl-CCNU), and Streptozocin (streptozotocin)), triazenes (for example, Dacarbazine (DTIC; dimethyltriazenoimidazolecarboxamide)), folic acid analogs (for example, Methotrexate (amethopterin)), pyrimidine analogs (for example, Fluorouacil (5-fluorouracil; 5-FU), Floxuridine (fluorodeoxyunridine; FudR), and Cytarabine (cytosine arabinoside)), purine analogs and related inhibitors (for example, Mercaptopurine (6-mercaptopurine; 6-MP), Thioguanine (6-thioguanine; TG), and Pentostatin (2′-deoxycoformycin)), vinca alkaloids (for example, Vinblastine (VLB, vinblastine sulfate)) and Vincristine (vincristine sulfate)), epipodophyllotoxins (for example, Etoposide and Teniposide), antibiotics (for example, Dactinomycin (actinomycin D), Daunorubicin (daunomycin; rubidomycin), Doxorubicin, Bleomycin, Plicamycin (mithramycin), and Mitomycin (mitomycin C), enzymes (for example, L-Asparaginase), biological response modifiers (for example, Interferon-alpha and interferon-alpha-2b), platinum coordination compounds (for example, Cisplatin (cis-DDP) and Carboplatin), anthracenedione (Mitoxantrone), substituted ureas (for example, Hydroxyurea), methylhydrazine derivatives (for example, Procarbazine (N-methylhydrazine; MIH), adrenocorticosteroids (for example, Prednisone), progestins (for example, Hydroxyprogesterone caproate, Medroxyprogesterone, Medroxyprogesterone acetate, and Megestrol acetate), estrogens (for example, Diethylstilbestrol (DES), Diethylstilbestrol diphosphate, Estradiol, and Ethinyl estradiol), antiestrogens (for example, Tamoxifen), androgens (Testosterone proprionate, and Fluoxymesterone), antiandrogens (for example, Flutamide), gonadotropin-releasing horomone analogs (for example, Leuprolide), other hormones and hormone analogs (for example, methyltestosterone, estramustine, estramustine phosphate sodium, chlorotrianisene, and testolactone), and others (for example, dicarbazine, glutamic acid, and mitotane).

[1001] In one embodiment, the compositions of the invention are administered in combination with one or more of the following drugs: infliximab (also known as Remicade™ Centocor, Inc.), Trocade (Roche, RO-32-3555), Leflunomide (also known as Arava™ from Hoechst Marion Roussel), Kineret™ (an IL-1 Receptor antagonist also known as Anakinra from Amgen, Inc.)

[1002] In a specific embodiment, compositions of the invention are administered in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or combination of one or more of the components of CHOP. In one embodiment, the compositions of the invention are administered in combination with anti-CD20 antibodies, human monoclonal anti-CD20 antibodies. In another embodiment, the compositions of the invention are administered in combination with anti-CD20 antibodies and CHOP, or anti-CD20 antibodies and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. In a specific embodiment, compositions of the invention are administered in combination with Rituximab. In a further embodiment, compositions of the invention are administered with Rituximab and CHOP, or Rituximab and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. In a specific embodiment, compositions of the invention are administered in combination with tositumomab. In a further embodiment, compositions of the invention are administered with tositumomab and CHOP, or tositumomab and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. The anti-CD20 antibodies may optionally be associated with radioisotopes, toxins or cytotoxic prodrugs.

[1003] In another specific embodiment, the compositions of the invention are administered in combination Zevalin™. In a further embodiment, compositions of the invention are administered with Zevalin™ and CHOP, or Zevalin™ and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. Zevalin™ may be associated with one or more radisotopes. Particularly preferred isotopes are 90Y and 111In.

[1004] In an additional embodiment, the Therapeutics of the invention are administered in combination with cytokines. Cytokines that may be administered with the Therapeutics of the invention include, but are not limited to, IL2, IL3, IL4, IL5, IL6, IL7, IL10, IL12, IL13, IL15, anti-CD40, CD40L, IFN-gamma and TNF-alpha. In another embodiment, Therapeutics of the invention may be administered with any interleukin, including, but not limited to, IL-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, and IL-21.

[1005] In one embodiment, the Therapeutics of the invention are administered in combination with members of the TNF family. TNF, TNF-related or TNF-like molecules that may be administered with the Therapeutics of the invention include, but are not limited to, soluble forms of TNF-alpha, lymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta (found in complex heterotrimer LT-alpha2-beta), OPGL, FasL, CD27L, CD30L, CD40L, 4-1BBL, DcR3, OX40L, TNF-gamma (International Publication No. WO 96/14328), AIM-I (International Publication No. WO 97/33899), endokine-alpha (International Publication No. WO 98/07880), OPG, and neutrokine-alpha (International Publication No. WO 98/18921, OX40, and nerve growth factor (NGF), and soluble forms of Fas, CD30, CD27, CD40 and 4-IBB, TR2 (International Publication No. WO 96/34095), DR3 (International Publication No. WO 97/33904), DR4 (International Publication No. WO 98/32856), TR5 (International Publication No. WO 98/30693), TRANK, TR9 (International Publication No. WO 98/56892), TR10 (International Publication No. WO 98/54202), 312C2 (International Publication No. WO 98/06842), and TR12, and soluble forms CD154, CD70, and CD153.

[1006] In an additional embodiment, the Therapeutics of the invention are administered in combination with angiogenic proteins. Angiogenic proteins that may be administered with the Therapeutics of the invention include, but are not limited to, Glioma Derived Growth Factor (GDGF), as disclosed in European Patent Number EP-399816; Platelet Derived Growth Factor-A (PDGF-A), as disclosed in European Patent Number EP-682110; Platelet Derived Growth Factor-B (PDGF-B), as disclosed in European Patent Number EP-282317; Placental Growth Factor (PlGF), as disclosed in International Publication Number WO 92/06194; Placental Growth Factor-2 (PlGF-2), as disclosed in Hauser et al., Growth Factors, 4:259-268 (1993); Vascular Endothelial Growth Factor (VEGF), as disclosed in International Publication Number WO 90/13649; Vascular Endothelial Growth Factor-A (VEGF-A), as disclosed in European Patent Number EP-506477; Vascular Endothelial Growth Factor-2 (VEGF-2), as disclosed in International Publication Number WO 96/39515; Vascular Endothelial Growth Factor B (VEGF-3); Vascular Endothelial Growth Factor B-186 (VEGF-B186), as disclosed in International Publication Number WO 96/26736; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed in International Publication Number WO 98/02543; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed in International Publication Number WO 98/07832; and Vascular Endothelial Growth Factor-E (VEGF-E), as disclosed in German Patent Number DE19639601. The above mentioned references are herein incorporated by reference in their entireties.

[1007] In an additional embodiment, the Therapeutics of the invention are administered in combination with Fibroblast Growth Factors. Fibroblast Growth Factors that may be administered with the Therapeutics of the invention include, but are not limited to, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, and FGF-15.

[1008] In an additional embodiment, the Therapeutics of the invention are administered in combination with hematopoietic growth factors. Hematopoietic growth factors that may be administered with the Therapeutics of the invention include, but are not limited to, granulocyte macrophage colony stimulating factor (GM-CSF) (sargramostim, LEUKINE™, PROKINE™), granulocyte colony stimulating factor (G-CSF) (filgrastim, NEUPOGEN™), macrophage colony stimulating factor (M-CSF, CSF-1) erythropoietin (epoetin alfa, EPOGEN™, PROCRIT™), stem cell factor (SCF, c-kit ligand, steel factor), megakaryocyte colony stimulating factor, PIXY321 (a GMCSF/IL-3 fusion protein), interleukins, especially any one or more of IL-1 through IL-12, interferon-gamma, or thrombopoietin.

[1009] In certain embodiments, Therapeutics of the present invention are administered in combination with adrenergic blockers, such as, for example, acebutolol, atenolol, betaxolol, bisoprolol, carteolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol.

[1010] In another embodiment, the Therapeutics of the invention are administered in combination with an antiarrhythmic drug (e.g., adenosine, amidoarone, bretylium, digitalis, digoxin, digitoxin, diliazem, disopyramide, esmolol, flecainide, lidocaine, mexiletine, moricizine, phenytoin, procainamide, N-acetyl procainamide, propafenone, propranolol, quini dine, sotalol, tocainide, and verapamil).

[1011] In another embodiment, the Therapeutics of the invention are administered in combination with diuretic agents, such as carbonic anhydrase-inhibiting agents (e.g., acetazolamide, dichlorphenamide, and methazolamide), osmotic diuretics (e.g., glycerin, isosorbide, mannitol, and urea), diuretics that inhibit Na+-K+-2Cl− symport (e.g., furosemide, bumetamide, azosemide, piretamide, tripamide, ethacrynic acid, muzolimine, and torsemide), thiazide and thiazide-like diuretics (e.g., bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichormethiazide, chlorthalidone, indapamide, metolazone, and quinethazone), potassium sparing diuretics (e.g., amiloride and triamterene), and mineralcorticoid receptor antagonists (e.g., spironolactone, canrenone, and potassium canrenoate).

[1012] In one embodiment, the Therapeutics of the invention are administered in combination with treatments for endocrine and/or hormone imbalance disorders. Treatments for endocrine and/or hormone imbalance disorders include, but are not limited to, 127I, radioactive isotopes of iodine such as 131I and 123I; recombinant growth hormone, such as HUMATROPE™ (recombinant somatropin); growth hormone analogs such as PROTROPIN™ (somatrem); dopamine agonists such as PARLODEL™ (bromocriptine); somatostatin analogs such as SANDOSTATIN™ (octreotide); gonadotropin preparations such as PREGNYL™, A.P.L. ™ and PROFASI™ (chorionic gonadotropin (CG)), PERGONAL™ (menotropins), and METRODIN™ (urofollitropin (uFSH)); synthetic human gonadotropin releasing hormone preparations such as FACTREL™ and LUTREPULSE™ (gonadorelin hydrochloride); synthetic gonadotropin agonists such as LUPRON™ (leuprolide acetate), SUPPRELIN™ (histrelin acetate), SYNAREL™ (nafarelin acetate), and ZOLADEX™ (goserelin acetate); synthetic preparations of thyrotropin-releasing hormone such as RELEFACT TRH™ and THYPINONE™ (protirelin); recombinant human TSH such as THYROGEN™; synthetic preparations of the sodium salts of the natural isomers of thyroid hormones such as L-T4™, SYNTHROID™ and LEVOTHROID™ (levothyroxine sodium), L-T3™, CYTOMEL™ and TRIOSTAT™ (liothyroine sodium), and THYROLAR™ (liotrix); antithyroid compounds such as 6-n-propylthiouracil (propylthiouracil), 1-methyl-2-mercaptoimidazole and TAPAZOLE™ (methimazole), NEO-MERCAZOLE™ (carbimazole); beta-adrenergic receptor antagonists such as propranolol and esmolol; Ca2+ channel blockers; dexamethasone and iodinated radiological contrast agents such as TELEPAQUE™ (iopanoic acid) and ORAGRAFIN™ (sodium ipodate).

[1013] Additional treatments for endocrine and/or hormone imbalance disorders include, but are not limited to, estrogens or congugated estrogens such as ESTRACE™ (estradiol), ESTINYL™ (ethinyl estradiol), PREMARIN™, ESTRATAB™, ORTHO-EST™, OGEN™ and estropipate (estrone), ESTROVIS™ (quinestrol), ESTRADERM™ (estradiol), DELESTROGEN™ and VALERGEN™ (estradiol valerate), DEPO-ESTRADIOL CYPIONATE™ and ESTROJECT LA™ (estradiol cypionate); antiestrogens such as NOLVADEX™ (tamoxifen), SEROPHENE™ and CLOMID™ (clomiphene); progestins such as DURALUTIN™ (hydroxyprogesterone caproate), MPA™ and DEPO-PROVERA™ (medroxyprogesterone acetate), PROVERAT™ and CYCRIN™ (MPA), MEGACE™ (megestrol acetate), NORLUTIN™ (norethindrone), and NORLUTATE™ and AYGESTIN™ (norethindrone acetate); progesterone implants such as NORPLANT SYSTEM™ (subdermal implants of norgestrel); antiprogestins such as RU 486™ (mifepristone); hormonal contraceptives such as ENOVID™ (norethynodrel plus mestranol), PROGESTASERT™ (intrauterine device that releases progesterone), LOESTRIN™, BREVICON™, MODICON™, GENORA™, NELONA™, NORINYL™, OVACON-35 ™ and OVACON-50™ (ethinyl estradiol/norethindrone), LEVLEN™, NORDETTE™, TR1-LEVLEN™ and TRIPHASIL-21™ (ethinyl estradiol/levonorgestrel) LO/OVRAL™ and OVRAL™ (ethinyl estradiol/norgestrel), DEMULEN™ (ethinyl estradiol/ethynodiol diacetate), NORINYL™, ORTHO-NOVUM™, NORETHIN™, GENORA™, and NELOVA™ (norethindrone/mestranol), DESOGEN™ and ORTHO-CEPT™ (ethinyl estradiol/desogestrel), ORTHO-CYCLEN™ and ORTHO-TRICYCLEN™ (ethinyl estradiol/norgestimate), MICRONOR™ and NOR-QD™ (norethindrone), and OVRETTE™ (norgestrel).

[1014] Additional treatments for endocrine and/or hormone imbalance disorders include, but are not limited to, testosterone esters such as methenolone acetate and testosterone undecanoate; parenteral and oral androgens such as TESTOJECT-50™ (testosterone), TESTEX™ (testosterone propionate), DELATESTRYL™ (testosterone enanthate), DEPO-TESTOSTERONE™ (testosterone cypionate), DANOCRINE™ (danazol), HALOTESTIN™ (fluoxymesterone), ORETON METHYL™, TESTRED™ and VIRILON™ (methyltestosterone), and OXANDRIN™ (oxandrolone); testosterone transdermal systems such as TESTODERM™; androgen receptor antagonist and 5-alpha-reductase inhibitors such as ANDROCUR™ (cyproterone acetate), EULEXIN™ (flutamide), and PROSCAR™ (finasteride); adrenocorticotropic hormone preparations such as CORTROSYN™ (cosyntropin); adrenocortical steroids and their synthetic analogs such as ACLOVATE™ (alclometasone dipropionate), CYCLOCORT™ (amcinonide), BECLOVENT™ and VANCERIL™ (beclomethasone dipropionate), CELESTONE™ (betamethasone), BENISONE™ and UTICORT™ (betamethasone benzoate), DIPROSONE™ (betamethasone dipropionate), CELESTONE PHOSPHATE™ (betamethasone sodium phosphate), CELESTONE SOLUSPAN™ (betamethasone sodium phosphate and acetate), BETA-VAL™ and VALISONE™ (betamethasone valerate), TEMOVATE™ (clobetasol propionate), CLODERM™ (clocortolone pivalate), CORTEF™ and HYDROCORTONE™ (cortisol (hydrocortisone)), HYDROCORTONE ACETATE™ (cortisol (hydrocortisone) acetate), LOCOID™ (cortisol (hydrocortisone) butyrate), HYDROCORTONE PHOSPHATE™ (cortisol (hydrocortisone) sodium phosphate), A-HYDROCORT™ and SOLU CORTEF™ (cortisol (hydrocortisone) sodium succinate), WESTCORT™ (cortisol (hydrocortisone) valerate), CORTISONE ACETATET™ (cortisone acetate), DESOWEN™ and TRIDESILON™ (desonide), TOPICORT™ (desoximetasone), DECADRON™ (dexamethasone), DECADRON LA™ (dexamethasone acetate), DECADRON PHOSPHATE™ and HEXADROL PHOSPHATE™ (dexamethasone sodium phosphate), FLORONE™ and MAXIFLOR™ (diflorasone diacetate), FLORINEF ACETATE™ (fludrocortisone acetate), AEROBID™ and NASALIDE™ (flunisolide), FLUONID™ and SYNALAR™ (fluocinolone acetonide), LIDEX™ (fluocinonide), FLUOR-OP™ and FML™ (fluorometholone), CORDRAN™ (flurandrenolide), HALOG™ (halcinonide), HMS LIZUIFILM™ (medrysone), MEDROL™ (methylprednisolone), DEPO-MEDROL™ and MEDROL ACETATE™ (methylprednisone acetate), A-METHAPRED™ and SOLUMEDROL™ (methylprednisolone sodium succinate), ELOCON™ (mometasone furoate), HALDRONE™ (paramethasone acetate), DELTA-CORTEF™ (prednisolone), ECONOPRED™ (prednisolone acetate), HYDELTRASOL™ (prednisolone sodium phosphate), HYDELTRA-T.B.A™ (prednisolone tebutate), DELTASONE™ (prednisone), ARISTOCORT™ and KENACORT™ (triamcinolone), KENALOG™ (triamcinolone acetonide), ARISTOCORT™ and KENACORT DIACETATE™ (triamcinolone diacetate), and ARISTOSPAN™ (triamcinolone hexacetonide); inhibitors of biosynthesis and action of adrenocortical steroids such as CYTADREN™ (aminoglutethimide), NIZORAL™ (ketoconazole), MODRASTANE™ (trilostane), and METOPIRONE™ (metyrapone); bovine, porcine or human insulin or mixtures thereof; insulin analogs; recombinant human insulin such as HUMULIN™ and NOVOLIN™; oral hypoglycemic agents such as ORAMIDE™ and ORINASE™ (tolbutamide), DIABINESE™ (chlorpropamide), TOLAMIDE™ and TOLINASE™ (tolazamide), DYMELOR™ (acetohexamide), glibenclamide, MICRONASE™, DIBETA™ and GLYNASE™ (glyburide), GLUCOTROL™ (glipizide), and DIAMICRON™ (gliclazide), GLUCOPHAGE™ (metformin), ciglitazone, pioglitazone, and alpha-glucosidase inhibitors; bovine or porcine glucagon; somatostatins such as SANDOSTATIN™ (octreotide); and diazoxides such as PROGLYCEM™ (diazoxide).

[1015] In one embodiment, the Therapeutics of the invention are administered in combination with treatments for uterine motility disorders. Treatments for uterine motility disorders include, but are not limited to, estrogen drugs such as conjugated estrogens (e.g., PREMARIN® and ESTRATAB®), estradiols (e.g., CLIMARA® and ALORA®), estropipate, and chlorotrianisene; progestin drugs (e.g., AMEN® (medroxyprogesterone), MICRONOR® (norethidrone acetate), PROMETRIUM® progesterone, and megestrol acetate); and estrogen/progesterone combination therapies such as, for example, conjugated estrogenslmedroxyprogesterone (e.g., PREMPRO™ and PREMPHASE®) and norethindrone acetate/ethinyl estsradiol (e.g., FEMHRT™).

[1016] In an additional embodiment, the Therapeutics of the invention are administered in combination with drugs effective in treating iron deficiency and hypochromic anemias, including but not limited to, ferrous sulfate (iron sulfate, FEOSOL™), ferrous fumarate (e.g., FEOSTAT™), ferrous gluconate (e.g., FERGON™), polysaccharide-iron complex (e.g., NIFEREX™), iron dextran injection (e.g., INFED™), cupric sulfate, pyroxidine, riboflavin, Vitamin B12, cyancobalamin injection (e.g., REDISOL™, RTUBRAMIN PC™), hydroxocobalamin, folic acid (e.g., FOLVITE™), leucovorin (folinic acid, 5-CHOH4PteGlu, citrovorum factor) or WELLCOVORIN (Calcium salt of leucovorin), transferrin or ferritin.

[1017] In certain embodiments, the Therapeutics of the invention are administered in combination with agents used to treat psychiatric disorders. Psychiatric drugs that may be administered with the Therapeutics of the invention include, but are not limited to, antipsychotic agents (e.g., chlorpromazine, chlorprothixene, clozapine, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, olanzapine, perphenazine, pimozide, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, and triflupromazine), antimanic agents (e.g., carbamazepine, divalproex sodium, lithium carbonate, and lithium citrate), antidepressants (e.g., amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, fluvoxamine, fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine), antianxiety agents (e.g., alprazolam, buspirone, chlordiazepoxide, clorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam), and stimulants (e.g., d-amphetamine, methylphenidate, and pemoline).

[1018] In other embodiments, the Therapeutics of the invention are administered in combination with agents used to treat neurological disorders. Neurological agents that may be administered with the Therapeutics of the invention include, but are not limited to, antiepileptic agents (e.g., carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproic acid, divalproex sodium, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, zonisamide, diazepam, lorazepam, and clonazepam), antiparkinsonian agents (e.g., levodopa/carbidopa, selegiline, amantidine, bromocriptine, pergolide, ropinirole, pramipexole, benztropine; biperiden; ethopropazine; procyclidine; trihexyphenidyl, tolcapone), and ALS therapeutics (e.g. riluzole).

[1019] In another embodiment, Therapeutics of the invention are administered in combination with vasodilating agents and/or calcium channel blocking agents. Vasodilating agents that may be administered with the Therapeutics of the invention include, but are not limited to, Angiotensin Converting Enzyme (ACE) inhibitors (e.g., papaverine, isoxsuprine, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril, and nylidrin), and nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate, and nitroglycerin). Examples of calcium channel blocking agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil.

[1020] In certain embodiments, the Therapeutics of the invention are administered in combination with treatments for gastrointestinal disorders. Treatments for gastrointestinal disorders that may be administered with the Therapeutic of the invention include, but are not limited to, H2 histamine receptor antagonists (e.g., TAGAMET™ (cimetidine), ZANTAC™ (ranitidine), PEPCID™ (famotidine), and AXID™ (nizatidine)); inhibitors of H+, K+ ATPase (e.g., PREVACID™ (lansoprazole) and PRILOSEC™ (omeprazole)); Bismuth compounds (e.g., PEPTO-BISMOL™ (bismuth subsalicylate) and DE-NOL™ (bismuth subeitrate)); various antacids; sucralfate; prostaglandin analogs (e.g. CYTOTEC™ (misoprostol)); muscarinic cholinergic antagonists; laxatives (e.g., surfactant laxatives, stimulant laxatives, saline and osmotic laxatives); antidiarrheal agents (e.g., LOMOTIL™ (diphenoxylate), MOTOFEN™ (diphenoxin), and IMODIUM™ (loperamide hydrochloride)), synthetic analogs of somatostatin such as SANDOSTATIN™ (octreotide), antiemetic agents (e.g., ZOFRAN™ (ondansetron), KYTRIL™ (granisetron hydrochloride), tropisetron, dolasetron, metoclopramide, chlorpromazine, perphenazine, prochlorperazine, promethazine, thiethylperazine, triflupromazine, domperidone, haloperidol, droperidol, trimethobenzamide, dexamethasone, methylprednisolone, dronabinol, and nabilone); D2 antagonists (e.g., metoclopramide, trimethobenzamide and chlorpromazine); bile salts; chenodeoxycholic acid; ursodeoxycholic acid; and pancreatic enzyme preparations such as pancreatin and pancrelipase.

[1021] In additional embodiments, the Therapeutics of the invention are administered in combination with other therapeutic or prophylactic regimens, such as, for example, radiation therapy.

Example 14

Method of Treating Decreased Levels of the Polypeptide

[1022] The present invention relates to a method for treating an individual in need of an increased level of a polypeptide of the invention in the body comprising administering to such an individual a composition comprising a therapeutically effective amount of an agonist of the invention (including polypeptides of the invention). Moreover, it will be appreciated that conditions caused by a decrease in the standard or normal expression level of a polypeptide of the present invention in an individual can be treated by administering the agonist or antagonist of the present invention. Thus, the invention also provides a method of treatment of an individual in need of an increased level of the polypeptide comprising administering to such an individual a Therapeutic comprising an amount of the agonist or antagonist to increase the activity level of the polypeptide in such an individual.

[1023] For example, a patient with decreased levels of a polypeptide receives a daily dose 0.1-100 ug/kg of the agonist or antagonist for six consecutive days. The exact details of the dosing scheme, based on administration and formulation, are provided in Example 13.

Example 15

Method of Treating Increased Levels of the Polypeptide

[1024] The present invention also relates to a method of treating an individual in need of a decreased level of a polypeptide of the invention in the body comprising administering to such an individual a composition comprising a therapeutically effective amount of an antagonist of the invention (including polypeptides and antibodies of the invention).

[1025] In one example, antisense technology is used to inhibit production of a polypeptide of the present invention. This technology is one example of a method of decreasing levels of a polypeptide, due to a variety of etiologies, such as cancer.

[1026] For example, a patient diagnosed with abnormally increased levels of a polypeptide is administered intravenously antisense polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment is repeated after a 7-day rest period if the treatment was well tolerated. The antisense polynucleotides of the present invention can be formulated using techniques and formulations described herein (e.g. see Example 13), or otherwise known in the art.

Example 16

Method of Treatment Using Gene Therapy—Ex Vivo

[1027] One method of gene therapy transplants fibroblasts, which are capable of expressing a polypeptide, onto a patient. Generally, fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in tissue-culture medium and separated into small pieces. Small chunks of the tissue are placed on a wet surface of a tissue culture flask, approximately ten pieces are placed in each flask. The flask is turned upside down, closed tight and left at room temperature over night. After 24 hours at room temperature, the flask is inverted and the chunks of tissue remain fixed to the bottom of the flask and fresh media (e.g., Ham's F12 media, with 10% FBS, penicillin and streptomycin) is added. The flasks are then incubated at 37 degree C. for approximately one week.

[1028] At this time, fresh media is added and subsequently changed every several days. After an additional two weeks in culture, a monolayer of fibroblasts emerge. The monolayer is trypsinized and scaled into larger flasks.

[1029] pMV-7 (Kirschmeier, P. T. et al., DNA, 7:219-25 (1988)), flanked by the long terminal repeats of the Moloney murine sarcoma virus, is digested with EcoRI and HindIII and subsequently treated with calf intestinal phosphatase. The linear vector is fractionated on agarose gel and purified, using glass beads.

[1030] The cDNA encoding a polypeptide of the present invention can be amplified using PCR primers which correspond to the 5′ and 3′ end sequences respectively as set forth in Example 1 using primers and having appropriate restriction sites and initiation/stop codons, if necessary. Preferably, the 5′ primer contains an EcoRI site and the 3′ primer includes a HindIII site. Equal quantities of the Moloney murine sarcoma virus linear backbone and the amplified EcoRI and HindIII fragment are added together, in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The ligation mixture is then used to transform bacteria HB101, which are then plated onto agar containing kanamycin for the purpose of confirming that the vector has the gene of interest properly inserted.

[1031] The amphotropic pA317 or GP+am12 packaging cells are grown in tissue culture to confluent density in Dulbecco's Modified Eagles Medium (DMEM) with 10% calf serum (CS), penicillin and streptomycin. The MSV vector containing the gene is then added to the media and the packaging cells transduced with the vector. The packaging cells now produce infectious viral particles containing the gene (the packaging cells are now referred to as producer cells).

[1032] Fresh media is added to the transduced producer cells, and subsequently, the media is harvested from a 10 cm plate of confluent producer cells. The spent media, containing the infectious viral particles, is filtered through a millipore filter to remove detached producer cells and this media is then used to infect fibroblast cells. Media is removed from a sub-confluent plate of fibroblasts and quickly replaced with the media from the producer cells. This media is removed and replaced with fresh media. If the titer of virus is high, then virtually all fibroblasts will be infected and no selection is required. If the titer is very low, then it is necessary to use a retroviral vector that has a selectable marker, such as neo or his. Once the fibroblasts have been efficiently infected, the fibroblasts are analyzed to determine whether protein is produced.

[1033] The engineered fibroblasts are then transplanted onto the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads.

Example 17

Gene Therapy Using Endogenous Genes Corresponding to Polynucleotides of the Invention

[1034] Another method of gene therapy according to the present invention involves operably associating the endogenous polynucleotide sequence of the invention with a promoter via homologous recombination as described, for example, in U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication NO: WO 96/29411, published Sep. 26, 1996; International Publication NO: WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA, 86:8932-8935 (1989); and Zijlstra et al., Nature, 342:435-438 (1989). This method involves the activation of a gene which is present in the target cells, but which is not expressed in the cells, or is expressed at a lower level than desired.

[1035] Polynucleotide constructs are made which contain a promoter and targeting sequences, which are homologous to the 5′ non-coding sequence of endogenous polynucleotide sequence, flanking the promoter. The targeting sequence will be sufficiently near the 5′ end of the polynucleotide sequence so the promoter will be operably linked to the endogenous sequence upon homologous recombination. The promoter and the targeting sequences can be amplified using PCR. Preferably, the amplified promoter contains distinct restriction enzyme sites on the 5′ and 3′ ends. Preferably, the 3′ end of the first targeting sequence contains the same restriction enzyme site as the 5′ end of the amplified promoter and the 5′ end of the second targeting sequence contains the same restriction site as the 3′ end of the amplified promoter.

[1036] The amplified promoter and the amplified targeting sequences are digested with the appropriate restriction enzymes and subsequently treated with calf intestinal phosphatase. The digested promoter and digested targeting sequences are added together in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The construct is size fractionated on an agarose gel, then purified by phenol extraction and ethanol precipitation.

[1037] In this Example, the polynucleotide constructs are administered as naked polynucleotides via electroporation. However, the polynucleotide constructs may also be administered with transfection-facilitating agents, such as liposomes, viral sequences, viral particles, precipitating agents, etc. Such methods of delivery are known in the art.

[1038] Once the cells are transfected, homologous recombination will take place which results in the promoter being operably linked to the endogenous polynucleotide sequence. This results in the expression of polynucleotide corresponding to the polynucleotide in the cell. Expression may be detected by immunological staining, or any other method known in the art.

[1039] Fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in DMEM+10% fetal calf serum. Exponentially growing or early stationary phase fibroblasts are trypsinized and rinsed from the plastic surface with nutrient medium. An aliquot of the cell suspension is removed for counting, and the remaining cells are subjected to centrifugation. The supernatant is aspirated and the pellet is resuspended in 5 ml of electroporation buffer (20 mM HEPES pH 7.3, 137 mM NaCl, 5 mM KCl, 0.7 mM Na2 HPO4, 6 mM dextrose). The cells are recentrifuged, the supernatant aspirated, and the cells resuspended in electroporation buffer containing 1 mg/ml acetylated bovine serum albumin. The final cell suspension contains approximately 3×106 cells/ml. Electroporation should be performed immediately following resuspension.

[1040] Plasmid DNA is prepared according to standard techniques. For example, to construct a plasmid for targeting to the locus corresponding to the polynucleotide of the invention, plasmid pUC18 (MBI Fermentas, Amherst, N.Y.) is digested with HindIII. The CMV promoter is amplified by PCR with an XbaI site on the 5′ end and a BamHI site on the 3′ end. Two non-coding sequences are amplified via PCR: one non-coding sequence (fragment 1) is amplified with a HindIII site at the 5′ end and an Xba site at the 3′end; the other non-coding sequence (fragment 2) is amplified with a BamHI site at the 5′end and a HindIII site at the 3′end. The CMV promoter and the fragments (1 and 2) are digested with the appropriate enzymes (CMV promoter—XbaI and BamHI; fragment 1—XbaI; fragment 2—BamHI) and ligated together. The resulting ligation product is digested with HindIII, and ligated with the HindIII-digested pUC18 plasmid.

[1041] Plasmid DNA is added to a sterile cuvette with a 0.4 cm electrode gap (Bio-Rad). The final DNA concentration is generally at least 120 μg/ml. 0.5 ml of the cell suspension (containing approximately 1.5.×106 cells) is then added to the cuvette, and the cell suspension and DNA solutions are gently mixed. Electroporation is performed with a Gene-Pulser apparatus (Bio-Rad). Capacitance and voltage are set at 960 μF and 250-300 V, respectively. As voltage increases, cell survival decreases, but the percentage of surviving cells that stably incorporate the introduced DNA into their genome increases dramatically. Given these parameters, a pulse time of approximately 14-20 mSec should be observed.

[1042] Electroporated cells are maintained at room temperature for approximately 5 min, and the contents of the cuvette are then gently removed with a sterile transfer pipette. The cells are added directly to 10 ml of prewarmed nutrient media (DMEM with 15% calf serum) in a 10 cm dish and incubated at 37 degree C. The following day, the media is aspirated and replaced with 10 ml of fresh media and incubated for a further 16-24 hours.

[1043] The engineered fibroblasts are then injected into the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads. The fibroblasts now produce the protein product. The fibroblasts can then be introduced into a patient as described above.

Example 18

Method of Treatment Using Gene Therapy—In Vivo

[1044] Another aspect of the present invention is using in vivo gene therapy methods to treat disorders, diseases and conditions. The gene therapy method relates to the introduction of naked nucleic acid (DNA, RNA, and antisense DNA or RNA) sequences into an animal to increase or decrease the expression of the polypeptide. The polynucleotide of the present invention may be operatively linked to (i.e., associated with) a promoter or any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques and methods are known in the art, see, for example, WO90/11092, WO98/11779; U.S. Pat. No. 5,693,622, 5705151, 5580859; Tabata et al., Cardiovasc. Res. 35(3):470-479 (1997); Chao et al., Pharmacol. Res. 35(6):517-522 (1997); Wolff, Neuromuscul. Disord. 7(5):314-318 (1997); Schwartz et al., Gene Ther. 3(5):405-411 (1996); Tsurumi et al., Circulation 94(12):3281-3290 (1996) (incorporated herein by reference).

[1045] The polynucleotide constructs may be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, intestine and the like). The polynucleotide constructs can be delivered in a pharmaceutically acceptable liquid or aqueous carrier.

[1046] The term “naked” polynucleotide, DNA or RNA, refers to sequences that are free from any delivery vehicle that acts to assist, promote, or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotides of the present invention may also be delivered in liposome formulations (such as those taught in Felgner P. L. et al. (1995) Ann. NY Acad. Sci. 772:126-139 and Abdallah B. et al. (1995) Biol. Cell 85(1):1-7) which can be prepared by methods well known to those skilled in the art.

[1047] The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Any strong promoter known to those skilled in the art can be used for driving the expression of DNA. Unlike other gene therapy techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.

[1048] The polynucleotide construct can be delivered to the interstitial space of tissues within an animal, including muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.

[1049] For the naked polynucleotide injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 g/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration. The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked polynucleotide constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.

[1050] The dose response effects of injected polynucleotide in muscle in vivo is determined as follows. Suitable template DNA for production of mRNA coding for polypeptide of the present invention is prepared in accordance with a standard recombinant DNA methodology. The template DNA, which may be either circular or linear, is either used as naked DNA or complexed with liposomes. The quadriceps muscles of mice are then injected with various amounts of the template DNA.

[1051] Five to six week old female and male Balb/C mice are anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision is made on the anterior thigh, and the quadriceps muscle is directly visualized. The template DNA is injected in 0.1 ml of carrier in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep. A suture is placed over the injection site for future localization, and the skin is closed with stainless steel clips.

[1052] After an appropriate incubation time (e.g., 7 days) muscle extracts are prepared by excising the entire quadriceps. Every fifth 15 um cross-section of the individual quadriceps muscles is histochemically stained for protein expression. A time course for protein expression may be done in a similar fashion except that quadriceps from different mice are harvested at different times. Persistence of DNA in muscle following injection may be determined by Southern blot analysis after preparing total cellular DNA and HIRT supernatants from injected and control mice. The results of the above experimentation in mice can be used to extrapolate proper dosages and other treatment parameters in humans and other animals using naked DNA.

Example 19

Transgenic Animals

[1053] The polypeptides of the invention can also be expressed in transgenic animals. Animals of any species, including, but not limited to, mice, rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep, cows and non-human primates, e.g., baboons, monkeys, and chimpanzees may be used to generate transgenic animals. In a specific embodiment, techniques described herein or otherwise known in the art, are used to express polypeptides of the invention in humans, as part of a gene therapy protocol.

[1054] Any technique known in the art may be used to introduce the transgene (i.e., polynucleotides of the invention) into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection (Paterson et al., Appl. Microbiol. Biotechnol. 40:691-698 (1994); Carver et al., Biotechnology (NY) 11:1263-1270 (1993); Wright et al., Biotechnology (NY) 9:830-834 (1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirus mediated gene transfer into germ lines (Van der Putten et al., Proc. Natl. Acad. Sci., USA 82:6148-6152 (1985)), blastocysts or embryos; gene targeting in embryonic stem cells (Thompson et al., Cell 56:313-321 (1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell. Biol. 3:1803-1814 (1983)); introduction of the polynucleotides of the invention using a gene gun (see, e.g., Ulmer et al., Science 259:1745 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm-mediated gene transfer (Lavitrano et al., Cell 57:717-723 (1989); etc. For a review of such techniques, see Gordon, “Transgenic Animals,” Intl. Rev. Cytol. 115:171-229 (1989), which is incorporated by reference herein in its entirety.

[1055] Any technique known in the art may be used to produce transgenic clones containing polynucleotides of the invention, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (Campell et al., Nature 380:64-66 (1996); Wilmut et al., Nature 385:810-813 (1997)).

[1056] The present invention provides for transgenic animals that carry the transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, i.e., mosaic animals or chimeric. The transgene may be integrated as a single transgene or as multiple copies such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, for example, the teaching of Lasko et al. (Lasko et al., Proc. Natl. Acad. Sci. USA 89:6232-6236 (1992)). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. When it is desired that the polynucleotide transgene be integrated into the chromosomal site of the endogenous gene, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous gene are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type, by following, for example, the teaching of Gu et al. (Gu et al., Science 265:103-106 (1994)). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[1057] Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (rt-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.

[1058] Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.

[1059] Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

Example 20

Knock-Out Animals

[1060] Endogenous gene expression can also be reduced by inactivating or “knocking out” the gene and/or its promoter using targeted homologous recombination. (e.g., see Smithies et al., Nature 317:230-234 (1985); Thomas & Capecchi, Cell 51:503-512 (1987); Thompson et al., Cell 5:313-321 (1989); each of which is incorporated by reference herein in its entirety). For example, a mutant, non-functional polynucleotide of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous polynucleotide sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene (e.g., see Thomas & Capecchi 1987 and Thompson 1989, supra). However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.

[1061] In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e.g., knockouts) are administered to a patient in vivo. Such cells may be obtained from the patient (i.e., animal, including human) or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e.g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc. The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e.g., in the circulation, or intraperitoneally.

[1062] Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. (See, for example, Anderson et al. U.S. Pat. No. 5,399,349; and Mulligan & Wilson, U.S. Pat. No. 5,460,959 each of which is incorporated by reference herein in its entirety).

[1063] When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host immune system.

[1064] Transgenic and “knock-out” animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

Example 21

Assays Detecting Stimulation or Inhibition of B cell Proliferation and Differentiation

[1065] Generation of functional humoral immune responses requires both soluble and cognate signaling between B-lineage cells and their microenvironment. Signals may impart a positive stimulus that allows a B-lineage cell to continue its programmed development, or a negative stimulus that instructs the cell to arrest its current developmental pathway. To date, numerous stimulatory and inhibitory signals have been found to influence B cell responsiveness including IL-2, IL-4, IL-5, IL-6, IL-7, IL10, IL-13, IL-14 and IL-15. Interestingly, these signals are by themselves weak effectors but can, in combination with various co-stimulatory proteins, induce activation, proliferation, differentiation, homing, tolerance and death among B cell populations.

[1066] One of the best studied classes of B-cell co-stimulatory proteins is the TNF-superfamily. Within this family CD40, CD27, and CD30 along with their respective ligands CD154, CD70, and CD153 have been found to regulate a variety of immune responses. Assays which allow for the detection and/or observation of the proliferation and differentiation of these B-cell populations and their precursors are valuable tools in determining the effects various proteins may have on these B-cell populations in terms of proliferation and differentiation. Listed below are two assays designed to allow for the detection of the differentiation, proliferation, or inhibition of B-cell populations and their precursors.

[1067] In Vitro Assay-Agonists or antagonists of the invention can be assessed for its ability to induce activation, proliferation, differentiation or inhibition and/or death in B-cell populations and their precursors. The activity of the agonists or antagonists of the invention on purified human tonsillar B cells, measured qualitatively over the dose range from 0.1 to 10,000 ng/mL, is assessed in a standard B-lymphocyte co-stimulation assay in which purified tonsillar B cells are cultured in the presence of either formalin-fixed Staphylococcus aureus Cowan I (SAC) or immobilized anti-human IgM antibody as the priming agent. Second signals such as IL-2 and IL-15 synergize with SAC and IgM crosslinking to elicit B cell proliferation as measured by tritiated-thymidine incorporation. Novel synergizing agents can be readily identified using this assay. The assay involves isolating human tonsillar B cells by magnetic bead (MACS) depletion of CD3-positive cells. The resulting cell population is greater than 95% B cells as assessed by expression of CD45R(B220).

[1068] Various dilutions of each sample are placed into individual wells of a 96-well plate to which are added 105 B-cells suspended in culture medium (RPMI 1640 containing 10% FBS, 5×10−5M 2ME, 100U/ml penicillin, 10 ug/ml streptomycin, and 10−5 dilution of SAC) in a total volume of 150 ul. Proliferation or inhibition is quantitated by a 20 h pulse (1 uCi/well) with 3H-thymidine (6.7 Ci/mM) beginning 72 h post factor addition. The positive and negative controls are IL2 and medium respectively.

[1069] In vivo Assay—BALB/c mice are injected (i.p.) twice per day with buffer only, or 2 mg/Kg of agonists or antagonists of the invention, or truncated forms thereof. Mice receive this treatment for 4 consecutive days, at which time they are sacrificed and various tissues and serum collected for analyses. Comparison of H&E sections from normal spleens and spleens treated with agonists or antagonists of the invention identify the results of the activity of the agonists or antagonists on spleen cells, such as the diffusion of peri-arterial lymphatic sheaths, and/or significant increases in the nucleated cellularity of the red pulp regions, which may indicate the activation of the differentiation and proliferation of B-cell populations. Immunohistochemical studies using a B cell marker, anti-CD45R(B220), are used to determine whether any physiological changes to splenic cells, such as splenic disorganization, are due to increased B-cell representation within loosely defined B-cell zones that infiltrate established T-cell regions.

[1070] Flow cytometric analyses of the spleens from mice treated with agonist or antagonist is used to indicate whether the agonists or antagonists specifically increases the proportion of ThB+, CD45R(B220)dull B cells over that which is observed in control mice.

[1071] Likewise, a predicted consequence of increased mature B-cell representation in vivo is a relative increase in serum Ig titers. Accordingly, serum IgM and IgA levels are compared between buffer and agonists or antagonists-treated mice.

[1072] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 22

T Cell Proliferation Assay

[1073] A CD3-induced proliferation assay is performed on PBMCs and is measured by the uptake of 3H-thymidine. The assay is performed as follows. Ninety-six well plates are coated with 100 μl/well of mAb to CD3 (HIT3a, Pharningen) or isotype-matched control mAb (B33.1) overnight at 4 degrees C. (1 μg/ml in 0.05M bicarbonate buffer, pH 9.5), then washed three times with PBS. PBMC are isolated by F/H gradient centrifugation from human peripheral blood and added to quadruplicate wells (5×104/well) of mAb coated plates in RPMI containing 10% FCS and P/S in the presence of varying concentrations of agonists or antagonists of the invention (total volume 200 ul). Relevant protein buffer and medium alone are controls. After 48 hr. culture at 37 degrees C., plates are spun for 2 min. at 1000 rpm and 100 μl of supernatant is removed and stored −20 degrees C. for measurement of IL-2 (or other cytokines) if effect on proliferation is observed. Wells are supplemented with 100 ul of medium containing 0.5 uCi of 3H-thymidine and cultured at 37 degrees C. for 18-24 hr. Wells are harvested and incorporation of 3H-thymidine used as a measure of proliferation. Anti-CD3 alone is the positive control for proliferation. IL-2 (100 U/ml) is also used as a control which enhances proliferation. Control antibody which does not induce proliferation of T cells is used as the negative control for the effects of agonists or antagonists of the invention.

[1074] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 23

Effect of Agonists or Antagonists of the Invention on the Expression of MHC Class II, Costimulatory and Adhesion Molecules and Cell Differentiation of Monocytes and Monocyte-Derived Human Dendritic Cells

[1075] Dendritic cells are generated by the expansion of proliferating precursors found in the peripheral blood; adherent PBMC or elutriated monocytic fractions are cultured for 7-10 days with GM-CSF (50 ng/ml) and IL-4 (20 ng/ml). These dendritic cells have the characteristic phenotype of immature cells (expression of CD1, CD80, CD86, CD40 and MHC class II antigens). Treatment with activating factors, such as TNF-α, causes a rapid change in surface phenotype (increased expression of MHC class I and II, costimulatory and adhesion molecules, downregulation of FCγ RII, upregulation of CD83). These changes correlate with increased antigen-presenting capacity and with functional maturation of the dendritic cells.

[1076] FACS analysis of surface antigens is performed as follows. Cells are treated 1-3 days with increasing concentrations of agonist or antagonist of the invention or LPS (positive control), washed with PBS containing 1% BSA and 0.02 mM sodium azide, and then incubated with 1:20 dilution of appropriate FITC- or PE-labeled monoclonal antibodies for 30 minutes at 4 degrees C. After an additional wash, the labeled cells are analyzed by flow cytometry on a FACScan (Becton Dickinson).

[1077] Effect on the production of cytokines. Cytokines generated by dendritic cells, in particular IL-12, are important in the initiation of T-cell dependent immune responses. IL-12 strongly influences the development of Th1 helper T-cell immune response, and induces cytotoxic T and NK cell function. An ELISA is used to measure the IL-12 release as follows. Dendritic cells (106/ml) are treated with increasing concentrations of agonists or antagonists of the invention for 24 hours. LPS (100 ng/ml) is added to the cell culture as positive control. Supernatants from the cell cultures are then collected and analyzed for IL-12 content using commercial ELISA kit (e.g., R & D Systems (Minneapolis, Minn.)). The standard protocols provided with the kits are used.

[1078] Effect on the expression of MHC Class II, costimulatory and adhesion molecules. Three major families of cell surface antigens can be identified on monocytes: adhesion molecules, molecules involved in antigen presentation, and Fc receptor. Modulation of the expression of MHC class II antigens and other costimulatory molecules, such as B7 and ICAM-1, may result in changes in the antigen presenting capacity of monocytes and ability to induce T cell activation. Increased expression of Fc receptors may correlate with improved monocyte cytotoxic activity, cytokine release and phagocytosis.

[1079] FACS analysis is used to examine the surface antigens as follows. Monocytes are treated 1-5 days with increasing concentrations of agonists or antagonists of the invention or LPS (positive control), washed with PBS containing 1% BSA and 0.02 mM sodium azide, and then incubated with 1:20 dilution of appropriate FITC— or PE-labeled monoclonal antibodies for 30 minutes at 4 degrees C. After an additional wash, the labeled cells are analyzed by flow cytometry on a FACScan (Becton Dickinson).

[1080] Monocyte activation and/or increased survival. Assays for molecules that activate (or alternatively, inactivate) monocytes and/or increase monocyte survival (or alternatively, decrease monocyte survival) are known in the art and may routinely be applied to determine whether a molecule of the invention functions as an inhibitor or activator of monocytes. Agonists or antagonists of the invention can be screened using the three assays described below. For each of these assays, Peripheral blood mononuclear cells (PBMC) are purified from single donor leukopacks (American Red Cross, Baltimore, Md.) by centrifugation through a Histopaque gradient (Sigma). Monocytes are isolated from PBMC by counterflow centrifugal elutriation.

[1081] Monocyte Survival Assay. Human peripheral blood monocytes progressively lose viability when cultured in absence of serum or other stimuli. Their death results from internally regulated processes (apoptosis). Addition to the culture of activating factors, such as TNF-alpha dramatically improves cell survival and prevents DNA fragmentation. Propidium iodide (PI) staining is used to measure apoptosis as follows. Monocytes are cultured for 48 hours in polypropylene tubes in serum-free medium (positive control), in the presence of 100 ng/ml TNF-alpha (negative control), and in the presence of varying concentrations of the compound to be tested. Cells are suspended at a concentration of 2×106/ml in PBS containing PI at a final concentration of 5 μg/ml, and then incubated at room temperature for 5 minutes before FACScan analysis. PI uptake has been demonstrated to correlate with DNA fragmentation in this experimental paradigm.

[1082] Effect on cytokine release. An important function of monocytes/macrophages is their regulatory activity on other cellular populations of the immune system through the release of cytokines after stimulation. An ELISA to measure cytokine release is performed as follows. Human monocytes are incubated at a density of 5×105 cells/ml with increasing concentrations of agonists or antagonists of the invention and under the same conditions, but in the absence of agonists or antagonists. For IL-12 production, the cells are primed overnight with IFN (100 U/ml) in the presence of agonist or antagonist of the invention. LPS (10 ng/ml) is then added. Conditioned media are collected after 24 h and kept frozen until use. Measurement of TNF-alpha, IL-10, MCP-1 and IL-8 is then performed using a commercially available ELISA kit (e.g., R & D Systems (Minneapolis, Minn.)) and applying the standard protocols provided with the kit.

[1083] Oxidative burst. Purified monocytes are plated in 96-w plate at 2-1×105 cell/well. Increasing concentrations of agonists or antagonists of the invention are added to the wells in a total volume of 0.2 ml culture medium (RPMI 1640+10% FCS, glutamine and antibiotics). After 3 days incubation, the plates are centrifuged and the medium is removed from the wells. To the macrophage monolayers, 0.2 ml per well of phenol red solution (140 mM NaCl, 10 mM potassium phosphate buffer pH 7.0, 5.5 mM dextrose, 0.56 mM phenol red and 19 U/ml of HRPO) is added, together with the stimulant (200 nM PMA). The plates are incubated at 37° C. for 2 hours and the reaction is stopped by adding 20 μl 1N NaOH per well. The absorbance is read at 610 nm. To calculate the amount of H2O2 produced by the macrophages, a standard curve of a H2O2 solution of known molarity is performed for each experiment.

[1084] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 24

Biological Effects of Agonists or Antagonists of the Invention

[1085] Astrocyte and Neuronal Assays

[1086] Agonists or antagonists of the invention, expressed in Escherichia coli and purified as described above, can be tested for activity in promoting the survival, neurite outgrowth, or phenotypic differentiation of cortical neuronal cells and for inducing the proliferation of glial fibrillary acidic protein immunopositive cells, astrocytes. The selection of cortical cells for the bioassay is based on the prevalent expression of FGF-1 and FGF-2 in cortical structures and on the previously reported enhancement of cortical neuronal survival resulting from FGF-2 treatment. A thymidine incorporation assay, for example, can be used to elucidate an agonist or antagonist of the invention's activity on these cells.

[1087] Moreover, previous reports describing the biological effects of FGF-2 (basic FGF) on cortical or hippocampal neurons in vitro have demonstrated increases in both neuron survival and neurite outgrowth (Walicke et al., “Fibroblast growth factor promotes survival of dissociated hippocampal neurons and enhances neurite extension.” Proc. Natl. Acad. Sci. USA 83:3012-3016. (1986), assay herein incorporated by reference in its entirety). However, reports from experiments done on PC-12 cells suggest that these two responses are not necessarily synonymous and may depend on not only which FGF is being tested but also on which receptor(s) are expressed on the target cells. Using the primary cortical neuronal culture paradigm, the ability of an agonist or antagonist of the invention to induce neurite outgrowth can be compared to the response achieved with FGF-2 using, for example, a thymidine incorporation assay.

[1088] Fibroblast and Endothelial Cell Assays

[1089] Human lung fibroblasts are obtained from Clonetics (San Diego, Calif.) and maintained in growth media from Clonetics. Dermal microvascular endothelial cells are obtained from Cell Applications (San Diego, Calif.). For proliferation assays, the human lung fibroblasts and dermal microvascular endothelial cells can be cultured at 5,000 cells/well in a 96-well plate for one day in growth medium. The cells are then incubated for one day in 0.1% BSA basal medium. After replacing the medium with fresh 0.1% BSA medium, the cells are incubated with the test proteins for 3 days. Alamar Blue (Alamar Biosciences, Sacramento, Calif.) is added to each well to a final concentration of 10%. The cells are incubated for 4 hr. Cell viability is measured by reading in a CytoFluor fluorescence reader. For the PGE2 assays, the human lung fibroblasts are cultured at 5,000 cells/well in a 96-well plate for one day. After a medium change to 0.1% BSA basal medium, the cells are incubated with FGF-2 or agonists or antagonists of the invention with or without IL-1α for 24 hours. The supernatants are collected and assayed for PGE2 by EIA kit (Cayman, Ann Arbor, Mich.). For the IL-6 assays, the human lung fibroblasts are cultured at 5,000 cells/well in a 96-well plate for one day. After a medium change to 0.1% BSA basal medium, the cells are incubated with FGF-2 or with or without agonists or antagonists of the invention IL-1α for 24 hours. The supernatants are collected and assayed for IL-6 by ELISA kit (Endogen, Cambridge, Mass.).

[1090] Human lung fibroblasts are cultured with FGF-2 or agonists or antagonists of the invention for 3 days in basal medium before the addition of Alamar Blue to assess effects on growth of the fibroblasts. FGF-2 should show a stimulation at 10-2500 ng/ml which can be used to compare stimulation with agonists or antagonists of the invention.

[1091] Parkinson Models.

[1092] The loss of motor function in Parkinson's disease is attributed to a deficiency of striatal dopamine resulting from the degeneration of the nigrostriatal dopaminergic projection neurons. An animal model for Parkinson's that has been extensively characterized involves the systemic administration of 1-methyl-4 phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the CNS, MPTP is taken-up by astrocytes and catabolized by monoamine oxidase B to 1-methyl-4-phenyl pyridine (MPP+) and released. Subsequently, MPP+ is actively accumulated in dopaminergic neurons by the high-affinity reuptake transporter for dopamine. MPP+ is then concentrated in mitochondria by the electrochemical gradient and selectively inhibits nicotidamide adenine disphosphate: ubiquinone oxidoreductionase (complex I), thereby interfering with electron transport and eventually generating oxygen radicals.

[1093] It has been demonstrated in tissue culture paradigms that FGF-2 (basic FGF) has trophic activity towards nigral dopaminergic neurons (Ferrari et al., Dev. Biol. 1989). Recently, Dr. Unsicker's group has demonstrated that administering FGF-2 in gel foam implants in the striatum results in the near complete protection of nigral dopaminergic neurons from the toxicity associated with MPTP exposure (Otto and Unsicker, J. Neuroscience, 1990).

[1094] Based on the data with FGF-2, agonists or antagonists of the invention call be evaluated to determine whether it has an action similar to that of FGF-2 in enhancing dopaminergic neuronal survival in vitro and it can also be tested in vivo for protection of dopaminergic neurons in the striatum from the damage associated with MPTP treatment. The potential effect of an agonist or antagonist of the invention is first examined in vitro in a dopaminergic neuronal cell culture paradigm. The cultures are prepared by dissecting the midbrain floor plate from gestation day 14 Wistar rat embryos. The tissue is dissociated with trypsin and seeded at a density of 200,000 cells/cm2 on polyorthinine-laminin coated glass coverslips. The cells are maintained in Dulbecco's Modified Eagle's medium and F12 medium containing hormonal supplements (N1). The cultures are fixed with paraformaldehyde after 8 days in vitro and are processed for tyrosine hydroxylase, a specific marker for dopaminergic neurons, immunohistochemical staining. Dissociated cell cultures are prepared from embryonic rats. The culture medium is changed every third day and the factors are also added at that time.

[1095] Since the dopaminergic neurons are isolated from animals at gestation day 14, a developmental time which is past the stage when the dopaminergic precursor cells are proliferating, an increase in the number of tyrosine hydroxylase immunopositive neurons would represent an increase in the number of dopaminergic neurons surviving in vitro. Therefore, if an agonist or antagonist of the invention acts to prolong the survival of dopaminergic neurons, it would suggest that the agonist or antagonist may be involved in Parkinson's Disease.

[1096] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 25

The Effect of Agonists or Antagonists of the Invention on the Growth of Vascular Endothelial Cells

[1097] On day 1, human umbilical vein endothelial cells (HUVEC) are seeded at 2-5×104 cells/35 mm dish density in M199 medium containing 4% fetal bovine serum (FBS), 16 units/ml heparin, and 50 units/ml endothelial cell growth supplements (ECGS, Biotechnique, Inc.). On day 2, the medium is replaced with Ml 99 containing 10% FBS, 8 units/ml heparin. An agonist or antagonist of the invention, and positive controls, such as VEGF and basic FGF (bFGF) are added, at varying concentrations. On days 4 and 6, the medium is replaced. On day 8, cell number is determined with a Coulter Counter.

[1098] An increase in the number of HUVEC cells indicates that the compound of the invention may proliferate vascular endothelial cells, while a decrease in the number of HUVEC cells indicates that the compound of the invention inhibits vascular endothelial cells.

[1099] The studies described in this example tested activity of a polypeptide of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), agonists, and/or antagonists of the invention.

Example 26

Rat Corneal Wound Healing Model

[1100] This animal model shows the effect of an agonist or antagonist of the invention on neovascularization. The experimental protocol includes:

[1101] a) Making a 1-1.5 mm long incision from the center of cornea into the stromal layer.

[1102] b) Inserting a spatula below the lip of the incision facing the outer corner of the eye.

[1103] c) Making a pocket (its base is 1-1.5 mm form the edge of the eye).

[1104] d) Positioning a pellet, containing 50 ng-5 ug of an agonist or antagonist of the invention, within the pocket.

[1105] e) Treatment with an agonist or antagonist of the invention can also be applied topically to the corneal wounds in a dosage range of 20 mg-500 mg (daily treatment for five days).

[1106] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 27

Diabetic Mouse and Glucocorticoid-Impaired Wound Healing Models

[1107] Diabetic db+/db+ Mouse Model.

[1108] To demonstrate that an agonist or antagonist of the invention accelerates the healing process, the genetically diabetic mouse model of wound healing is used. The full thickness wound healing model in the db+/db+ mouse is a well characterized, clinically relevant and reproducible model of impaired wound healing. Healing of the diabetic wound is dependent on formation of granulation tissue and re-epithelialization rather than contraction (Gartner, M. H. et al., J. Surg. Res. 52:389 (1992); Greenhalgh, D. G. et al., Am. J. Pathol. 136:1235 (1990)).

[1109] The diabetic animals have many of the characteristic features observed in Type II diabetes mellitus. Homozygous (db+/db+) mice are obese in comparison to their normal heterozygous (db+/+m) littermates. Mutant diabetic (db+/db+) mice have a single autosomal recessive mutation on chromosome 4 (db+) (Coleman et al. Proc. Nat?. Acad. Sci. USA 77:283-293 (1982)). Animals show polyphagia, polydipsia and polyuria. Mutant diabetic mice (db+/db+) have elevated blood glucose, increased or normal insulin levels, and suppressed cell-mediated immunity (Mandel et al., J. Immunol. 120:1375 (1978); Debray-Sachs, M. et al., Clin. Exp. Immunol. 51(1):1-7 (1983); Leiter et al., Am. J. of Pathol. 114:46-55 (1985)). Peripheral neuropathy, myocardial complications, and microvascular lesions, basement membrane thickening and glomerular filtration abnormalities have been described in these animals (Norido, F. et al., Exp. Neurol. 83(2):221-232 (1984); Robertson et al., Diabetes 29(1):60-67 (1980); Giacomelli et al., Lab Invest. 40(4):460-473 (1979); Coleman, D. L., Diabetes 31 (Suppl):1-6 (1982)). These homozygous diabetic mice develop hyperglycemia that is resistant to insulin analogous to human type II diabetes (Mandel et al., J. Immunol. 120:1375-1377 (1978)).

[1110] The characteristics observed in these animals suggests that healing in this model may be similar to the healing observed in human diabetes (Greenhalgh, et al., Am. J. of Pathol. 136:1235-1246 (1990)).

[1111] Genetically diabetic female C57BL/KsJ (db+/db+) mice and their non-diabetic (db+/+m) heterozygous littermates are used in this study (Jackson Laboratories). The animals are purchased at 6 weeks of age and are 8 weeks old at the beginning of the study. Animals are individually housed and received food and water ad libitum. All manipulations are performed using aseptic techniques. The experiments are conducted according to the rules and guidelines of Human Genome Sciences, Inc. Institutional Animal Care and Use Committee and the Guidelines for the Care and Use of Laboratory Animals.

[1112] Wounding protocol is performed according to previously reported methods (Tsuboi, R. and Rifkin, D. B., J. Exp. Med. 172:245-251 (1990)). Briefly, on the day of wounding, animals are anesthetized with an intraperitoneal injection of Avertin (0.01 mg/mL), 2,2,2-tribromoethanol and 2-methyl-2-butanol dissolved in deionized water. The dorsal region of the animal is shaved and the skin washed with 70% ethanol solution and iodine. The surgical area is dried with sterile gauze prior to wounding. An 8 mm full-thickness wound is then created using a Keyes tissue punch. Immediately following wounding, the surrounding skin is gently stretched to eliminate wound expansion. The wounds are left open for the duration of the experiment. Application of the treatment is given topically for 5 consecutive days commencing on the day of wounding. Prior to treatment, wounds are gently cleansed with sterile saline and gauze sponges.

[1113] Wounds are visually examined and photographed at a fixed distance at the day of surgery and at two day intervals thereafter. Wound closure is determined by daily measurement on days 1-5 and on day 8. Wounds are measured horizontally and vertically using a calibrated Jameson caliper. Wounds are considered healed if granulation tissue is no longer visible and the wound is covered by a continuous epithelium.

[1114] An agonist or antagonist of the invention is administered using at a range different doses, from 4 mg to 500 mg per wound per day for 8 days in vehicle. Vehicle control groups received 50 mL of vehicle solution.

[1115] Animals are euthanized on day 8 with an intraperitoneal injection of sodium pentobarbital (300 mg/kg). The wounds and surrounding skin are then harvested for histology and immunohistochemistry. Tissue specimens are placed in 10% neutral buffered formalin in tissue cassettes between biopsy sponges for further processing.

[1116] Three groups of 10 animals each (5 diabetic and 5 non-diabetic controls) are evaluated: 1) Vehicle placebo control, 2) untreated group, and 3) treated group.

[1117] Wound closure is analyzed by measuring the area in the vertical and horizontal axis and obtaining the total square area of the wound. Contraction is then estimated by establishing the differences between the initial wound area (day 0) and that of post treatment (day 8). The wound area on day 1 is 64 mm2, the corresponding size of the dermal punch. Calculations are made using the following formula:

[Open area on day 8]−[Open area on day 1]/[Open area on day 1]

[1118] Specimens are fixed in 10% buffered formalin and paraffin embedded blocks are sectioned perpendicular to the wound surface (5 mm) and cut using a Reichert-Jung microtome. Routine hematoxylin-eosin (H&E) staining is performed on cross-sections of bisected wounds. Histologic examination of the wounds are used to assess whether the healing process and the morphologic appearance of the repaired skin is altered by treatment with an agonist or antagonist of the invention. This assessment included verification of the presence of cell accumulation, inflammatory cells, capillaries, fibroblasts, re-epithelialization and epidermal maturity (Greenhalgh, D. G. et al., Am. J. Pathol. 136:1235 (1990)). A calibrated lens micrometer is used by a blinded observer.

[1119] Tissue sections are also stained immunohistochemically with a polyclonal rabbit anti-human keratin antibody using ABC Elite detection system. Human skin is used as a positive tissue control while non-immune IgG is used as a negative control. Keratinocyte growth is determined by evaluating the extent of reepithelialization of the wound using a calibrated lens micrometer.

[1120] Proliferating cell nuclear antigen/cyclin (PCNA) in skin specimens is demonstrated by using anti-PCNA antibody (1:50) with an ABC Elite detection system. Human colon cancer served as a positive tissue control and human brain tissue is used as a negative tissue control. Each specimen included a section with omission of the primary antibody and substitution with non-immune mouse IgG. Ranking of these sections is based on the extent of proliferation on a scale of 0-8, the lower side of the scale reflecting slight proliferation to the higher side reflecting intense proliferation.

[1121] Experimental data are analyzed using an unpaired t test. A p value of <0.05 is considered significant.

[1122] Steroid Impaired Rat Model

[1123] The inhibition of wound healing by steroids has been well documented in various in vitro and in vivo systems (Wahl, Glucocorticoids and Wound healing. In: Anti-Inflammatory Steroid Action: Basic and Clinical Aspects. 280-302 (1989); Wahlet al., J. Immunol. 115: 476-481 (1975); Werb et al., J. Exp. Med. 147:1684-1694 (1978)). Glucocorticoids retard wound healing by inhibiting angiogenesis, decreasing vascular permeability (Ebert et al., An. Intern. Med. 37:701-705 (1952)), fibroblast proliferation, and collagen synthesis (Beck et al., Growth Factors. 5: 295-304 (1991); Haynes et al., J. Clin. Invest. 61: 703-797 (1978)) and producing a transient reduction of circulating monocytes (Haynes et al., J. Clin. Invest. 61: 703-797 (1978); Wahl, “Glucocorticoids and wound healing”, In: Antiinflammatory Steroid Action: Basic and Clinical Aspects, Academic Press, New York, pp. 280-302 (1989)). The systemic administration of steroids to impaired wound healing is a well establish phenomenon in rats (Beck et al., Growth Factors. 5: 295-304 (1991); Haynes et al., J. Clin. Invest. 61: 703-797 (1978); Wahl, “Glucocorticoids and wound healing”, In: Antiinflammatory Steroid Action: Basic and Clinical Aspects, Academic Press, New York, pp. 280-302 (1989); Pierce et al., Proc. Natl. Acad. Sci. USA 86: 2229-2233 (1989)).

[1124] To demonstrate that an agonist or antagonist of the invention can accelerate the healing process, the effects of multiple topical applications of the agonist or antagonist on full thickness excisional skin wounds in rats in which healing has been impaired by the systemic administration of methylprednisolone is assessed.

[1125] Young adult male Sprague Dawley rats weighing 250-300 g (Charles River Laboratories) are used in this example. The animals are purchased at 8 weeks of age and are 9 weeks old at the beginning of the study. The healing response of rats is impaired by the systemic administration of methylprednisolone (17 mg/kg/rat intramuscularly) at the time of wounding. Animals are individually housed and received food and water ad libitum. All manipulations are performed using aseptic techniques. This study is conducted according to the rules and guidelines of Human Genome Sciences, Inc. Institutional Animal Care and Use Committee and the Guidelines for the Care and Use of Laboratory Animals.

[1126] The wounding protocol is followed according to section A, above. On the day of wounding, animals are anesthetized with an intramuscular injection of ketamine (50 mg/kg) and xylazine (5 mg/kg). The dorsal region of the animal is shaved and the skin washed with 70% ethanol and iodine solutions. The surgical area is dried with sterile gauze prior to wounding. An 8 mm full-thickness wound is created using a Keyes tissue punch. The wounds are left open for the duration of the experiment. Applications of the testing materials are given topically once a day for 7 consecutive days commencing on the day of wounding and subsequent to methylprednisolone administration. Prior to treatment, wounds are gently cleansed with sterile saline and gauze sponges.

[1127] Wounds are visually examined and photographed at a fixed distance at the day of wounding and at the end of treatment. Wound closure is determined by daily measurement on days 1-5 and on day 8. Wounds are measured horizontally and vertically using a calibrated Jameson caliper. Wounds are considered healed if granulation tissue is no longer visible and the wound is covered by a continuous epithelium.

[1128] The agonist or antagonist of the invention is administered using at a range different doses, from 4 mg to 500 mg per wound per day for 8 days in vehicle. Vehicle control groups received 50 mL of vehicle solution.

[1129] Animals are euthanized on day 8 with an intraperitoneal injection of sodium pentobarbital (300 mg/kg). The wounds and surrounding skin are then harvested for histology. Tissue specimens are placed in 10% neutral buffered formalin in tissue cassettes between biopsy sponges for further processing.

[1130] Three groups of 10 animals each (5 with methylprednisolone and 5 without glucocorticoid) are evaluated: 1) Untreated group 2) Vehicle placebo control 3) treated groups.

[1131] Wound closure is analyzed by measuring the area in the vertical and horizontal axis and obtaining the total area of the wound. Closure is then estimated by establishing the differences between the initial wound area (day 0) and that of post treatment (day 8). The wound area on day 1 is 64 mm2, the corresponding size of the dermal punch. Calculations are made using the following formula:

[Open area on day 8]−[Open area on day 1]/[Open area on day 1]

[1132] Specimens are fixed in 10% buffered formalin and paraffin embedded blocks are sectioned perpendicular to the wound surface (5 mm) and cut using an Olympus microtome. Routine hematoxylin-eosin (H&E) staining is performed on cross-sections of bisected wounds. Histologic examination of the wounds allows assessment of whether the healing process and the morphologic appearance of the repaired skin is improved by treatment with an agonist or antagonist of the invention. A calibrated lens micrometer is used by a blinded observer to determine the distance of the wound gap.

[1133] Experimental data are analyzed using an unpaired t test. A p value of <0.05 is considered significant.

[1134] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 28

Lymphadema Animal Model

[1135] The purpose of this experimental approach is to create an appropriate and consistent lymphedema model for testing the therapeutic effects of an agonist or antagonist of the invention in lymphangiogenesis and re-establishment of the lymphatic circulatory system in the rat hind limb. Effectiveness is measured by swelling volume of the affected limb, quantification of the amount of lymphatic vasculature, total blood plasma protein, and histopathology. Acute lymphedema is observed for 7-10 days. Perhaps more importantly, the chronic progress of the edema is followed for up to 3-4 weeks.

[1136] Prior to beginning surgery, blood sample is drawn for protein concentration analysis. Male rats weighing approximately ˜350 g are dosed with Pentobarbital. Subsequently, the right legs are shaved from knee to hip. The shaved area is swabbed with gauze soaked in 70% EtOH. Blood is drawn for serum total protein testing. Circumference and volumetric measurements are made prior to injecting dye into paws after marking 2 measurement levels (0.5 cm above heel, at mid-pt of dorsal paw). The intradermal dorsum of both right and left paws are injected with 0.05 ml of 1% Evan's Blue. Circumference and volumetric measurements are then made following injection of dye into paws.

[1137] Using the knee joint as a landmark, a mid-leg inguinal incision is made circumferentially allowing the femoral vessels to be located. Forceps and hemostats are used to dissect and separate the skin flaps. After locating the femoral vessels, the lymphatic vessel that runs along side and underneath the vessel(s) is located. The main lymphatic vessels in this area are then electrically coagulated or suture ligated.

[1138] Using a microscope, muscles in back of the leg (near the semitendinosis and adductors) are bluntly dissected. The popliteal lymph node is then located. The 2 proximal and 2 distal lymphatic vessels and distal blood supply of the popliteal node are then ligated by suturing. The popliteal lymph node, and any accompanying adipose tissue, is then removed by cutting connective tissues.

[1139] Care is taken to control any mild bleeding resulting from this procedure. After lymphatics are occluded, the skin flaps are sealed by using liquid skin (Vetbond) (AJ Buck). The separated skin edges are sealed to the underlying muscle tissue while leaving a gap of ˜0.5 cm around the leg. Skin also may be anchored by suturing to underlying muscle when necessary.

[1140] To avoid infection, animals are housed individually with mesh (no bedding). Recovering animals are checked daily through the optimal edematous peak, which typically occurred by day 5-7. The plateau edematous peak are then observed. To evaluate the intensity of the lymphedema, the circumference and volumes of 2 designated places on each paw before operation and daily for 7 days are measured. The effect of plasma proteins on lymphedema is determined and whether protein analysis is a useful testing perimeter is also investigated. The weights of both control and edematous limbs are evaluated at 2 places. Analysis is performed in a blind manner.

[1141] Circumference Measurements: Under brief gas anesthetic to prevent limb movement, a cloth tape is used to measure limb circumference. Measurements are done at the ankle bone and dorsal paw by 2 different people and those 2 readings are averaged. Readings are taken from both control and edematous limbs.

[1142] Volumetric Measurements: On the day of surgery, animals are anesthetized with Pentobarbital and are tested prior to surgery. For daily volumetrics animals are under brief halothane anesthetic (rapid immobilization and quick recovery), and both legs are shaved and equally marked using waterproof marker on legs. Legs are first dipped in water, then dipped into instrument to each marked level then measured by Buxco edema software(Chen/Victor). Data is recorded by one person, while the other is dipping the limb to marked area.

[1143] Blood-plasma protein measurements: Blood is drawn, spun, and serum separated prior to surgery and then at conclusion for total protein and Ca2+ comparison.

[1144] Limb Weight Comparison: After drawing blood, the animal is prepared for tissue collection. The limbs are amputated using a quillitine, then both experimental and control legs are cut at the ligature and weighed. A second weighing is done as the tibio-cacaneal joint is disarticulated and the foot is weighed.

[1145] Histological Preparations: The transverse muscle located behind the knee (popliteal) area is dissected and arranged in a metal mold, filled with freezeGel, dipped into cold methylbutane, placed into labeled sample bags at −80EC until sectioning. Upon sectioning, the muscle is observed under fluorescent microscopy for lymphatics.

[1146] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 29

Suppression of TNF Alpha-Induced Adhesion Molecule Expression by an Agonist or Antagonist of the Invention

[1147] The recruitment of lymphocytes to areas of inflammation and angiogenesis involves specific receptor-ligand interactions between cell surface adhesion molecules (CAMs) on lymphocytes and the vascular endothelium. The adhesion process, in both normal and pathological settings, follows a multi-step cascade that involves intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) expression on endothelial cells (EC). The expression of these molecules and others on the vascular endothelium determines the efficiency with which leukocytes may adhere to the local vasculature and extravasate into the local tissue during the development of an inflammatory response. The local concentration of cytokines and growth factor participate in the modulation of the expression of these CAMs.

[1148] Tumor necrosis factor alpha (TNF-a), a potent proinflammatory cytokine, is a stimulator of all three CAMs on endothelial cells and may be involved in a wide variety of inflammatory responses, often resulting in a pathological outcome.

[1149] The potential of an agonist or antagonist of the invention to mediate a suppression of TNF-a induced CAM expression can be examined. A modified ELISA assay which uses ECs as a solid phase absorbent is employed to measure the amount of CAM expression on TNF-a treated ECs when co-stimulated with a member of the FGF family of proteins.

[1150] To perform the experiment, human umbilical vein endothelial cell (HUVEC) cultures are obtained from pooled cord harvests and maintained in growth medium (EGM-2; Clonetics, San Diego, Calif.) supplemented with 10% FCS and 1% penicillin/streptomycin in a 37 degree C. humidified incubator containing 5% CO2. HUVECs are seeded in 96-well plates at concentrations of 1×104 cells/well in EGM medium at 37 degree C. for 18-24 hrs or until confluent. The monolayers are subsequently washed 3 times with a serum-free solution of RPMI-1640 supplemented with 100 U/ml penicillin and 100 mg/ml streptomycin, and treated with a given cytokine and/or growth factor(s) for 24 h at 37 degree C. Following incubation, the cells are then evaluated for CAM expression.

[1151] Human Umbilical Vein Endothelial cells (HUVECs) are grown in a standard 96 well plate to confluence. Growth medium is removed from the cells and replaced with 90 ul of 199 Medium (10% FBS). Samples for testing and positive or negative controls are added to the plate in triplicate (in 10 ul volumes). Plates are incubated at 37 degree C. for either 5 h (selectin and integrin expression) or 24 h (integrin expression only). Plates are aspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS(with Ca++ and Mg++) is added to each well. Plates are held at 4° C. for 30 min.

[1152] Fixative is then removed from the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained. Do not allow the wells to dry. Add 10 μl of diluted primary antibody to the test and control wells. Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody). Cells are incubated at 37° C. for 30 min. in a humidified environment. Wells are washed ×3 with PBS(+Ca,Mg)+0.5% BSA.

[1153] Then add 20 μl of diluted ExtrAvidin-Alkaline Phosphotase (1:5,000 dilution) to each well and incubated at 37° C. for 30 min. Wells are washed X3 with PBS(+Ca,Mg)+0.5% BSA. 1 tablet of p-Nitrophenol Phosphate pNPP is dissolved in 5 ml of glycine buffer (pH 10.4). 100 μl of pNPP substrate in glycine buffer is added to each test well. Standard wells in triplicate are prepared from the working dilution of the ExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000 (100)>10−0.5>10−1>10−1.5. 5 μl of each dilution is added to triplicate wells and the resulting AP content in each well is 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent must then be added to each of the standard wells. The plate must be incubated at 37° C. for 4 h. A volume of 50 μl of 3M NaOH is added to all wells. The results are quantified on a plate reader at 405 nm. The background subtraction option is used on blank wells filled with glycine buffer only. The template is set up to indicate the concentration of AP-conjugate in each standard well [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated as amount of bound AP-conjugate in each sample.

[1154] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 30

Production of Polypeptide of the Invention For High-Throughput Screening Assays

[1155] The following protocol produces a supernatant containing polypeptide of the present invention to be tested. This supernatant can then be used in the Screening Assays described in Examples 32-41.

[1156] First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim) stock solution (1 mg/ml in PBS) 1:20 in PBS (w/o calcium or magnesium 17-516F Biowhittaker) for a working solution of 50 ug/ml. Add 200 ul of this solution to each well (24 well plates) and incubate at RT for 20 minutes. Be sure to distribute the solution over each well (note: a 12-channel pipetter may be used with tips on every other channel). Aspirate off the Poly-D-Lysine solution and rinse with 1 ml PBS (Phosphate Buffered Saline). The PBS should remain in the well until just prior to plating the cells and plates may be poly-lysine coated in advance for up to two weeks.

[1157] Plate 293T cells (do not carry cells past P+20) at 2×105 cells/well in 0.5 ml DMEM(Dulbecco's Modified Eagle Medium)(with 4.5 G/L glucose and L-glutamine (12-604F Biowhittaker))/10% heat inactivated FBS(14-503F Biowhittaker)/1×Penstrep(17-602E Biowhittaker). Let the cells grow overnight.

[1158] The next day, mix together in a sterile solution basin: 300 ul Lipofectamine (18324-012 Gibco/BRL) and 5 ml Optimem 1 (31985070 Gibco/BRL)/96-well plate. With a small volume multi-channel pipetter, aliquot approximately 2 ug of an expression vector containing a polynucleotide insert, produced by the methods described in Examples 8-10, into an appropriately labeled 96-well round bottom plate. With a multi-channel pipetter, add 50 ul of the Lipofectamine/Optimem I mixture to each well. Pipette up and down gently to mix. Incubate at RT 15-45 minutes. After about 20 minutes, use a multi-channel pipetter to add 150 ul Optimem I to each well. As a control, one plate of vector DNA lacking an insert should be transfected with each set of transfections.

[1159] Preferably, the transfection should be performed by tag-teaming the following tasks. By tag-teaming, hands on time is cut in half, and the cells do not spend too much time on PBS. First, person A aspirates off the media from four 24-well plates of cells, and then person B rinses each well with 0.5-1 ml PBS. Person A then aspirates off PBS rinse, and person B, using al2-channel pipetter with tips on every other channel, adds the 200 ul of DNA/Lipofectamine/Optimem I complex to the odd wells first, then to the even wells, to each row on the 24-well plates. Incubate at 37 degree C. for 6 hours.

[1160] While cells are incubating, prepare appropriate media, either 1%BSA in DMEM with 1× penstrep, or HGS CHO-5 media (116.6 mg/L of CaCl2 (anhyd); 0.00130 mg/L CuSO4-5H2O; 0.050 mg/L of Fe(NO3)3-9H2O; 0.417 mg/L of FeSO4-7H2O; 311.80 mg/L of Kcl; 28.64 mg/L of MgCl2; 48.84 mg/L of MgSO4; 6995.50 mg/L of NaCl; 2400.0 mg/L of NaHCO3; 62.50 mg/L of NaH2PO4—H2O; 71.02 mg/L of Na2HPO4; 0.4320 mg/L of ZnSO4-7H2O; 0.002 mg/L of Arachidonic Acid; 1.022 mg/L of Cholesterol; 0.070 mg/L of DL-alpha-Tocopherol-Acetate; 0.0520 mg/L of Linoleic Acid; 0.010 mg/L of Linolenic Acid; 0.010 mg/L of Myristic Acid; 0.010 mg/L of Oleic Acid; 0.010 mg/L of Palmitric Acid; 0.010 mg/L of Palmitic Acid; 100 mg/L of Pluronic F-68; 0.010 mg/L of Stearic Acid; 2.20 mg/L of Tween 80; 4551 mg/L of D-Glucose; 130.85 mg/ml of L-Alanine; 147.50 mg/ml of L-Arginine-HCL; 7.50 mg/ml of L-Asparagine-H2O; 6.65 mg/ml of L-Aspartic Acid; 29.56 mg/ml of L-Cystine-2HCL-H2O; 31.29 mg/ml of L-Cystine-2HCL; 7.35 mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75 mg/ml of Glycine; 52.48 mg/ml of L-Histidine-HCL-H2O; 106.97 mg/ml of L-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml of L-Lysine HCL; 32.34 mg/ml of L-Methionine; 68.48 mg/ml of L-Phenylalainine; 40.0 mg/ml of L-Proline; 26.25 mg/ml of L-Serine; 101.05 mg/ml of L-Threonine; 19.22 mg/ml of L-Tryptophan; 91.79 mg/ml of L-Tryrosine-2Na-2H2O; and 99.65 mg/ml of L-Valine; 0.0035 mg/L of Biotin; 3.24 mg/L of D-Ca Pantothenate; 11.78 mg/L of Choline Chloride; 4.65 mg/L of Folic Acid; 15.60 mg/L of i-Inositol; 3.02 mg/L of Niacinamide; 3.00 mg/L of Pyridoxal HCL; 0.031 mg/L of Pyridoxine HCL; 0.319 mg/L of Riboflavin; 3.17 mg/L of Thiamine HCL; 0.365 mg/L of Thymidine; 0.680 mg/L of Vitamin B12; 25 mM of HEPES Buffer; 2.39 mg/L of Na Hypoxanthine; 0.105 mg/L of Lipoic Acid; 0.081 mg/L of Sodium Putrescine-2HCL; 55.0 mg/L of Sodium Pyruvate; 0.0067 mg/L of Sodium Selenite; 20 uM of Ethanolamine; 0.122 mg/L of Ferric Citrate; 41.70 mg/L of Methyl-B-Cyclodextrin complexed with Linoleic Acid; 33.33 mg/L of Methyl-B-Cyclodextrin complexed with Oleic Acid; 10 mg/L of Methyl-B-Cyclodextrin complexed with Retinal Acetate. Adjust osmolarity to 327 mOsm) with 2 mm glutamine and 1× penstrep. (BSA (81-068-3 Bayer) 100 gm dissolved in IL DMEM for a 10% BSA stock solution). Filter the media and collect 50 ul for endotoxin assay in 15 ml polystyrene conical.

[1161] The transfection reaction is terminated, preferably by tag-teaming, at the end of the incubation period. Person A aspirates off the transfection media, while person B adds 1.5 ml appropriate media to each well. Incubate at 37 degree C. for 45 or 72 hours depending on the media used: 1%BSA for 45 hours or CHO-5 for 72 hours.

[1162] On day four, using a 300 ul multichannel pipetter, aliquot 600 ul in one 1 ml deep well plate and the remaining supernatant into a 2 ml deep well. The supernatants from each well can then be used in the assays described in Examples 32-39.

[1163] It is specifically understood that when activity is obtained in any of the assays described below using a supernatant, the activity originates from either the polypeptide of the present invention directly (e.g., as a secreted protein) or by polypeptide of the present invention inducing expression of other proteins, which are then secreted into the supernatant. Thus, the invention further provides a method of identifying the protein in the supernatant characterized by an activity in a particular assay.

Example 31

Construction of GAS Reporter Construct

[1164] One signal transduction pathway involved in the differentiation and proliferation of cells is called the Jaks-STATs pathway. Activated proteins in the Jaks-STATs pathway bind to gamma activation site “GAS” elements or interferon-sensitive responsive element (“ISRE”), located in the promoter of many genes. The binding of a protein to these elements alter the expression of the associated gene.

[1165] GAS and ISRE elements are recognized by a class of transcription factors called Signal Transducers and Activators of Transcription, or “STATs.” There are six members of the STATs family. Stat1 and Stat3 are present in many cell types, as is Stat2 (as response to IFN-alpha is widespread). Stat4 is more restricted and is not in many cell types though it has been found in T helper class I, cells after treatment with IL-12. Stat5 was originally called mammary growth factor, but has been found at higher concentrations in other cells including myeloid cells. It can be activated in tissue culture cells by many cytokines.

[1166] The STATs are activated to translocate from the cytoplasm to the nucleus upon tyrosine phosphorylation by a set of kinases known as the Janus Kinase (“Jaks”) family. Jaks represent a distinct family of soluble tyrosine kinases and include Tyk2, Jak1, Jak2, and Jak3. These kinases display significant sequence similarity and are generally catalytically inactive in resting cells.

[1167] The Jaks are activated by a wide range of receptors summarized in the Table below. (Adapted from review by Schidler and Darnell, Ann. Rev. Biochem. 64:621-51 (1995)). A cytokine receptor family, capable of activating Jaks, is divided into two groups: (a) Class I includes receptors for IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-11, IL-12, IL-15, Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and thrombopoietin; and (b) Class 2 includes IFN-a, IFN-g, and IL-10. The Class 1 receptors share a conserved cysteine motif (a set of four conserved cysteines and one tryptophan) and a WSXWS motif (a membrane proximal region encoding Trp-Ser-Xaa-Trp-Ser (SEQ ID NO: 2)).

[1168] Thus, on binding of a ligand to a receptor, Jaks are activated, which in turn activate STATs, which then translocate and bind to GAS elements. This entire process is encompassed in the Jaks-STATs signal transduction pathway. Therefore, activation of the Jaks-STATs pathway, reflected by the binding of the GAS or the ISRE element, can be used to indicate proteins involved in the proliferation and differentiation of cells. For example, growth factors and cytokines are known to activate the Jaks-STATs pathway (See Table below). Thus, by using GAS elements linked to reporter molecules, activators of the Jaks-STATs pathway can be identified.

	JAKs
Ligand	tyk2	Jak1	Jak2	Jak3	STATS	GAS (elements) or ISRE
IFN family
IFN-a/B	+	+	−	−	1, 2, 3	ISRE
IFN-g		+	+	−	1	GAS (IRF1 > Lys6 > IFP)
Il-10	+	?	?	−	1, 3
gp130 family
IL-6 (Pleiotropic)	+	+	+	?	1, 3	GAS (IRF1 > Lys6 > IFP)
Il-11 (Pleiotropic)	?	+	?	?	1, 3
OnM (Pleiotropic)	?	+	+	?	1, 3
LIF (Pleiotropic)	?	+	+	?	1, 3
CNTF (Pleiotropic)	−/+	+	+	+	1, 3
G-CSF (Pleiotropic)	?	+	?	?	1, 3
IL-12 (Pleiotropic)	+	−	+	+	1, 3
g-C family
IL-2 (lymphocytes)	−	+	−	+	1, 3, 5	GAS
IL-4 (lymph/myeloid)	−	+	−	+	6	GAS (IRF1 = IFP >> Ly6)(IgH)
IL-7 (lymphocytes)	−	+	−	+	5	GAS
IL-9 (lymphocytes)	−	+	−	+	5	GAS
IL-13 (lymphocyte)	−	+	?	?	6	GAS
IL-15	?	+	?	+	5	GAS
gp140 family
IL-3 (myeloid)	−	−	+	−	5	GAS (IRF1 > IFP >> Ly6)
IL-5 (myeloid)	−	−	+	−	5	GAS
GM-CSF (myeloid)	−	−	+	−	5	GAS
Growth hormone family
GH	?	−	+	−	5
PRL	?	+/−	+	−	1, 3, 5
EPO	?	−	+	−	5	GAS (B-CAS > IRF1 = IFP >> Ly6)
Receptor Tyrosine Kinases
EGF	?	+	+	−	1, 3	GAS(IRF1)
PDGF	?	+	+	−	1, 3
CSF-1	?	+	+	−	1, 3	GAS (not IRF1)

[1169] To construct a synthetic GAS containing promoter element, which is used in the Biological Assays described in Examples 32-33, a PCR based strategy is employed to generate a GAS-SV40 promoter sequence. The 5′ primer contains four tandem copies of the GAS binding site found in the IRFI promoter and previously demonstrated to bind STATs upon induction with a range of cytokines (Rothman et al., Immunity 1:457-468 (1994).), although other GAS or ISRE elements can be used instead. The 5′ primer also contains 18 bp of sequence complementary to the SV40 early promoter sequence and is flanked with an XhoI site. The sequence of the 5′ primer is:

(SEQ ID NO: 3)
5′:GCGCCTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCC
CCGAAATGATTTCCCCGAAATATCTGCCATCTCAATTAG:3′

[1170] The downstream primer is complementary to the SV40 promoter and is flanked with a Hind III site: 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ ID NO: 4)

[1171] PCR amplification is performed using the SV40 promoter template present in the B-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI/Hind III and subcloned into BLSK2-. (Stratagene.) Sequencing with forward and reverse primers confirms that the insert contains the following sequence:

(SEQ ID NO: 5)
5′:CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGA
AATGATTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTC
CCGCCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCA
TTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGG
CCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGA
GGCCTAGGCTTTTGCAAAAAGCTT:3′

[1172] With this GAS promoter element linked to the SV40 promoter, a GAS:SEAP2 reporter construct is next engineered. Here, the reporter molecule is a secreted alkaline phosphatase, or “SEAP.” Clearly, however, any reporter molecule can be instead of SEAP, in this or in any of the other Examples. Well known reporter molecules that can be used instead of SEAP include chloramphenicol acetyltransferase (CAT), luciferase, alkaline phosphatase, B-galactosidase, green fluorescent protein (GFP), or any protein detectable by an antibody.

[1173] The above sequence confirmed synthetic GAS-SV40 promoter element is subcloned into the pSEAP-Promoter vector obtained from Clontech using HindIII and XhoI, effectively replacing the SV40 promoter with the amplified GAS:SV40 promoter element, to create the GAS-SEAP vector. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.

[1174] Thus, in order to generate mammalian stable cell lines expressing the GAS-SEAP reporter, the GAS-SEAP cassette is removed from the GAS-SEAP vector using SalI and NotI, and inserted into a backbone vector containing the neomycin resistance gene, such as pGFP-1 (Clontech), using these restriction sites in the multiple cloning site, to create the GAS-SEAP/Neo vector. Once this vector is transfected into mammalian cells, this vector can then be used as a reporter molecule for GAS binding as described in Examples 32-33.

[1175] Other constructs can be made using the above description and replacing GAS with a different promoter sequence. For example, construction of reporter molecules containing EGR and NF-KB promoter sequences are described in Examples 34 and 35. However, many other promoters can be substituted using the protocols described in these Examples. For instance, SRE, IL-2, NFAT, or Osteocalcin promoters can be substituted, alone or in combination (e.g., GAS/NF-KB/EGR, GAS/NF-KB, Il-2/NFAT, or NF-KB/GAS). Similarly, other cell lines can be used to test reporter construct activity, such as HELA (epithelial), HUVEC (endothelial), Reh (B-cell), Saos-2 (osteoblast), HUVAC (aortic), or Cardiomyocyte.

Example 32

High-Throughput Screening Assay for T-cell Activity

[1176] The following protocol is used to assess T-cell activity by identifying factors, and determining whether sup emate containing a polypeptide of the invention proliferates and/or differentiates T-cells. T-cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 31. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The T-cell used in this assay is Jurkat T-cells (ATCC Accession No. TIB-152), although Molt-3 cells (ATCC Accession No. CRL-1552) and Molt-4 cells (ATCC Accession No. CRL-1582) cells can also be used.

[1177] Jurkat T-cells are lymphoblastic CD4+ Th1 helper cells. In order to generate stable cell lines, approximately 2 million Jurkat cells are transfected with the GAS-SEAP/neo vector using DMRIE-C (Life Technologies)(transfection procedure described below). The transfected cells are seeded to a density of approximately 20,000 cells per well and transfectants resistant to 1 mg/ml genticin selected. Resistant colonies are expanded and then tested for their response to increasing concentrations of interferon gamma. The dose response of a selected clone is demonstrated.

[1178] Specifically, the following protocol will yield sufficient cells for 75 wells containing 200 ul of cells. Thus, it is either scaled up, or performed in multiple to generate sufficient cells for multiple 96 well plates. Jurkat cells are maintained in RPMI+10% serum with 1%Pen-Strep. Combine 2.5 mls of OPTI-MEM (Life Technologies) with 10 ug of plasmid DNA in a T25 flask. Add 2.5 ml OPTI-MEM containing 50 ul of DMRIE-C and incubate at room temperature for 15-45 mins.

[1179] During the incubation period, count cell concentration, spin down the required number of cells (107 per transfection), and resuspend in OPTI-MEM to a final concentration of 107 cells/ml. Then add 1 ml of 1×107 cells in OPTI-MEM to T25 flask and incubate at 37 degree C. for 6 hrs. After the incubation, add 10 ml of RPMI+15% serum.

[1180] The Jurkat:GAS-SEAP stable reporter lines are maintained in RPMI+10% serum, 1 mg/ml Genticin, and 1% Pen-Strep. These cells are treated with supernatants containing polypeptide of the present invention or polypeptide of the present invention induced polypeptides as produced by the protocol described in Example 30.

[1181] On the day of treatment with the supernatant, the cells should be washed and resuspended in fresh RPMI+10% serum to a density of 500,000 cells per ml. The exact number of cells required will depend on the number of supernatants being screened. For one 96 well plate, approximately 10 million cells (for 10 plates, 100 million cells) are required.

[1182] Transfer the cells to a triangular reservoir boat, in order to dispense the cells into a 96 well dish, using a 12 channel pipette. Using a 12 channel pipette, transfer 200 ul of cells into each well (therefore adding 100, 000 cells per well).

[1183] After all the plates have been seeded, 50 ul of the supernatants are transferred directly from the 96 well plate containing the supernatants into each well using a 12 channel pipette. In addition, a dose of exogenous interferon gamma (0.1, 1.0, 10 ng) is added to wells H9, H10, and H11 to serve as additional positive controls for the assay.

[1184] The 96 well dishes containing Jurkat cells treated with supernatants are placed in an incubator for 48 hrs (note: this time is variable between 48-72 hrs). 35 ul samples from each well are then transferred to an opaque 96 well plate using a 12 channel pipette. The opaque plates should be covered (using sellophene covers) and stored at −20 degree C. until SEAP assays are performed according to Example 36. The plates containing the remaining treated cells are placed at 4 degree C. and serve as a source of material for repeating the assay on a specific well if desired.

[1185] As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate Jurkat T cells. Over 30 fold induction is typically observed in the positive control wells.

[1186] The above protocol may be used in the generation of both transient, as well as, stable transfected cells, which would be apparent to those of skill in the art.

Example 33

High-Throughput Screening Assay Identifying Myeloid Activity

[1187] The following protocol is used to assess myeloid activity of polypeptide of the present invention by determining whether polypeptide of the present invention proliferates and/or differentiates myeloid cells. Myeloid cell activity is assessed using the GAS/SEAPINeo construct produced in Example 31. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The myeloid cell used in this assay is U937, a pre-monocyte cell line, although TF-1, HL60, or KG1 can be used.

[1188] To transiently transfect U937 cells with the GAS/SEAP/Neo construct produced in Example 31, a DEAE-Dextran method (Kharbanda et. al., 1994, Cell Growth & Differentiation, 5:259-265) is used. First, harvest 2×107 U937 cells and wash with PBS. The U937 cells are usually grown in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 mg/ml streptomycin.

[1189] Next, suspend the cells in 1 ml of 20 mM Tris-HCl (pH 7.4) buffer containing 0.5 mg/ml DEAE-Dextran, 8 ug GAS-SEAP2 plasmid DNA, 140 mM NaCl, 5 mM KCl, 375 uM Na2HPO4.7H2O, 1 mM MgCl2, and 675 uM CaCl2. Incubate at 37 degrees C. for 45 min.

[1190] Wash the cells with RPMI 1640 medium containing 10% FBS and then resuspend in 10 ml complete medium and incubate at 37 degree C. for 36 hr.

[1191] The GAS-SEAP/U937 stable cells are obtained by growing the cells in 400 ug/ml G418. The G418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 400 ug/ml G418 for couple of passages.

[1192] These cells are tested by harvesting 1×108 cells (this is enough for ten 96-well plates assay) and wash with PBS. Suspend the cells in 200 ml above described growth medium, with a final density of 5×105 cells/ml. Plate 200 ul cells per well in the 96-well plate (or 1×005 cells/well).

[1193] Add 50 ul of the supernatant prepared by the protocol described in Example 30. Incubate at 37 degee C for 48 to 72 hr. As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate U937 cells. Over 30 fold induction is typically observed in the positive control wells. SEAP assay the supernatant according to the protocol described in Example 36.

Example 34

High-Throughput Screening Assay Identifying Neuronal Activity

[1194] When cells undergo differentiation and proliferation, a group of genes are activated through many different signal transduction pathways. One of these genes, EGR1 (early growth response gene 1), is induced in various tissues and cell types upon activation. The promoter of EGR1 is responsible for such induction. Using the EGR1 promoter linked to reporter molecules, activation of cells can be assessed by polypeptide of the present invention.

[1195] Particularly, the following protocol is used to assess neuronal activity in PC12 cell lines. PC12 cells (rat phenochromocytoma cells) are known to proliferate and/or differentiate by activation with a number of mitogens, such as TPA (tetradecanoyl phorbol acetate), NGF (nerve growth factor), and EGF (epidermal growth factor). The EGR1 gene expression is activated during this treatment. Thus, by stably transfecting PC12 cells with a construct containing an EGR promoter linked to SEAP reporter, activation of PC12 cells by polypeptide of the present invention can be assessed.

[1196] The EGR/SEAP reporter construct can be assembled by the following protocol. The EGR-1 promoter sequence (−633 to +1)(Sakamoto K et al., Oncogene 6:867-871 (1991)) can be PCR amplified from human genomic DNA using the following primers:

(SEQ ID NO: 6)
5′ GCGCTCGAGGGATGACAGCGATAGAACCCCGG-3′
(SEQ ID NO: 7)
5′ GCGAAGCTTCGCGACTCCCCGGATCCGCCTC-3′

[1197] Using the GAS:SEAP/Neo vector produced in Example 31, EGR1 amplified product can then be inserted into this vector. Linearize the GAS:SEAP/Neo vector using restriction enzymes XhoI/HindIII, removing the GAS/SV40 stuffer. Restrict the EGR1 amplified product with these same enzymes. Ligate the vector and the EGR1 promoter.

[1198] To prepare 96 well-plates for cell culture, two mls of a coating solution (1:30 dilution of collagen type I (Upstate Biotech Inc. Cat#08-115) in 30% ethanol (filter sterilized)) is added per one 10 cm plate or 50 ml per well of the 96-well plate, and allowed to air dry for 2 hr.

[1199] PC12 cells are routinely grown in RPMI-1640 medium (Bio Whittaker) containing 10% horse serum (JRH BIOSCIENCES, Cat. # 12449-78P), 5% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 ug/ml streptomycin on a precoated 10 cm tissue culture dish. One to four split is done every three to four days. Cells are removed from the plates by scraping and resuspended with pipetting up and down for more than 15 times.

[1200] Transfect the EGR/SEAP/Neo construct into PCl2 using the Lipofectamine protocol described in Example 30. EGR-SEAP/PC12 stable cells are obtained by growing the cells in 300 ug/ml G418. The G418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 300 ug/ml G418 for couple of passages.

[1201] To assay for neuronal activity, a 10 cm plate with cells around 70 to 80% confluent is screened by removing the old medium. Wash the cells once with PBS (Phosphate buffered saline). Then starve the cells in low serum medium (RPMI-1640 containing 1% horse serum and 0.5% FBS with antibiotics) overnight.

[1202] The next morning, remove the medium and wash the cells with PBS. Scrape off the cells from the plate, suspend the cells well in 2 ml low serum medium. Count the cell number and add more low serum medium to reach final cell density as 5×105 cells/ml.

[1203] Add 200 ul of the cell suspension to each well of 96-well plate (equivalent to 1×105 cells/well). Add 50 ul supernatant produced by Example 30, 37 degree C. for 48 to 72 hr. As a positive control, a growth factor known to activate PC12 cells through EGR can be used, such as 50 ng/ul of Neuronal Growth Factor (NGF). Over fifty-fold induction of SEAP is typically seen in the positive control wells. SEAP assay the supernatant according to Example 36.

Example 35

High-Throughput Screening Assay for T-cell Activity

[1204] NF-KB (Nuclear Factor KB) is a transcription factor activated by a wide variety of agents including the inflammatory cytokines IL-1 and TNF, CD30 and CD40, lymphotoxin-alpha and lymphotoxin-beta, by exposure to LPS or thrombin, and by expression of certain viral gene products. As a transcription factor, NF-KB regulates the expression of genes involved in immune cell activation, control of apoptosis (NF-KB appears to shield cells from apoptosis), B and T-cell development, anti-viral and antimicrobial responses, and multiple stress responses.

[1205] In non-stimulated conditions, NF-KB is retained in the cytoplasm with I-KB (Inhibitor KB). However, upon stimulation, I-KB is phosphorylated and degraded, causing NF-KB to shuttle to the nucleus, thereby activating transcription of target genes. Target genes activated by NF-KB include IL-2, IL-6, GM-CSF, ICAM-1 and class I MHC.

[1206] Due to its central role and ability to respond to a range of stimuli, reporter constructs utilizing the NF-KB promoter element are used to screen the supernatants produced in Example 30. Activators or inhibitors of NF-KB would be useful in treating, preventing, and/or diagnosing diseases. For example, inhibitors of NF-KB could be used to treat those diseases related to the acute or chronic activation of NF-KB, such as rheumatoid arthritis.

[1207] To construct a vector containing the NF-KB promoter element, a PCR based strategy is employed. The upstream primer contains four tandem copies of the NF-KB binding site (GGGGACTTTCCC) (SEQ ID NO: 8), 18 bp of sequence complementary to the 5′ end of the SV40 early promoter sequence, and is flanked with an XhoI site:

(SEQ ID NO: 9)
5′:GCGGCCTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGG
ACTTTCCATCCTGCCATCTCAATTAG:3′

[1208] The downstream primer is complementary to the 3′ end of the SV40 promoter and is flanked with a Hind III site: 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′(SEQ ID NO: 4)

[1209] PCR amplification is performed using the SV40 promoter template present in the pB-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI and Hind III and subcloned into BLSK2-. (Stratagene) Sequencing with the T7 and T3 primers confirms the insert contains the following sequence:

(SEQ ID NO: 10)
5′:CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGACTTT
CCATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCG
CCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGG
CTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTG
AGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGC
AAAAAGCTT:3′

[1210] Next, replace the SV40 minimal promoter element present in the pSEAP2-promoter plasmid (Clontech) with this NF-KB/SV40 fragment using XhoI and HindIII. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.

[1211] In order to generate stable mammalian cell lines, the NF-KB/SV40/SEAP cassette is removed from the above NF-KB/SEAP vector using restriction enzymes SalI and NotI, and inserted into a vector containing neomycin resistance. Particularly, the NF-KB/SV40/SEAP cassette was inserted into pGFP-1 (Clontech), replacing the GFP gene, after restricting pGFP-1 with SalI and NotI.

[1212] Once NF-KB/SV40/SEAP/Neo vector is created, stable Jurkat T-cells are created and maintained according to the protocol described in Example 32. Similarly, the method for assaying supernatants with these stable Jurkat T-cells is also described in Example 32. As a positive control, exogenous TNF alpha (0.1,1, 10 ng) is added to wells H9, H10, and H11, with a 5-10 fold activation typically observed.

Example 36

Assay for SEAP Activity

[1213] As a reporter molecule for the assays described in Examples 32-35, SEAP activity is assayed using the Tropix Phospho-light Kit (Cat. BP-400) according to the following general procedure. The Tropix Phospho-light Kit supplies the Dilution, Assay, and Reaction Buffers used below.

[1214] Prime a dispenser with the 2.5× Dilution Buffer and dispense 15 ul of 2.5× dilution buffer into Optiplates containing 35 ul of a supernatant. Seal the plates with a plastic sealer and incubate at 65 degree C. for 30 min. Separate the Optiplates to avoid uneven heating.

[1215] Cool the samples to room temperature for 15 minutes. Empty the dispenser and prime with the Assay Buffer. Add 50 ml Assay Buffer and incubate at room temperature 5 min. Empty the dispenser and prime with the Reaction Buffer (see the Table below). Add 50 ul Reaction Buffer and incubate at room temperature for 20 minutes. Since the intensity of the chemiluminescent signal is time dependent, and it takes about 10 minutes to read 5 plates on a luminometer, thus one should treat 5 plates at each time and start the second set 10 minutes later.

[1216] Read the relative light unit in the luminometer. Set H12 as blank, and print the results. An increase in chemiluminescence indicates reporter activity.

Reaction Buffer Formulation:
# of plates	Rxn buffer diluent (ml)	CSPD (ml)
10	60	3
11	65	3.25
12	70	3.5
13	75	3.75
14	80	4
15	85	4.25
16	90	4.5
17	95	4.75
18	100	5
19	105	5.25
20	110	5.5
21	115	5.75
22	120	6
23	125	6.25
24	130	6.5
25	135	6.75
26	140	7
27	145	7.25
28	150	7.5
29	155	7.75
30	160	8
31	165	8.25
32	170	8.5
33	175	8.75
34	180	9
35	185	9.25
36	190	9.5
37	195	9.75
38	200	10
39	205	10.25
40	210	10.5
41	215	10.75
42	220	11
43	225	11.25
44	230	11.5
45	235	11.75
46	240	12
47	245	12.25
48	250	12.5
49	255	12.75
50	260	13

Example 37

High-Throughput Screening Assay Identifying Changes in Small Molecule Concentration and Membrane Permeability

[1217] Binding of a ligand to a receptor is known to alter intracellular levels of small molecules, such as calcium, potassium, sodium, and pH, as well as alter membrane potential. These alterations can be measured in an assay to identify supernatants which bind to receptors of a particular cell. Although the following protocol describes an assay for calcium, this protocol can easily be modified to detect changes in potassium, sodium, pH, membrane potential, or any other small molecule which is detectable by a fluorescent probe.

[1218] The following assay uses Fluorometric Imaging Plate Reader (“FLIPR”) to measure changes in fluorescent molecules (Molecular Probes) that bind small molecules. Clearly, any fluorescent molecule detecting a small molecule can be used instead of the calcium fluorescent molecule, fluo-4 (Molecular Probes, Inc.; catalog no. F-14202), used here. RPTKs for which the corresponding ligand is unknown. Ligands for RPTKs include mainly secreted small proteins, but also membrane-bound and extracellular matrix proteins.

[1219] Activation of RPTK by ligands involves ligand-mediated receptor dimerization, resulting in transphosphorylation of the receptor subunits and activation of the cytoplasmic tyrosine kinases. The cytoplasmic tyrosine kinases include receptor associated tyrosine kinases of the src-family (e.g., src, yes, lck, lyn, fyn) and non-receptor linked and cytosolic protein tyrosine kinases, such as the Jak family, members of which mediate signal transduction triggered by the cytokine superfamily of receptors (e.g., the Interleukins, Interferons, GM-CSF, and Leptin).

[1220] Because of the wide range of known factors capable of stimulating tyrosine kinase activity, identifying whether polypeptide of the present invention or a molecule induced by polypeptide of the present invention is capable of activating tyrosine kinase signal transduction pathways is of interest. Therefore, the following protocol is designed to identify such molecules capable of activating the tyrosine kinase signal transduction pathways.

[1221] Seed target cells (e.g., primary keratinocytes) at a density of approximately 25,000 cells per well in a 96 well Loprodyne Silent Screen Plates purchased from Nalge Nunc (Naperville, Ill.). The plates are sterilized with two 30 minute rinses with 100% ethanol, rinsed with water and dried overnight. Some plates are coated for 2 hr with 100 ml of cell culture grade type I collagen (50 mg/ml), gelatin (2%) or polylysine (50 mg/ml), all of which can be purchased from Sigma Chemicals (St. Louis, Mo.) or 10% Matri gel purchased from Becton Dickinson (Bedford,Mass.), or calf serum, rinsed with PBS and stored at 4 degree C. Cell growth on these plates is assayed by seeding 5,000 cells/well in growth medium and indirect quantitation of cell number through use of alamarBlue as described by the manufacturer Alamar Biosciences, Inc. (Sacramento, Calif.) after 48 hr. Falcon plate covers #3071 from Becton Dickinson (Bedford,Mass.) are used to cover the Loprodyne Silent Screen Plates. Falcon Microtest III cell culture plates can also be used in some proliferation experiments.

[1222] To prepare extracts, A431 cells are seeded onto the nylon membranes of Loprodyne plates (20,000/200 ml/well) and cultured overnight in complete medium. Cells are quiesced by incubation in serum-free basal medium for 24 hr. After 5-20 minutes treatment with EGF (60 ng/ml) or 50 ul of the supernatant produced in Example 30, the medium was removed and 100 ml of extraction buffer ((20 mM HEPES pH 7.5, 0.15 M NaCl, 1% Triton X-100, 0.1% SDS, 2 mM Na3VO4, 2 mM Na4P2O7 and a cocktail of protease inhibitors (# 1836170) obtained from Boeheringer Mannheim (Indianapolis, Ind.)) is added to each well and the plate is shaken on a rotating shaker for 5 minutes at 4° C. The plate is then placed in a vacuum transfer manifold and the extract filtered through the 0.45 mm membrane bottoms of each well using house vacuum. Extracts are collected in a 96-well catch/assay plate in the bottom of the vacuum manifold and immediately placed on ice. To obtain extracts clarified by centrifugation, the content of each well, after detergent solubilization for 5 minutes, is removed and centrifuged for 15 minutes at 4 degree C. at 16,000×g.

[1223] Test the filtered extracts for levels of tyrosine kinase activity. Although many methods of detecting tyrosine kinase activity are known, one method is described here.

[1224] Generally, the tyrosine kinase activity of a supernatant is evaluated by determining its ability to phosphorylate a tyrosine residue on a specific substrate (a biotinylated peptide). Biotinylated peptides that can be used for this purpose include PSK1 (corresponding to amino acids 6-20 of the cell division kinase cdc2-p34) and PSK2 (corresponding to amino acids 1-17 of gastrin). Both peptides are substrates for a range of tyrosine kinases and are available from Boehringer Mannheim.

[1225] The tyrosine kinase reaction is set up by adding the following components in order. First, add 10 ul of 5 uM Biotinylated Peptide, then 10 ul ATP/Mg2+(5 mM ATP/50 mM MgCl2), then 10 ul of 5× Assay Buffer (40 mM imidazole hydrochloride, pH 7.3, 40 mM beta-glycerophosphate, 1 mM EGTA, 100 mM MgCl2, 5 mM MnCl2, 0.5 mg/ml BSA), then 5 ul of Sodium Vanadate(1 mM), and then 5 ul of water. Mix the components gently and preincubate the reaction mix at 30 degree C. for 2 min. Initial the reaction by adding 10 ul of the control enzyme or the filtered supernatant.

[1226] The tyrosine kinase assay reaction is then terminated by adding 10 ul of 120 mm EDTA and place the reactions on ice.

[1227] Tyrosine kinase activity is determined by transferring 50 ul aliquot of reaction mixture to a microtiter plate (MTP) module and incubating at 37 degree C. for 20 min. This allows the streptavidin coated 96 well plate to associate with the biotinylated peptide. Wash the MTP module with 300 ul/well of PBS four times. Next add 75 ul of anti-phospolyrosine antibody conjugated to horse radish peroxidase(anti-P-Tyr-POD(0.5u/ml)) to each well and incubate at 37 degree C. for one hour. Wash the well as above.

[1228] Next add 100 ul of peroxidase substrate solution (Boehringer Mannheim) and incubate at room temperature for at least 5 mins (up to 30 min). Measure the absorbance of the sample at 405 nm by using ELISA reader. The level of bound peroxidase activity is quantitated using an ELISA reader and reflects the level of tyrosine kinase activity.

Example 39

High-Throughput Screening Assay Identifying Phosphorylation Activity

[1229] As a potential alternative and/or complement to the assay of protein tyrosine kinase activity described in Example 38, an assay which detects activation (phosphorylation) of major intracellular signal transduction intermediates can also be used. For example, as described below one particular assay can detect tyrosine phosphorylation of the Erk-1 and Erk-2 kinases. However, phosphorylation of other molecules, such as Raf, JNK, p38 MAP, Map kinase kinase (MEK), MEK kinase, Src, Muscle specific kinase (MuSK), IRAK, Tec, and Janus, as well as any other phosphoserine, phosphotyrosine, or phosphothreonine molecule, can be detected by substituting these molecules for Erk-1 or Erk-2 in the following assay.

[1230] Specifically, assay plates are made by coating the wells of a 96-well ELISA plate with 0.1 ml of protein G (lug/ml) for 2 hr at room temp, (RT). The plates are then rinsed with PBS and blocked with 3% BSA/PBS for 1 hr at RT. The protein G plates are then treated with 2 commercial monoclonal antibodies (100 ng/well) against Erk-1 and Erk-2 (1 hr at RT) (Santa Cruz Biotechnology). (To detect other molecules, this step can easily be modified by substituting a monoclonal antibody detecting any of the above described molecules.) After 3-5 rinses with PBS, the plates are stored at 4 degree C. until use.

[1231] A431 cells are seeded at 20,000/well in a 96-well Loprodyne filterplate and cultured overnight in growth medium. The cells are then starved for 48 hr in basal medium (DMEM) and then treated with EGF (6 ng/well) or 50 ul of the supernatants obtained in Example 30 for 5-20 minutes. The cells are then solubilized and extracts filtered directly into the assay plate.

[1232] After incubation with the extract for 1 hr at RT, the wells are again rinsed. As a positive control, a commercial preparation of MAP kinase (10 ng/well) is used in place of A431 extract. Plates are then treated with a commercial polyclonal (rabbit) antibody (1 ug/ml) which specifically recognizes the phosphorylated epitope of the Erk-1 and Erk-2 kinases (1 hr at RT). This antibody is biotinylated by standard procedures. The bound polyclonal antibody is then quantitated by successive incubations with Europium-streptavidin and Europium fluorescence enhancing reagent in the Wallac DELFIA instrument (time-resolved fluorescence). An increased fluorescent signal over background indicates a phosphorylation by polypeptide of the present invention or a molecule induced by polypeptide of the present invention.

Example 40

Assay for the Stimulation of Bone Marrow CD34+ Cell Proliferation

[1233] This assay is based on the ability of human CD34+ to proliferate in the presence of hematopoietic growth factors and evaluates the ability of isolated polypeptides expressed in mammalian cells to stimulate proliferation of CD34+ cells.

[1234] It has been previously shown that most mature precursors will respond to only a single signal. More immature precursors require at least two signals to respond. Therefore, to test the effect of polypeptides on hematopoietic activity of a wide range of progenitor cells, the assay contains a given polypeptide in the presence or absence of other hematopoietic growth factors. Isolated cells are cultured for 5 days in the presence of Stem Cell Factor (SCF) in combination with tested sample. SCF alone has a very limited effect on the proliferation of bone marrow (BM) cells, acting in such conditions only as a “survival” factor. However, combined with any factor exhibiting stimulatory effect on these cells (e.g., IL-3), SCF will cause a synergistic effect. Therefore, if the tested polypeptide has a stimulatory effect on hematopoietic progenitors, such activity can be easily detected. Since normal BM cells have a low level of cycling cells, it is likely that any inhibitory effect of a given polypeptide, or agonists or antagonists thereof, might not be detected. Accordingly, assays for an inhibitory effect on progenitors is preferably tested in cells that are first subjected to in vitro stimulation with SCF+IL+3, and then contacted with the compound that is being evaluated for inhibition of such induced proliferation.

[1235] Briefly, CD34+ cells are isolated using methods known in the art. The cells are thawed and resuspended in medium (QBSF 60 serum-free medium with 1% L-glutamine (SOOml) Quality Biological, Inc., Gaithersburg, Md. Cat# 160-204-101). After several gentle centrifugation steps at 200×g, cells are allowed to rest for one hour. The cell count is adjusted to 2.5×105 cells/ml. During this time, 100 μl of sterile water is added to the peripheral wells of a 96-well plate. The cytokines that can be tested with a given polypeptide in this assay is rhSCF (R&D Systems, Minneapolis, Minn., Cat# 255-SC) at 50 ng/ml alone and in combination with rhSCF and rhIL-3 (R&D Systems, Minneapolis, Minn., Cat# 203-ML) at 30 ng/ml. After one hour, 10 μl of prepared cytokines, 50 μl of the supernatants prepared in Example 30 (supernatants at 1:2 dilution=50 μl) and 20 μl of diluted cells are added to the media which is already present in the wells to allow for a final total volume of 100 μl. The plates are then placed in a 37° C./5% CO2 incubator for five days.

[1236] Eighteen hours before the assay is harvested, 0.5 μCi/well of [3H] Thymidine is added in a 10 μl volume to each well to determine the proliferation rate. The experiment is terminated by harvesting the cells from each 96-well plate to a filtermat using the Tomtec Harvester 96. After harvesting, the filtermats are dried, trimmed and placed into OmniFilter assemblies consisting of one OmniFilter plate and one OmniFilter Tray. 60 μl Microscint is added to each well and the plate sealed with TopSeal-A press-on sealing film A bar code 15 sticker is affixed to the first plate for counting. The sealed plates are then loaded and the level of radioactivity determined via the Packard Top Count and the printed data collected for analysis. The level of radioactivity reflects the amount of cell proliferation.

[1237] The studies described in this example test the activity of a given polypeptide to stimulate bone marrow CD34+ cell proliferation. One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof. As a nonlimiting example, potential antagonists tested in this assay would be expected to inhibit cell proliferation in the presence of cytokines and/or to increase the inhibition of cell proliferation in the presence of cytokines and a given polypeptide. In contrast, potential agonists tested in this assay would be expected to enhance cell proliferation and/or to decrease the inhibition of cell proliferation in the presence of cytokines and a given polypeptide.

[1238] The ability of a gene to stimulate the proliferation of bone marrow CD34+ cells indicates that polynucleotides and polypeptides corresponding to the gene are useful for the diagnosis and treatment of disorders affecting the immune system and hematopoiesis. Representative uses are described in the “Immune Activity” and “Infectious Disease” sections above, and elsewhere herein.

Example 41

Assay for Extracellular Matrix Enhanced Cell Response (EMECR)

[1239] The objective of the Extracellular Matrix Enhanced Cell Response (EMECR) assay is to identify gene products (e.g., isolated polypeptides) that act on the hematopoietic stem cells in the context of the extracellular matrix (ECM) induced signal.

[1240] Cells respond to the regulatory factors in the context of signal(s) received from the surrounding microenvironment. For example, fibroblasts, and endothelial and epithelial stem cells fail to replicate in the absence of signals from the ECM. Hematopoietic stem cells can undergo self-renewal in the bone marrow, but not in in vitro suspension culture. The ability of stem cells to undergo self-renewal in vitro is dependent upon their interaction with the stromal cells and the ECM protein fibronectin (fn). Adhesion of cells to fn is mediated by the α5.β1 and α4.β1 integrin receptors, which are expressed by human and mouse hematopoietic stem cells. The factor(s) which integrate with the ECM environment and are responsible for stimulating stem cell self-renewal havea not yet been identified. Discovery of such factors should be of great interest in gene therapy and bone marrow transplant applications

[1241] Briefly, polystyrene, non tissue culture treated, 96-well plates are coated with fn fragment at a coating concentration of 0.2 μg/cm2. Mouse bone marrow cells are plated (1,000 cells/well) in 0.2 ml of serum-free medium. Cells cultured in the presence of IL-3 (5 ng/ml)+SCF (50 ng/ml) would serve as the positive control, conditions under which little self-renewal but pronounced differentiation of the stem cells is to be expected. Gene products of the invention (e.g., including, but not limited to, polynucleotides and polypeptides of the present invention, and supernatants produced in Example 30), are tested with appropriate negative controls in the presence and absence of SCF(5.0 ng/ml), where test factor supernatants represent 10% of the total assay volume. The plated cells are then allowed to grow by incubating in a low oxygen environment (5% CO2, 7% O2, and 88% N2) tissue culture incubator for 7 days. The number of proliferating cells within the wells is then quantitated by measuring thymidine incorporation into cellular DNA. Verification of the positive hits in the assay will require phenotypic characterization of the cells, which can be accomplished by scaling up of the culture system and using appropriate antibody reagents against cell surface antigens and FACScan.

[1242] One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.

[1243] If a particular polypeptide of the present invention is found to be a stimulator of hematopoietic progenitors, polynucleotides and polypeptides corresponding to the gene encoding said polypeptide may be useful for the diagnosis and treatment of disorders affecting the immune system and hematopoiesis. Representative uses are described in the “Immune Activity” and “Infectious Disease” sections above, and elsewhere herein. The gene product may also be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.

[1244] Additionally, the polynucleotides and/or polypeptides of the gene of interest and/or agonists and/or antagonists thereof, may also be employed to inhibit the proliferation and differentiation of hematopoietic cells and therefore may be employed to protect bone marrow stem cells from chemotherapeutic agents during chemotherapy. This antiproliferative effect may allow administration of higher doses of chemotherapeutic agents and, therefore, more effective chemotherapeutic treatment.

[1245] Moreover, polynucleotides and polypeptides corresponding to the gene of interest may also be useful for the treatment and diagnosis of hematopoietic related disorders such as, for example, anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia.

Example 42

Human Dermal Fibroblast and Aortic Smooth Muscle Cell Proliferation

[1246] The polypeptide of interest is added to cultures of normal human dermal fibroblasts (NHDF) and human aortic smooth muscle cells (AoSMC) and two co-assays are performed with each sample. The first assay examines the effect of the polypeptide of interest on the proliferation of normal human dermal fibroblasts (NHDF) or aortic smooth muscle cells (AoSMC). Aberrant growth of fibroblasts or smooth muscle cells is a part of several pathological processes, including fibrosis, and restenosis. The second assay examines IL6 production by both NHDF and SMC. IL6 production is an indication of functional activation. Activated cells will have increased production of a number of cytokines and other factors, which can result in a proinflammatory or immunomodulatory outcome. Assays are run with and without co-TNFa stimulation, in order to check for costimulatory or inhibitory activity.

[1247] Briefly, on day 1, 96-well black plates are set up with 1000 cells/well (NHDF) or 2000 cells/well (AOSMC) in 100 μl culture media. NHDF culture media contains: Clonetics FB basal media, 1 mg/ml hFGF, 5 mg/ml insulin, 50 mg/ml gentamycin, 2%FBS, while AoSMC culture media contains Clonetics SM basal media, 0.5 μg/ml HEGF, 5 mg/ml insulin, 1 μg/ml hFGF, 50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 5%FBS. After incubation at 37° C. for at least 4-5 hours culture media is aspirated and replaced with growth arrest media. Growth arrest media for NHDF contains fibroblast basal media, 50 mg/ml gentamycin, 2% FBS, while growth arrest media for AoSMC contains SM basal media, 50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 0.4% FBS. Incubate at 37° C. until day 2.

[1248] On day 2, serial dilutions and templates of the polypeptide of interest are designed such that they always include media controls and known-protein controls. For both stimulation and inhibition experiments, proteins are diluted in growth arrest media. For inhibition experiments, TNFa is added to a final concentration of 2 ng/ml (NHDF) or 5 ng/ml (AoSMC). Add ⅓ vol media containing controls or polypeptides of the present invention and incubate at 37 degrees C./5% CO2 until day 5.

[1249] Transfer 60 μl from each well to another labeled 96-well plate, cover with a plate-sealer, and store at 4 degrees C. until Day 6 (for IL6 ELISA). To the remaining 100 μl in the cell culture plate, aseptically add Alamar Blue in an amount equal to 10% of the culture volume (10 μl). Return plates to incubator for 3 to 4 hours. Then measure fluorescence with excitation at 530 nm and emission at 590 nm using the CytoFluor. This yields the growth stimulation/inhibition data.

[1250] On day 5, the IL6 ELISA is performed by coating a 96 well plate with 50-100 ul/well of Anti-Human IL6 Monoclonal antibody diluted in PBS, pH 7.4, incubate ON at room temperature.

[1251] On day 6, empty the plates into the sink and blot on paper towels. Prepare Assay Buffer containing PBS with 4% BSA. Block the plates with 200 μl/well of Pierce Super Block blocking buffer in PBS for 1-2 hr and then wash plates with wash buffer (PBS, 0.05% Tween-20). Blot plates on paper towels. Then add 50 μl/well of diluted Anti-Human IL-6 Monoclonal, Biotin-labeled antibody at 0.50 mg/ml. Make dilutions of IL-6 stock in media (30, 10, 3, 1, 0.3, 0 ng/ml). Add duplicate samples to top row of plate. Cover the plates and incubate for 2 hours at RT on shaker.

[1252] Plates are washed with wash buffer and blotted on paper towels. Dilute EU-labeled Streptavidin 1:1000 in Assay buffer, and add 100 μl/well. Cover the plate and incubate 1 h at RT. Plates are again washed with wash buffer and blotted on paper towels.

[1253] Add 100 μl/well of Enhancement Solution. Shake for 5 minutes. Read the plate on the Wallac DELFIA Fluorometer. Readings from triplicate samples in each assay were tabulated and averaged.

[1254] A positive result in this assay suggests AoSMC cell proliferation and that the polypeptide of the present invention may be involved in dermal fibroblast proliferation and/or smooth muscle cell proliferation. A positive result also suggests many potential uses of polypeptides, polynucleotides, agonists and/or antagonists of the polynucleotide/polypeptide of the present invention which gives a positive result. For example, inflammation and immune responses, wound healing, and angiogenesis, as detailed throughout this specification. Particularly, polypeptides of the present invention and polynucleotides of the present invention may be used in wound healing and dermal regeneration, as well as the promotion of vasculogenesis, both of the blood vessels and lymphatics. The growth of vessels can be used in the treatment of, for example, cardiovascular diseases. Additionally, antagonists of polypeptides and polynucleotides of the invention may be useful in treating diseases, disorders, and/or conditions which involve angiogenesis by acting as an anti-vascular agent (e.g., anti-angiogenesis). These diseases, disorders, and/or conditions are known in the art and/or are described herein, such as, for example, malignancies, solid tumors, benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, uvietis and Pterygia (abnormal blood vessel growth) of the eye; rheumatoid arthritis; psoriasis; delayed wound healing; endometriosis; vasculogenesis; granulations; hypertrophic scars (keloids); nonunion fractures; scleroderma; trachoma; vascular adhesions; myocardial angiogenesis; coronary collaterals; cerebral collaterals; arterioyenous malformations; ischemic limb angiogenesis; Osler-Webber Syndrome; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; fibromuscular dysplasia; wound granulation; Crohn's disease; and atherosclerosis. Moreover, antagonists of polypeptides and polynucleotides of the invention may be useful in treating anti-hyperproliferative diseases and/or anti-inflammatory known in the art and/or described herein.

[1255] One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.

Example 43

Cellular Adhesion Molecule (CAM) Expression on Endothelial Cells

[1256] The recruitment of lymphocytes to areas of inflammation and angiogenesis involves specific receptor-ligand interactions between cell surface adhesion molecules (CAMs) on lymphocytes and the vascular endothelium. The adhesion process, in both normal and pathological settings, follows a multi-step cascade that involves intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) expression on endothelial cells (EC). The expression of these molecules and others on the vascular endothelium determines the efficiency with which leukocytes may adhere to the local vasculature and extravasate into the local tissue during the development of an inflammatory response. The local concentration of cytokines and growth factor participate in the modulation of the expression of these CAMs.

[1257] Briefly, endothelial cells (e.g., Human Umbilical Vein Endothelial cells (HUVECs)) are grown in a standard 96 well plate to confluence, growth medium is removed from the cells and replaced with 100 μl of 199 Medium (10% fetal bovine serum (FBS)). Samples for testing and positive or negative controls are added to the plate in triplicate (in 10 μl volumes). Plates are then incubated at 37° C. for either 5 h (selectin and integrin expression) or 24 h (integrin expression only). Plates are aspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS(with Ca++ and Mg++) is added to each well. Plates are held at 4° C. for 30 min. Fixative is removed from the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained. 10 μl of diluted primary antibody is added to the test and control wells. Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody). Cells are incubated at 37° C. for 30 min. in a humidified environment. Wells are washed three times with PBS(+Ca,Mg)+0.5% BSA. 20 μl of diluted ExtrAvidin-Alkaline Phosphatase (1:5,000 dilution, referred to herein as the working dilution) are added to each well and incubated at 37° C. for 30 min. Wells are washed three times with PBS(+Ca,Mg)+0.5% BSA. Dissolve 1 tablet of p-Nitrophenol Phosphate pNPP per 5 ml of glycine buffer (pH 10.4). 100 Ill of pNPP substrate in glycine buffer is added to each test well. Standard wells in triplicate are prepared from the working dilution of the ExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000 (100)>10−0.5>10−1>10−1.5. 5 μl of each dilution is added to triplicate wells and the resulting AP content in each well is 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent is then added to each of the standard wells. The plate is incubated at 37° C. for 4 h. A volume of 50 ill of 3M NaOH is added to all wells. The plate is read on a plate reader at 405 nm using the background subtraction option on blank wells filled with glycine buffer only. Additionally, the template is set up to indicate the concentration of AP-conjugate in each standard well [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated as amount of bound AP-conjugate in each sample.

Example 44

Alamar Blue Endothelial Cells Proliferation Assay

[1258] This assay may be used to quantitatively determine protein mediated inhibition of bFGF-induced proliferation of Bovine Lymphatic Endothelial Cells (LECs), Bovine Aortic Endothelial Cells (BAECs) or Human Microvascular Uterine Myometrial Cells (UTMECs). This assay incorporates a fluorometric growth indicator based on detection of metabolic activity. A standard Alamar Blue Proliferation Assay is prepared in EGM-2MV with 10 ng/ml of bFGF added as a source of endothelial cell stimulation. This assay may be used with a variety of endothelial cells with slight changes in growth medium and cell concentration. Dilutions of the protein batches to be tested are diluted as appropriate. Serum-free medium (GIBCO SFM) without bFGF is used as a non-stimulated control and Angiostatin or TSP-1 are included as a known inhibitory controls.

[1259] Briefly, LEC, BAECs or UTMECs are seeded in growth media at a density of 5000 to 2000 cells/well in a 96 well plate and placed at 37 degreesC overnight. After the overnight incubation of the cells, the growth media is removed and replaced with GIBCO EC-SFM. The cells are treated with the appropriate dilutions of the protein of interest or control protein sample(s) (prepared in SFM) in triplicate wells with additional bFGF to a concentration of 10 ng/ml. Once the cells have been treated with the samples, the plate(s) is/are placed back in the 37° C. incubator for three days. After three days 10 ml of stock alamar blue (Biosource Cat# DALI 100) is added to each well and the plate(s) is/are placed back in the 37° C. incubator for four hours. The plate(s) are then read at 530 nm excitation and 590 nm emission using the CytoFluor fluorescence reader. Direct output is recorded in relative fluorescence units.

[1260] Alamar blue is an oxidation-reduction indicator that both fluoresces and changes color in response to chemical reduction of growth medium resulting from cell growth. As cells grow in culture, innate metabolic activity results in a chemical reduction of the immediate surrounding environment. Reduction related to growth causes the indicator to change from oxidized (non-fluorescent blue) form to reduced (fluorescent red) form (i.e., stimulated proliferation will produce a stronger signal and inhibited proliferation will produce a weaker signal and the total signal is proportional to the total number of cells as well as their metabolic activity). The background level of activity is observed with the starvation medium alone. This is compared to the output observed from the positive control samples (bFGF in growth medium) and protein dilutions.

Example 45

Detection of Inhibition of a Mixed Lymphocyte Reaction

[1261] This assay can be used to detect and evaluate inhibition of a Mixed Lymphocyte Reaction (MLR) by gene products (e.g., isolated polypeptides). Inhibition of a MLR may be due to a direct effect on cell proliferation and viability, modulation of costimulatory molecules on interacting cells, modulation of adhesiveness between lymphocytes and accessory cells, or modulation of cytokine production by accessory cells. Multiple cells may be targeted by these polypeptides since the peripheral blood mononuclear fraction used in this assay includes T, B and natural killer lymphocytes, as well as monocytes and dendritic cells.

[1262] Polypeptides of interest found to inhibit the MLR may find application in diseases associated with lymphocyte and monocyte activation or proliferation. These include, but are not limited to, diseases such as asthma, arthritis, diabetes, inflammatory skin conditions, psoriasis, eczema, systemic lupus erythematosus, multiple sclerosis, glomerulonephritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, arteriosclerosis, cirrhosis, graft vs. host disease, host vs. graft disease, hepatitis, leukemia and lymphoma.

[1263] Briefly, PBMCs from human donors are purified by density gradient centrifugation using Lymphocyte Separation Medium (LSM®, density 1.0770 g/ml, Organon Teknika Corporation, West Chester, Pa.). PBMCs from two donors are adjusted to 2×106 cells/ml in RPMI-1640 (Life Technologies, Grand Island, N.Y.) supplemented with 10% FCS and 2 mM glutamine. PBMCs from a third donor is adjusted to 2×105 cells/ml. Fifty microliters of PBMCs from each donor is added to wells of a 96-well round bottom microtiter plate. Dilutions of test materials (50 μl) is added in triplicate to microtiter wells. Test samples (of the protein of interest) are added for final dilution of 1:4; rhuIL-2 (R&D Systems, Minneapolis, Minn., catalog number 202-IL) is added to a final concentration of 1 μg/ml; anti-CD4 mAb (R&D Systems, clone 34930.11, catalog number MAB379) is added to a final concentration of 10 μg/ml. Cells are cultured for 7-8 days at 37° C. in 5% CO2, and 1 μC of [3H] thymidine is added to wells for the last 16 hrs of culture. Cells are harvested and thymidine incorporation determined using a Packard TopCount. Data is expressed as the mean and standard deviation of triplicate determinations.

[1264] Samples of the protein of interest are screened in separate experiments and compared to the negative control treatment, anti-CD4 mAb, which inhibits proliferation of lymphocytes and the positive control treatment, IL-2 (either as recombinant material or supernatant), which enhances proliferation of lymphocytes.

[1265] One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.

Example 46

Assays for Protease Activity

[1266] The following assay may be used to assess protease activity of the polypeptides of the invention.

[1267] Gelatin and casein zymography are performed essentially as described (Heusen et al., Anal. Biochem., 102:196-202 (1980); Wilson et al., Journal of Urology, 149:653-658 (1993)). Samples are run on 10% polyacryamide/0.1% SDS gels containing 1% gelain orcasein, soaked in 2.5% triton at room temperature for 1 hour, and in 0.1M glycine, pH 8.3 at 37° C. 5 to 16 hours. After staining in amido black areas of proteolysis apear as clear areas agains the blue-black background. Trypsin (Sigma T8642) is used as a positive control.

[1268] Protease activity is also determined by monitoring the cleavage of n-a-benzoyl-L-arginine ethyl ester (BAEE) (Sigma B-4500. Reactions are set up in (25 mMNaPO4, 1 mM EDTA, and 1 mM BAEE), pH 7.5. Samples are added and the change in adsorbance at 260 nm is monitored on the Beckman DU-6 spectrophotometer in the time-drive mode. Trypsin is used as a positive control.

[1269] Additional assays based upon the release of acid-soluble peptides from casein or hemoglobin measured as adsorbance at 280 nm or calorimetrically using the Folin method are performed as described in Bergmeyer, et al., Methods of Enzymatic Analysis, 5 (1984). Other assays involve the solubilization of chromogenic substrates (Ward, Applied Science, 251-317 (1983)).

Example 47

Identifying Serine Protease Substrate Specificity

[1270] Methods known in the art or described herein may be used to determine the substrate specificity of the polypeptides of the present invention having serine protease activity. A preferred method of determining substrate specificity is by the use of positional scanning synthetic combinatorial libraries as described in GB 2 324 529 (incorporated herein in its entirety).

Example 48

Ligand Binding Assays

[1271] The following assay may be used to assess ligand binding activity of the polypeptides of the invention.

[1272] Ligand binding assays provide a direct method for ascertaining receptor pharmacology and are adaptable to a high throughput format. The purified ligand for a polypeptide is radiolabeled to high specific activity (50-2000 Ci/mmol) for binding studies. A determination is then made that the process of radiolabeling does not diminish the activity of the ligand towards its polypeptide. Assay conditions for buffers, ions, pH and other modulators such as nucleotides are optimized to establish a workable signal to noise ratio for both membrane and whole cell polypeptide sources. For these assays, specific polypeptide binding is defined as total associated radioactivity minus the radioactivity measured in the presence of an excess of unlabeled competing ligand. Where possible, more than one competing ligand is used to define residual nonspecific binding.

Example 49

Functional Assay in Xenopus Oocytes

[1273] Capped RNA transcripts from linearized plasmid templates encoding the polypeptides of the invention are synthesized in vitro with RNA polymerases in accordance with standard procedures. In vitro transcripts are suspended in water at a final concentration of 0.2 mg/ml. Ovarian lobes are removed from adult female toads, Stage V defolliculated oocytes are obtained, and RNA transcripts (10 ng/oocytc) are injected in a 50 nl bolus using a microinjection apparatus. Two electrode voltage clamps are used to measure the currents from individual Xenopus oocytes in response polypeptides and polypeptide agonist exposure. Recordings are made in Ca2+ free Barth's medium at room temperature. The Xenopus system can be used to screen known ligands and tissue/cell extracts for activating ligands.

Example 50

Microphysiometric Assays

[1274] Activation of a wide variety of secondary messenger systems results in extrusion of small amounts of acid from a cell. The acid formed is largely as a result of the increased metabolic activity required to fuel the intracellular signaling process. The pH changes in the media surrounding the cell are very small but are detectable by the CYTOSENSOR microphysiometer (Molecular Devices Ltd., Menlo Park, Calif). The CYTOSENSOR is thus capable of detecting the activation of polypeptide which is coupled to an energy utilizing intracellular signaling pathway.

Example 51

Extract/Cell Supernatant Screening

[1275] A large number of mammalian receptors exist for which there remains, as yet, no cognate activating ligand (agonist). Thus, active ligands for these receptors may not be included within the ligands banks as identified to date. Accordingly, the polypeptides of the invention can also be functionally screened (using calcium, cAMP, microphysiometer, oocyte electrophysiology, etc., functional screens) against tissue extracts to identify its natural ligands. Extracts that produce positive functional responses can be sequentially subfractionated until an activating ligand is isolated and identified.

Example 52

Calcium and cAMP Functional Assays

[1276] Seven transmembrane receptors which are expressed in HEK 293 cells have been shown to be coupled functionally to activation of PLC and calcium mobilization and/or cAMP stimulation or inhibition. Basal calcium levels in the HEK 293 cells in receptor-transfected or vector control cells were observed to be in the normal, 100 nM to 200 nM, range. HEK 293 cells expressing recombinant receptors are loaded with fura 2 and in a single day >150 selected ligands or tissue/cell extracts are evaluated for agonist induced calcium mobilization. Similarly, HEK 293 cells expressing recombinant receptors are evaluated for the stimulation or inhibition of cAMP production using standard cAMP quantitation assays. Agonists presenting a calcium transient or cAMP fluctuation are tested in vector control cells to determine if the response is unique to the transfected cells expressing receptor.

Example 53

ATP-Binding Assay

[1277] The following assay may be used to assess ATP-binding activity of polypeptides of the invention.

[1278] ATP-binding activity of the polypeptides of the invention may be detected using the ATP-binding assay described in U.S. Pat. No. 5,858,719, which is herein incorporated by reference in its entirety. Briefly, ATP-binding to polypeptides of the invention is measured via photoaffinity labeling with 8-azido-ATP in a competition assay. Reaction mixtures containing 1 mg/ml of the ABC transport protein of the present invention are incubated with varying concentrations of ATP, or the non-hydrolyzable ATP analog adenyl-5′-imidodiphosphate for 10 minutes at 4° C. A mixture of 8-azido-ATP (Sigma Chem. Corp., St. Louis, Mo.) plus 8-azido-ATP (32P-ATP) (5 mCi/μmol, ICN, Irvine Calif.) is added to a final concentration of 100 μM and 0.5 ml aliquots are placed in the wells of a porcelain spot plate on ice. The plate is irradiated using a short wave 254 nm UV lamp at a distance of 2.5 cm from the plate for two one-minute intervals with a one-minute cooling interval in between. The reaction is stopped by addition of dithiothreitol to a final concentration of 2 mM. The incubations are subjected to SDS-PAGE electrophoresis, dried, and autoradiographed. Protein bands corresponding to the particular polypeptides of the invention are excised, and the radioactivity quantified. A decrease in radioactivity with increasing ATP or adenly-5′-imidodiphosphate provides a measure of ATP affinity to the polypeptides.

Example 54

Small Molecule Screening

[1279] This invention is particularly useful for screening therapeutic compounds by using the polypeptides of the invention, or binding fragments thereof, in any of a variety of drug screening techniques. The polypeptide or fragment employed in such a test may be affixed to a solid support, expressed on a cell surface, free in solution, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. One may measure, for example, the formulation of complexes between the agent being tested and polypeptide of the invention.

[1280] Thus, the present invention provides methods of screening for drugs or any other agents which affect activities mediated by the polypeptides of the invention. These methods comprise contacting such an agent with a polypeptide of the invention or fragment thereof and assaying for the presence of a complex between the agent and the polypeptide or fragment thereof, by methods well known in the art. In such a competitive binding assay, the agents to screen are typically labeled. Following incubation, free agent is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of a particular agent to bind to the polypeptides of the invention.

[1281] Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to the polypeptides of the invention, and is described in great detail in European Patent Application 84/03564, published on Sep. 13, 1984, which is herein incorporated by reference in its entirety. Briefly stated, large numbers of different small molecule test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The test compounds are reacted with polypeptides of the invention and washed. Bound polypeptides are then detected by methods well known in the art. Purified polypeptides are coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies may be used to capture the peptide and immobilize it on the solid support.

[1282] This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding polypeptides of the invention specifically compete with a test compound for binding to the polypeptides or fragments thereof. In this manner, the antibodies are used to detect the presence of any peptide which shares one or more antigenic epitopes with a polypeptide of the invention.

Example 55

Phosphorylation Assay

[1283] In order to assay for phosphorylation activity of the polypeptides of the invention, a phosphorylation assay as described in U.S. Pat. No. 5,958,405 (which is herein incorporated by reference) is utilized. Briefly, phosphorylation activity may be measured by phosphorylation of a protein substrate using gamma-labeled 32P-ATP and quantitation of the incorporated radioactivity using a gamma radioisotope counter. The polypeptides of the invention are incubated with the protein substrate, 32P-ATP, and a kinase buffer. The 32P incorporated into the substrate is then separated from free 32P-ATP by electrophoresis, and the incorporated 32P is counted and compared to a negative control. Radioactivity counts above the negative control are indicative of phosphorylation activity of the polypeptides of the invention.

Example 56

Detection of Phosphorylation Activity (Activation) of the Polypeptides of the Invention in the Presence of Polypeptide Ligands

[1284] Methods known in the art or described herein may be used to determine the phosphorylation activity of the polypeptides of the invention. A preferred method of determining phosphorylation activity is by the use of the tyrosine phosphorylation assay as described in U.S. Pat. No. 5,817,471 (incorporated herein by reference).

Example 57

Identification of Signal Transduction Proteins that Interact with Polypeptides of the Present Invention

[1285] The purified polypeptides of the invention are research tools for the identification, characterization and purification of additional signal transduction pathway proteins or receptor proteins. Briefly, labeled polypeptides of the invention are useful as reagents for the purification of molecules with which it interacts. In one embodiment of affinity purification, polypeptides of the invention are covalently coupled to a chromatography column. Cell-free extract derived from putative target cells, such as carcinoma tissues, is passed over the column, and molecules with appropriate affinity bind to the polypeptides of the invention. The protein complex is recovered from the column, dissociated, and the recovered molecule subjected to N-terminal protein sequencing. This amino acid sequence is then used to identify the captured molecule or to design degenerate oligonucleotide probes for cloning the relevant gene from an appropriate cDNA library.

Example 58

IL-6 Bioassay

[1286] To test the proliferative effects of the polypeptides of the invention, the IL-6 Bioassay as described by Marz et al. is utilized (Proc. Natl. Acad. Sci., U.S.A., 95:3251-56 (1998), which is herein incorporated by reference). Briefly, IL-6 dependent B9 murine cells are washed three times in IL-6 free medium and plated at a concentration of 5,000 cells per well in 50 μl, and 50 μl of the IL-6-like polypeptide is added. After 68 hrs. at 37° C., the number of viable cells is measured by adding the tetrazolium salt thiazolyl blue (MTT) and incubating for a further 4 hrs. at 37° C. B9 cells are lysed by SDS and optical density is measured at 570 nm. Controls containing IL-6 positive) and no cytokine (negative) are utilized. Enhanced proliferation in the test sample(s) relative to the negative control is indicative of proliferative effects mediated by polypeptides of the invention.

Example 59

Support of Chicken Embryo Neuron Survival

[1287] To test whether sympathetic neuronal cell viability is supported by polypeptides of the invention, the chicken embryo neuronal survival assay of Senaldi et al is utilized (Proc. Natl. Acad. Sci., U.S.A., 96:11458-63 (1998), which is herein incorporated by reference). Briefly, motor and sympathetic neurons are isolated from chicken embryos, resuspended in L15 medium (with 10% FCS, glucose, sodium selenite, progesterone, conalbumin, putrescine, and insulin; Life Technologies, Rockville, Md.) and Dulbecco's modified Eagles medium [with 10% FCS, glutamine, penicillin, and 25 mM Hepes buffer (pH 7.2); Life Technologies, Rockville, Md.], respectively, and incubated at 37° C. in 5% CO2 in the presence of different concentrations of the purified IL-6-like polypeptide, as well as a negative control lacking any cytokine. After 3 days, neuron survival is determined by evaluation of cellular morphology, and through the use of the colorimetric assay of Mosmann (Mosmann, T., J. Immunol. Methods, 65:55-63 (1983)). Enhanced neuronal cell viability as compared to the controls lacking cytokine is indicative of the ability of the inventive purified IL-6-like polypeptide(s) to enhance the survival of neuronal cells.

Example 60

Assay for Phosphatase Activity

[1288] The following assay may be used to assess serine/threonine phosphatase (PTPase) activity of the polypeptides of the invention.

[1289] In order to assay for serine/threonine phosphatase (PTPase) activity, assays can be utilized which are widely known to those skilled in the art. For example, the serine/threonine phosphatase (PSPase) activity is measured using a PSPase assay kit from New England Biolabs, Inc. Myelin basic protein (MyBP), a substrate for PSPase, is phosphorylated on serine and threonine residues with cAMP-dependent Protein Kinase in the presence of [32P]ATP. Protein serine/threonine phosphatase activity is then determined by measuring the release of inorganic phosphate from 32P-labeled MyBP.

Example 61

Interaction of Serine/Threonine Phosphatases with other Proteins

[1290] The polypeptides of the invention with serine/threonine phosphatase activity as determined in Example 60 are research tools for the identification, characterization and purification of additional interacting proteins or receptor proteins, or other signal transduction pathway proteins. Briefly, labeled polypeptide(s) of the invention is useful as a reagent for the purification of molecules with which it interacts. In one embodiment of affinity purification, polypeptide of the invention is covalently coupled to a chromatography column. Cell-free extract derived from putative target cells, such as neural or liver cells, is passed over the column, and molecules with appropriate affinity bind to the polypeptides of the invention. The polypeptides of the invention-complex is recovered from the column, dissociated, and the recovered molecule subjected to N-terminal protein sequencing. This amino acid sequence is then used to identify the captured molecule or to design degenerate oligonucleotide probes for cloning the relevant gene from an appropriate cDNA library.

Example 62

Assaying for Heparanase Activity

[1291] In order to assay for heparanase activity of the polypeptides of the invention, the heparanase assay described by Vlodavsky et al is utilized (Vlodavsky, I., et al., Nat. Med., 5:793-802 (1999)). Briefly, cell lysates, conditioned media or intact cells (1×106 cells per 35-mm dish) are incubated for 18 hrs at 37° C., pH 6.2-6.6, with 35S-labeled ECM or soluble ECM derived peak I proteoglycans. The incubation medium is centrifuged and the supernatant is analyzed by gel filtration on a Sepharose CL-6B column (0.9×30 cm). Fractions are eluted with PBS and their radioactivity is measured. Degradation fragments of heparan sulfate side chains are eluted from Sepharose 6B at 0.5<Kav <0.8 (peak II). Each experiment is done at least three times. Degradation fragments corresponding to “peak II,” as described by Vlodavsky et al., is indicative of the activity of the polypeptides of the invention in cleaving heparan sulfate.

Example 63

Immobilization of Biomolecules

[1292] This example provides a method for the stabilization of polypeptides of the invention in non-host cell lipid bilayer constucts (see, e.g., Bieri et al., Nature Biotech 17:1105-1108 (1999), hereby incorporated by reference in its entirety herein) which can be adapted for the study of polypeptides of the invention in the various functional assays described above. Briefly, carbohydrate-specific chemistry for biotinylation is used to confine a biotin tag to the extracellular domain of the polypeptides of the invention, thus allowing uniform orientation upon immobilization. A 50 uM solution of polypeptides of the invention in washed membranes is incubated with 20 mM NaIO4 and 1.5 mg/ml (4 mM) BACH or 2 mg/ml (7.5 mM) biotin-hydrazide for 1 hr at room temperature (reaction volume, 150 ul). Then the sample is dialyzed (Pierce Slidealizer Cassett, 10 kDa cutoff; Pierce Chemical Co., Rockford Ill.) at 4C first for 5 h, exchanging the buffer after each hour, and finally for 12 h against 500 ml buffer R (0.15 M NaCl, 1 mM MgCl2, 10 mM sodium phosphate, pH 7). Just before addition into a cuvette, the sample is diluted 1:5 in buffer ROG50 (Buffer R supplemented with 50 mM octylglucoside).

Example 64

TAQMAN

[1293] Quantitative PCR (QPCR). Total RNA from cells in culture are extracted by Trizol separation as recommended by the supplier (LifeTechnologies). (Total RNA is treated with DNase I (Life Technologies) to remove any contaminating genomic DNA before reverse transcription.) Total RNA (50 ng) is used in a one-step, 50 ul, RT-QPCR, consisting of Taqman Buffer A (Perkin-Elmer; 50 mM KCl/10 mM Tris, pH 8.3), 5.5 mM MgCl2, 240 μM each dNTP, 0.4 units RNase inhibitor(Promega), 8%glycerol, 0.012% Tween-20, 0.05% gelatin, 0.3 uM primers, O. 1 uM probe, 0.025units Amplitaq Gold (Perkin-Elmer) and 2.5 units Superscript II reverse transcriptase (Life Technologies). As a control for genomic contamination, parallel reactions are setup without reverse transcriptase. The relative abundance of (unknown) and 18S RNAs are assessed by using the Applied Biosystems Prism 7700 Sequence Detection System (Livak, K. J., Flood, S. J., Marmaro, J., Giusti, W. & Deetz, K. (1995) PCR Methods Appl. 4, 357-362). Reactions are carried out at 48° C. for 30 min, 95° C. for 10 min, followed by 40 cycles of 95° C. for 15s, 60° C. for 1 min. Reactions are performed in triplicate.

[1294] Primers (f & r) and FRET probes sets are designed using Primer Express Software (Perkin-Elmer). Probes are labeled at the 5′-end with the reporter dye 6-FAM and on the 3′-end with the quencher dye TAMRA (Biosource International, Camarillo, Calif. or Perkin-Elmer).

Example 65

Assays for Metalloproteinase Activity

[1295] Metalloproteinases (EC 3.4.24.-) are peptide hydrolases which use metal ions, such as Zn2+, as the catalytic mechanism. Metalloproteinase activity of polypeptides of the present invention can be assayed according to the following methods.

[1296] Proteolysis of alpha-2-macroglobulin

[1297] To confirm protease activity, purified polypeptides of the invention are mixed with the substrate alpha-2-macroglobulin (0.2 unit/ml; Boehringer Mannheim, Germany) in 1× assay buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl2, 25 μM ZnCl2 and 0.05% Brij-35) and incubated at 37° C. for 1-5 days. Trypsin is used as positive control. Negative controls contain only alpha-2-macroglobulin in assay buffer. The samples are collected and boiled in SDS-PAGE sample buffer containing 5% 2-mercaptoethanol for 5-min, then loaded onto 8% SDS-polyacrylamide gel. After electrophoresis the proteins are visualized by silver staining. Proteolysis is evident by the appearance of lower molecular weight bands as compared to the negative control.

[1298] Inhibition of alpha-2-macroglobulin Proteolysis by Inhibitors of Metalloproteinases

[1299] Known metalloproteinase inhibitors (metal chelators (EDTA, EGTA, AND HgCl2), peptide metalloproteinase inhibitors (TIMP-1 and TIMP-2), and commercial small molecule MMP inhibitors) are used to characterize the proteolytic activity of polypeptides of the invention. The three synthetic MMP inhibitors used are: MMP inhibitor I, [IC50=1.0 μM against MMP-1 and MMP-8; IC50=30 μM against MMP-9; IC50=150 μM against MMP-3]; MMP-3 (stromelysin-1) inhibitor I [IC50=5 μM against MMP-3], and MMP-3 inhibitor II [Ki=130 nM against MMP-3]; inhibitors available through Calbiochem, catalog # 444250, 444218, and 444225, respectively). Briefly, different concentrations of the small molecule MMP inhibitors are mixed with purified polypeptides of the invention (50 μg/ml) in 22.9 μl of 1×HEPES buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl2, 25 μM ZnCl2 and 0.05%Brij-35) and incubated at room temperature (24° C.) for 2-hr, then 7.1 μl of substrate alpha-2-macroglobulin (0.2 unit/ml) is added and incubated at 37° C. for 20-hr. The reactions are stopped by adding 4× sample buffer and boiled immediately for 5 minutes. After SDS-PAGE, the protein bands are visualized by silver stain.

[1300] Synthetic Fluorogenic Peptide Substrates Cleavage Assay

[1301] The substrate specificity for polypeptides of the invention with demonstrated metalloproteinase activity can be determined using synthetic fluorogenic peptide substrates (purchased from BACHEM Bioscience Inc). Test substrates include, M-1985, M-2225, M-2105, M-2110, and M-2255. The first four are MMP substrates and the last one is a substrate of tumor necrosis factor-α (TNF-α) converting enzyme (TACE). All the substrates are prepared in 1:1 dimethyl sulfoxide (DMSO) and water. The stock solutions are 50-500 μM. Fluorescent assays are performed by using a Perkin Elmer LS 50B luminescence spectrometer equipped with a constant temperature water bath. The excitation λ is 328 nm and the emission λ is 393 nm. Briefly, the assay is carried out by incubating 176 μl 1× HEPES buffer (0.2 M NaCl, 10 mM CaCl2, 0.05% Brij-35 and 50 mM HEPES, pH 7.5) with 4 μM of substrate solution (50 μM) at 25<C for 15 minutes, and then adding 20 μl of a purified polypeptide of the invention into the assay cuvett. The final concentration of substrate is 1 μM. Initial hydrolysis rates are monitored for 30-min.

Example 66

Characterization of the cDNA Contained in a Deposited Plasmid

[1302] The size of the cDNA insert contained in a deposited plasmid may be routinely determined using techniques known in the art, such as PCR amplification using synthetic primers hybridizable to the 3′ and 5′ ends of the cDNA sequence. For example, two primers of 17-30 nucleotides derived from each end of the cDNA (i.e., hybridizable to the absolute 5′ nucleotide or the 3′ nucleotide end of the sequence of SEQ ID NO:X, respectively) are synthesized and used to amplify the cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 ul of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM MgCl2, 0.01% (w/v) gelatin, 20 uM each of DATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturation at 94 degree C. for 1 min; annealing at 55 degree C. for 1 min; elongation at 72 degree C. for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product.

[1303] Use of the above methodologies and/or other methodologies known in the art generates fragments from the clone corresponding to the approximate fragments described in Table 8, below. Accordingly, Table 8 provides a physical characterization of certain clones encompassed by the invention. The first column provides the unique clone identifier, “Clone ID NO:Z”, for cDNA clones of the invention, as described in Table 1A. The second column provides the approximate size of the cDNA insert contained in the corresponding cDNA clone.

TABLE 8
         cDNA
Clone ID Insert
NO: Z    Size:
HTOBE75  1800
HCFAT05  2200
HFIAH37  1700
HSVAW49  1000
HCUEV29  700
HLQDT35  1300
HWLHK29  1000
HDPRU43  3000
HOHCE47  2200
HSDII69  1500
HHASQ32  900
HTNGF69  800
HMSJL96  1900
HTTIE47  900
HSLCF96  1600
HSFAM09  300
HNFHK77  1300
HSDIW73  1600
HFVGD23  1900
HWHHB69  2900
HFXLC69  1700
HTEFO45  900
HOHBN82  1400
HWHGF52  2200
HFPBW22  1000
HE8UX76  1800
HTEMV66  800
HOUHL51  700
HFRBN81  3000
HACCH94  1400
HE8TI39  2800
H7TBC95  700
HAPPX52  2400
HBGSJ13  700
HTLGP15  900
HCFCF47  1900
HDQHB19  1600
HAGDN53  1600
HUFDB74  1600
HOUGD29  2300
HWWDN34  1300
HDMAV01  1800
HMCGL45  1100
HELEF11  1400
HSOBC04  1200
HNHNP81  1100
HFIDL68  1100
HRDBH58  2000
HCE5J51  2800
HHEFQ42  1200
HE8QH09  1500
HHFOC79  2100
HTLIY52  1300
HWAGU62  2200
HPMFI38  1000
HOFMS43  1100
HTEPE35  700
HAJAV28  1600
HMTBB17  400
HKGDE58  1300
HCHMW40  900
HE8QZ34  1900
HBXDMO7  2200
HKADO36  1300
HFXKG51  1100
HFPHR82  1600
HMVAM09  1800
HSLJD02  1000
HBGMG39  300
HSXBV89  2200
HDPLT62  2700
HSDJI44  2100
HFXDP53  1600
HLDBC63  900
HCFMT57  2200
HTEON29  600
HE9TK49  1400
HCEEN06  800
HSPBQ12  1200
HCMSL08  1800
HOUDH19  400
HDPFF24  1800
HWLFH94  1200
HWMBM13  900
HBIBQ89  2600
HWBEG18  500
HFCBB56  2200
HLHCR16  3800
HE6GF02  600
HOUFT36  1900
HUJAD24  1700
HCOMM05  1700
HSLJE54  2000
HWNCY05  1000
HHFJH79  2300
HCE5I78  3200
HWHGW72  1700
HNSAA28  1600
HLWAR77  1300
HTTJW49  1500
HUFCN91  2500
HCEMU86  2200
HRDAF83  1300
HUVGZ88  2100
HOEET48  1500
HEOPL36  2100
HMCFS02  1500
HDPSR15  1700

[1304] It will be clear that the invention may be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations of the present invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.

[1305] The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, laboratory manuals, books, or other disclosures) in the Background of the Invention, Detailed Description, and Examples is hereby incorporated herein by reference. In addition, the CD-R copy of the sequence listing submitted herewith and the corresponding computer readable form are both incorporated herein by reference in their entireties. The specification and sequence listing of each of the following U.S. applications are herein incorporated by reference in their entirety: Application No. 60/179,065, filed on Jan. 31, 2000; Application No. 60/180,628, filed on Feb. 4, 2000; Application No. 60/214,886, filed on Jun. 28, 2000; Application No. 60/217,487, filed on Jul. 11, 2000; Application No. 60/225,758, filed on Aug. 14, 2000; Application No. 60/220,963, filed on Jul. 26, 2000; Application No. 60/217,496, filed on Jul. 11, 2000; Application No. 60/225,447, filed on Aug. 14, 2000; Application No. 60/218,290, filed on Jul. 14, 2000; Application No. 60/225,757, filed on Aug. 14, 2000; Application No. 60/226,868, filed on Aug. 22, 2000; Application No. 60/216,647, filed on Jul. 7, 2000; Application No. 60/225,267, filed on Aug. 14, 2000; Application No. 60/216,880, filed on Jul. 7, 2000; Application No. 60/225,270, filed on Aug. 14, 2000; Application No. 60/251,869, filed on Dec. 8, 2000; Application No. 60/235,834, filed on Sep. 27, 2000; Application No. 60/234,274, filed on Sep. 21, 2000; Application No. 60/234,223, filed on Sep. 21, 2000; Application No. 60/228,924, filed on Aug. 30, 2000; Application No. 60/224,518, filed on Aug. 14, 2000; Application No. 60/236,369, filed on Sep. 29, 2000; Application No. 60/224,519, filed on Aug. 14, 2000; Application No. 60/220,964, filed on Jul. 26, 2000; Application No. 60/241,809, filed on Oct. 20, 2000; Application No. 60/249,299, filed on Nov. 17, 2000; Application No. 60/236,327, filed on Sep. 29, 2000; Application No. 60/241,785, filed on Oct. 20, 2000; Application No. 60/244,617, filed on Nov. 1, 2000; Application No. 60/225,268, filed on Aug. 14, 2000; Application No. 60/236,368, filed on Sep. 29, 2000; Application No. 60/251,856, filed on Dec. 8, 2000; Application No. 60/251,868, filed on Dec. 8, 2000; Application No. 60/229,344, filed on Sep. 1, 2000; Application No. 60/234,997, filed on Sep. 25, 2000; Application No. 60/229,343, filed on Sep. 1, 2000; Application No. 60/229,345, filed on Sep. 1, 2000; Application No. 60/229,287, filed on Sep. 1, 2000; Application No. 60/229,513, filed on Sep. 5, 2000; Application No. 60/231,413, filed on Sep. 8, 2000; Application No. 60/229,509, filed on Sep. 5, 2000; Application No. 60/236,367, filed on Sep. 29, 2000; Application No. 60/237,039, filed on Oct. 2, 2000; Application No. 60/237,038, filed on Oct. 2, 2000; Application No. 60/236,370, filed on Sep. 29, 2000; Application No. 60/236,802, filed on Oct. 2, 2000; Application No. 60/237,037, filed on Oct. 2, 2000; Application No. 60/237,040, filed on Oct. 2, 2000; Application No. 60/240,960, filed on Oct. 20, 2000; Application No. 60/239,935, filed on Oct. 13, 2000; Application No. 60/239,937, filed on Oct. 13, 2000; Application No. 60/241,787, filed on Oct. 20, 2000; Application No. 60/246,474, filed on Nov. 8, 2000; Application No. 60/246,532, filed on Nov. 8, 2000; Application No. 60/249,216, filed on Nov. 17, 2000; Application No. 60/249,210, filed on Nov. 17, 2000; Application No. 60/226,681, filed on Aug. 22, 2000; Application No. 60/225,759, filed on Aug. 14, 2000; Application No. 60/225,213, filed on Aug. 14, 2000; Application No. 60/227,182, filed on Aug. 22, 2000; Application No. 60/225,214, filed on Aug. 14, 2000; Application No. 60/235,836, filed on Sep. 27, 2000; Application No. 60/230,438, filed on Sep. 6, 2000; Application No. 60/215,135, filed on Jun. 30, 2000; Application No. 60/225,266, filed on Aug. 14, 2000; Application No. 60/249,218, filed on Nov. 17, 2000; Application No. 60/249,208, filed on Nov. 17, 2000; Application No. 60/249,213, filed on Nov. 17, 2000; Application No. 60/249,212, filed on Nov. 17, 2000; Application No. 60/249,207, filed on Nov. 17, 2000; Application No. 60/249,245, filed on Nov. 17, 2000; Application No. 60/249,244, filed on Nov. 17, 2000; Application No. 60/249,217, filed on Nov. 17, 2000; Application No. 60/249,211, filed on Nov. 17, 2000; Application No. 60/249,215, filed on Nov. 17, 2000; Application No. 60/249,264, filed on Nov. 17, 2000; Application No. 60/249,214, filed on Nov. 17, 2000; Application No. 60/249,297, filed on Nov. 17, 2000; Application No. 60/232,400, filed on Sep. 14, 2000; Application No. 60/231,242, filed on Sep. 8, 2000; Application No. 60/232,081, filed on Sep. 8, 2000; Application No. 60/232,080, filed on Sep. 8, 2000; Application No. 60/231,414, filed on Sep. 8, 2000; Application No. 60/231,244, filed on Sep. 8, 2000; Application No. 60/233,064, filed on Sep. 14, 2000; Application No. 60/233,063, filed on Sep. 14, 2000; Application No. 60/232,397, filed on Sep. 14, 2000; Application No. 60/232,399, filed on Sep. 14, 2000; Application No. 60/232,401, filed on Sep. 14, 2000; Application No. 60/241,808, filed on Oct. 20, 2000; Application No. 60/241,826, filed on Oct. 20, 2000; Application No. 60/241,786, filed on Oct. 20, 2000; Application No. 60/241,221, filed on Oct. 20, 2000; Application No. 60/246,475, filed on Nov. 8, 2000; Application No. 60/231,243, filed on Sep. 8, 2000; Application No. 60/233,065, filed on Sep. 14, 2000; Application No. 60/232,398, filed on Sep. 14, 2000; Application No. 60/234,998, filed on Sep. 25, 2000; Application No. 60/246,477, filed on Nov. 8, 2000; Application No. 60/246,528, filed on Nov. 8, 2000; Application No. 60/246,525, filed on Nov. 8, 2000; Application No. 60/246,476, filed on Nov. 8, 2000; Application No. 60/246,526, filed on Nov. 8, 2000; Application No. PT172, filed on Nov. 17, 2000; Application No. 60/246,527, filed on Nov. 8, 2000; Application No. 60/246,523, filed on Nov. 8, 2000; Application No. 60/246,524, filed on Nov. 8, 2000; Application No. 60/246,478, filed on Nov. 8, 2000; Application No. 60/246,609, filed on Nov. 8, 2000; Application No. 60/246,613, filed on Nov. 8, 2000; Application No. 60/249,300, filed on Nov. 17, 2000; Application No. 60/249,265, filed on Nov. 17, 2000; Application No. 60/246,610, filed on Nov. 8, 2000; Application No. 60/246,611, filed on Nov. 8, 2000; Application No. 60/230,437, filed on Sep. 6, 2000; Application No. 60/251,990, filed on Dec. 8, 2000; Application No. 60/251,988, filed on Dec. 5, 2000; Application No. 60/251,030, filed on Dec. 5, 2000; Application No. 60/251,479, filed on Dec. 6, 2000; Application No. PJ005, filed on Dec. 5, 2000; Application No. PJ006, filed on Dec. 6, 2000; Application No. 60/251,989, filed on Dec. 8, 2000; Application No. 60/250,391, filed on Dec. 1, 2000; and Application No. 60/254,097, filed on Dec. 11, 2000.

[1306] Moreover, the microfiche copy and the corresponding computer readable form of the Sequence Listing of U.S. Application Serial No. 60/179,065, and the hard copy of and the corresponding computer readable form of the Sequence Listing of U.S. Application Serial No. 60/180,628 are also incorporated herein by reference in their entireties.

Claims

1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of: (a) a polynucleotide fragment of SEQ ID NO:X or a polynucleotide fragment of the cDNA sequence contained in Clone ID NO:Z, which is hybridizable to SEQ ID NO:X; (b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X; (c) a polynucleotide encoding a polypeptide fragment of a polypeptide encoded by SEQ ID NO:X or a polypeptide fragment encoded by the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X; (d) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y or a polypeptide domain encoded by the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X; (e) a polynucleotide encoding a polypeptide epitope of SEQ ID NO:Y or a polypeptide epitope encoded by the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X; (f) a polynucleotide encoding a polypeptide of SEQ ID NO:Y or the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X, having biological activity; (g) a polynucleotide which is a variant of SEQ ID NO:X; (h) a polynucleotide which is an allelic variant of SEQ ID NO:X; (i) a polynucleotide which encodes a species homologue of the SEQ ID NO:Y; (j) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(i), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.

2. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a protein.

3. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID NO:Y or the polypeptide encoded by the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X.

4. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID NO:X or the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X.

5. The isolated nucleic acid molecule of claim 2, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

6. The isolated nucleic acid molecule of claim 3, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

7. A recombinant vector comprising the isolated nucleic acid molecule of claim 1.

8. A method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim 1.

9. A recombinant host cell produced by the method of claim 8.

10. The recombinant host cell of claim 9 comprising vector sequences.

11. An isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence selected from the group consisting of: (a) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z; (b) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z, having biological activity; (c) a polypeptide domain of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z; (d) a polypeptide epitope of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z; (e) a full length protein of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z; (f) a variant of SEQ ID NO:Y; (g) an allelic variant of SEQ ID NO:Y; or (h) a species homologue of the SEQ ID NO:Y.

12. The isolated polypeptide of claim 11, wherein the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.

13. An isolated antibody that binds specifically to the isolated polypeptide of claim 11.

14. A recombinant host cell that expresses the isolated polypeptide of claim 11.

15. A method of making an isolated polypeptide comprising: (a) culturing the recombinant host cell of claim 14 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.

16. The polypeptide produced by claim 15.

17. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polynucleotide of claim 1.

18. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising: (a) determining the presence or absence of a mutation in the polynucleotide of claim 1; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.

19. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising: (a) determining the presence or amount of expression of the polypeptide of claim 11 in a biological sample; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of the polypeptide.

20. A method for identifying a binding partner to the polypeptide of claim 11 comprising: (a) contacting the polypeptide of claim 11 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.

21. The gene corresponding to the cDNA sequence of SEQ ID NO:Y.

22. A method of identifying an activity in a biological assay, wherein the method comprises: (a) expressing SEQ ID NO:X in a cell; (b) isolating the supernatant; (c) detecting an activity in a biological assay; and identifying the protein in the supernatant having the activity.

23. The product produced by the method of claim 20.

24. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim 11.