Secretory molecules

TECHNICAL FIELD

[0001] The present invention relates to secretory molecules and to the use of these sequences in the diagnosis, study, prevention, and treatment of diseases associated with, as well as effects of exogenous compounds on, cell signaling and the expression of secretory molecules.

BACKGROUND OF THE INVENTION

[0002] Protein transport and secretion are essential for cellular function. Protein transport is mediated by a signal peptide located at the amino terminus of the protein to be transported or secreted. The signal peptide is comprised of about ten to twenty hydrophobic amino acids which target the nascent protein from the ribosome to a particular membrane bound compartment such as the endoplasmic reticulum (ER). Proteins targeted to the ER may either proceed through the secretory pathway or remain in any of the secretory organelles such as the ER, Golgi apparatus, or lysosomes. Proteins that transit through the secretory pathway are either secreted into the extracellular space or retained in the plasma membrane. Proteins that are retained in the plasma membrane contain one or more transmembrane domains, each comprised of about 20 hydrophobic amino acid residues. Proteins that are secreted from the cell are generally synthesized as inactive precursors that are activated by post-translational processing events during transit through the secretory pathway. Such events include glycosylation, proteolysis, and removal of the signal peptide by a signal peptidase. Other events that may occur during protein transport include chaperone-dependent unfolding and folding of the nascent protein and interaction of the protein with a receptor or pore complex. Examples of secretory proteins with amino terminal signal peptides are discussed below and include proteins with important roles in cell-to-cell signaling. Such proteins include transmembrane receptors and cell surface markers, extracellular matrix molecules, cytokines, hormones, growth and differentiation factors, neuropeptides, vasomediators, ion channels, transporters/pumps, and proteases. (Reviewed in Alberts, B. et al. (1994) Molecular Biology of The Cell, Garland Publishing, New York N.Y., pp. 557-560, 582-592.)

[0003] G-protein coupled receptors (GPCRs) comprise a superfamily of integral membrane proteins which transduce extracellular signals. Not all GPCRs contain N-terminal signal peptides. GPCRs include receptors for biogenic amines such as dopamine, epinephrine, histamine, glutamate (metabotropic-type), acetylcholine (muscarinic-type), and serotonin; for lipid mediators of inflammation such as prostaglandins, platelet activating factor, and leukotrienes; for peptide hormones such as calcitonin, C5a anaphylatoxin, follicle stimulating hormone, gonadotropin releasing hormone, neurokinin, oxytocin, and thrombin; and for sensory signal mediators such as retinal photopigments and olfactory stimulatory molecules. The structure of these highly conserved receptors consists of seven hydrophobic transmembrane regions, cysteine disulfide bridges between the second and third extracellular loops, an extracellular N-terminus, and a cytoplasmic C-terminus. The N-terminus interacts with ligands, the disulfide bridges interact with agonists and antagonists, and the large third intracellular loop interacts with G proteins to activate second messengers such as cyclic AMP, phospholipase C, inositol triphosphate, or ion channels. (Reviewed in Watson, S. and Arkinstall, S. (1994) The G-protein Linked Receptor Facts Book, Academic Press, San Diego Calif., pp. 2-6; and Bolander, F. F. (1994) Molecular Endocrinology, Academic Press, San Diego Calif., pp. 162-176.)

[0004] Other types of receptors include cell surface antigens identified on leukocytic cells of the immune system. These antigens have been identified using systematic, monoclonal antibody (mAb)-based “shot gun” techniques. These techniques have resulted in the production of hundreds of mAbs directed against unknown cell surface leukocytic antigens. These antigens have been grouped into “clusters of differentiation” based on common immunocytochemical localization patterns in various differentiated and undifferentiated leukocytic cell types. Antigens in a given cluster are presumed to identify a single cell surface protein and are assigned a “cluster of differentiation” or “CD” designation. Some of the genes encoding proteins identified by CD antigens have been cloned and verified by standard molecular biology techniques. CD antigens have been characterized as both transmembrane proteins and cell surface proteins anchored to the plasma membrane via covalent attachment to fatty acid-containing glycolipids such as glycosylphosphatidylinositol (GPI). (Reviewed in Barclay, A. N. et al. (1995) The Leucocyte Antigen Facts Book, Academic Press, San Diego Calif., pp. 20 17-20.)

[0005] Matrix proteins (MPs) are transmembrane and extracellular proteins which function in formation, growth, remodeling, and maintenance of tissues and as important mediators and regulators of the inflammatory response. The expression and balance of MPs may be perturbed by biochemical changes that result from congenital, epigenetic, or infectious diseases. In addition, MPs affect leukocyte migration, proliferation, differentiation, and activation in the immune response. MPs are frequently characterized by the presence of one or more domains which may include collagen-like domains, EGF-like domains, immunoglobulin-like domains, and fibronectin-like domains. In addition, MPs may be heavily glycosylated and may contain an Arginine-Glycine-Aspartate (RGD) tripeptide motif which may play a role in adhesive interactions. MPs include extracellular proteins such as fibronectin, collagen, galectin, vitronectin and its proteolytic derivative somatomedin B; and cell adhesion receptors such as cell adhesion molecules (CAMs), cadherins, and integrins. (Reviewed in Ayad, S. et al. (1994) The Extracellular Matrix Facts Book, Academic Press, San Diego Calif., pp. 2-16;

[0006] Ruoslahti, E. (1997) Kidney Int. 51:1413-1417; Sjaastad, M. D. and Nelson, W. J. (1997) BioEssays 19:47-55.)

[0007] Cytokines are secreted by hematopoietic cells in response to injury or infection. Interleukins, neurotrophins, growth factors, interferons, and chemokines all define cytokine families that work in conjunction with cellular receptors to regulate cell proliferation and differentiation. In addition, cytokines effect activities such as leukocyte migration and function, hematopoietic cell proliferation, temperature regulation, acute response to infection, tissue remodeling, and apoptosis.

[0008] Chemokines, in particular, are small chemoattractant cytokines involved in inflammation, leukocyte proliferation and migration, angiogenesis and angiostasis, regulation of hematopoiesis, HIV infectivity, and stimulation of cytokine secretion. Chemokines generally contain 70-100 amino acids and are subdivided into four subfamilies based on the presence of conserved cysteine-based motifs. (Callard, R. and Gearing, A. (1994) The Cytokine Facts Book, Academic Press, New York N.Y., pp. 181-190, 210-213, 223-227.)

[0009] Growth and differentiation factors are secreted proteins which function in intercellular communication. Some factors require oligomerization or association with MPs for activity. Complex interactions among these factors and their receptors trigger intracellular signal transduction pathways that stimulate or inhibit cell division, cell differentiation, cell signaling, and cell motility. Most growth and differentiation factors act on cells in their local environment (paracrine signaling). There are three broad classes of growth and differentiation factors. The first class includes the large polypeptide growth factors such as epidermal growth factor, fibroblast growth factor, transforming growth factor, insulin-like growth factor, and platelet-derived growth factor. The second class includes the hematopoietic growth factors such as the colony stimulating factors (CSFs). Hematopoietic growth factors stimulate the proliferation and differentiation of blood cells such as B-lymphocytes, T-lymphocytes, erythrocytes, platelets, eosinophils, basophils, neutrophils, macrophages, and their stem cell precursors. The third class includes small peptide factors such as bombesin, vasopressin, oxytocin, endothelin, transferrin, angiotensin II, vasoactive intestinal peptide, and bradykinin which function as hormones to regulate cellular functions other than proliferation.

[0010] Growth and differentiation factors play critical roles in neoplastic transformation of cells in vitro and in tumor progression in vivo. Inappropriate expression of growth factors by tumor cells may contribute to vascularization and metastasis of tumors. During hematopoiesis, growth factor misregulation can result in anemias, leukemias, and lymphomas. Certain growth factors such as interferon are cytotoxic to tumor cells both in vivo and in vitro. Moreover, some growth factors and growth factor receptors are related both structurally and functionally to oncoproteins. In addition, growth factors affect transcriptional regulation of both proto-oncogenes and oncosuppressor genes. (Reviewed in Pimentel, E. (1994) Handbook of Growth Factors, CRC Press, Ann Arbor Mich., pp. 1-9.)

[0011] Proteolytic enzymes or proteases either activate or deactivate proteins by hydrolyzing peptide bonds. Proteases are found in the cytosol, in membrane-bound compartments, and in the extracellular space. The major families are the zinc, serine, cysteine, thiol, and carboxyl proteases.

[0012] Ion channels, ion pumps, and transport proteins mediate the transport of molecules across cellular membranes. Transport can occur by a passive, concentration-dependent mechanism or can be linked to an energy source such as ATP hydrolysis. Symporters and antiporters transport ions and small molecules such as amino acids, glucose, and drugs. Symporters transport molecules and ions unidirectionally, and antiporters transport molecules and ions bidirectionally. Transporter superfamilies include facilitative transporters and active ATP-binding cassette transporters which are involved in multiple-drug resistance and the targeting of antigenic peptides to MHC Class I molecules. These transporters bind to a specific ion or other molecule and undergo a conformational change in order to transfer the ion or molecule across the membrane. (Reviewed in Alberts, B. et al. (1994) Molecular Biology of The Cell, Garland Publishing, New York N.Y., pp. 523-546.)

[0013] Ion channels are formed by transmembrane proteins which create a lined passageway across the membrane through which water and ions, such as Na+, K+, Ca2+, and Cl−, enter and exit the cell. For example, chloride channels are involved in the regulation of the membrane electric potential as well as absorption and secretion of ions across the membrane. Chloride channels also regulate the internal pH of membrane-bound organelles.

[0014] Ion pumps are ATPases which actively maintain membrane gradients. Ion pumps are classified as P, V, or F according to their structure and function. All have one or more binding sites for ATP in their cytosolic domains. The P-class ion pumps include Ca2+ATPase and Na+/K+ATPase and function in transporting H+, Na+, K+, and Ca2+ ions. P-class pumps consist of two α and two β transmembrane subunits. The V- and F-class ion pumps have similar structures but transport only H+. F class H+ pumps mediate transport across the membranes of mitochondria and chloroplasts, while V-class H+ pumps regulate acidity inside lysosomes, endosomes, and plant vacuoles.

[0015] A family of structurally related intrinsic membrane proteins known as facilitative glucose transporters catalyze the movement of glucose and other selected sugars across the plasma membrane. The proteins in this family contain a highly conserved, large transmembrane domain comprised of 12 α-helices, and several weakly conserved, cytoplasmic and exoplasmic domains. (Pessin, J. E. and Bell, G. I. (1992) Annu. Rev. Physiol. 54:911-930.)

[0016] Amino acid transport is mediated by Na+ dependent amino acid transporters. These transporters are involved in gastrointestinal and renal uptake of dietary and cellular amino acids and in neuronal reuptake of neurotransmitters. Transport of cationic amino acids is mediated by the system y+ family and the cationic amino acid transporter (CAT) family. Members of the CAT family share a high degree of sequence homology, and each contains 12-14 putative transmembrane domains. (Ito, K. and Groudine, M. (1997) J. Biol. Chem. 272:26780-26786.)

[0017] Hormones are secreted molecules that travel through the circulation and bind to specific receptors on the surface of, or within, target cells. Although they have diverse biochemical compositions and mechanisms of action, hormones can be grouped into two categories. One category includes small lipophilic hormones that diffuse through the plasma membrane of target cells, bind to cytosolic or nuclear receptors, and form a complex that alters gene expression. Examples of these molecules include retinoic acid, thyroxine, and the cholesterol-derived steroid hormones such as progesterone, estrogen, testosterone, cortisol, and aldosterone. The second category includes hydrophilic hormones that function by binding to cell surface receptors that transduce signals across the plasma membrane. Examples of such hormones include amino acid derivatives such as catecholamines and peptide hormones such as glucagon, insulin, gastrin, secretin, cholecystokinin, adrenocorticotropic hormone, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, and vasopressin. (See, for example, Lodish et al. (1995) Molecular Cell Biology, Scientific American Books Inc., New York N.Y., pp. 856-864.)

[0018] Neuropeptides and vasomediators (NP/VM) comprise a large family of endogenous signaling molecules. Included in this family are neuropeptides and neuropeptide hormones such as bombesin, neuropeptide Y, neurotensin, neuromedin N, melanocortins, opioids, galanin, somatostatin, tachykinins, urotensin II and related peptides involved in smooth muscle stimulation, vasopressin, vasoactive intestinal peptide, and circulatory system-borne signaling molecules such as angiotensin, complement, calcitonin, endothelins, formyl-methionyl peptides, glucagon, cholecystokinin and gastrin. NP/VMs can transduce signals directly, modulate the activity or release of other neurotransmitters and hormones, and act as catalytic enzymes in cascades. The effects of NP/VMs range from extremely brief to long-lasting. (Reviewed in Martin, C. R. et al. (1985) Endocrine Physiology, Oxford University Press, New York, N.Y., pp. 57-62.)

[0019] The discovery of new secretory molecules satisfies a need in the art by providing new compositions which are useful in the diagnosis, study, prevention, and treatment of diseases associated with, as well as effects of exogenous compounds on, cell signaling and the expression of secretory molecules.

SUMMARY OF THE INVENTION

[0020] The present invention relates to nucleic acid sequences comprising human polynucleotides encoding secretory polypeptides that contain signal peptides and/or transmembrane domains. These human polynucleotides (sptm) as presented in the Sequence Listing uniquely identify partial or full length genes encoding structural, functional, and regulatory polypeptides involved in cell signaling.

[0021] The invention provides an isolated polynucleotide comprising a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence complementary to b); and e) an RNA equivalent of a) through d). In one alternative, the polynucleotide comprises a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79. In another alternative, the polynucleotide comprises at least 60 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence complementary to b); and e) an RNA equivalent of a) through d). The invention further provides a composition for the detection of expression of secretory polynucleotides comprising at least one isolated polynucleotide comprising a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence complementary to b); and e) an RNA equivalent of a) through d); and a detectable label.

[0022] The invention also provides a method for detecting a target polynucleotide in a sample, said target polynucleotide comprising a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence complementary to b); and e) an RNA equivalent of a) through d). The method comprises a) amplifying said target polynucleotide or a fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.

[0023] The invention also provides a method for detecting a target polynucleotide in a sample, said target polynucleotide comprising a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence complementary to b); and e) an RNA equivalent of a) through d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof. In one alternative, the probe comprises at least 30 contiguous nucleotides. In another alternative, the probe comprises at least 60 contiguous nucleotides.

[0024] The invention further provides a recombinant polynucleotide comprising a promoter sequence operably linked to an isolated polynucleotide comprising a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence complementary to b); and e) an RNA equivalent of a) through d). In one alternative, the invention provides a cell transformed with the recombinant polynucleotide. In another alternative, the invention provides a transgenic organism comprising the recombinant polynucleotide. In a further alternative, the invention provides a method for producing a secretory polypeptide, the method comprising a) culturing a cell under conditions suitable for expression of the secretory polypeptide, wherein said cell is transformed with the recombinant polynucleotide, and b) recovering the secretory polypeptide so expressed.

[0025] The invention also provides a purified secretory polypeptide (SPTM) encoded by at least one polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79. Additionally, the invention provides an isolated antibody which specifically binds to the secretory polypeptide. The invention further provides a method of identifying a test compound which specifically binds to the secretory polypeptide, the method comprising the steps of a) providing a test compound; b) combining the secretory polypeptide with the test compound for a sufficient time and under suitable conditions for binding; and c) detecting binding of the secretory polypeptide to the test compound, thereby identifying the test compound which specifically binds the secretory polypeptide.

[0026] The invention further provides a microarray wherein at least one element of the microarray is an isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide comprising a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence complementary to b); and e) an RNA equivalent of a) through d). The invention also provides a method for generating a transcript image of a sample which contains polynucleotides. The method comprises a) labeling the polynucleotides of the sample, b) contacting the elements of the microarray with the labeled polynucleotides of the sample under conditions suitable for the formation of a hybridization complex, and c) quantifying the expression of the polynucleotides in the sample.

[0027] Additionally, the invention provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a polynucleotide sequence selected from the group consisting of a) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; b) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; c) a polynucleotide sequence complementary to a); d) a polynucleotide sequence s complementary to b); and e) an RNA equivalent of a) through d). The method comprises a) exposing a sample comprising the target polynucleotide to a compound, and b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

[0028] The invention further provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound; b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide comprising a polynucleotide sequence selected from the group consisting of i) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; ii) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; iii) a polynucleotide sequence complementary to i), iv) a polynucleotide sequence complementary to ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence selected from the group consisting of i) a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; ii) a naturally occurring polynucleotide sequence having at least 90% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-79; iii) a polynucleotide sequence complementary to i), iv) a polynucleotide sequence complementary to ii), and v) an RNA equivalent of i)-iv), and alternatively, the target polynucleotide comprises a fragment of a polynucleotide sequence selected from the group consisting of i-v above; c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

DESCRIPTION OF THE TABLES

[0029] Table 1 shows tile sequence identification numbers (SEQ ID NO:s) and template identification numbers (template IDs) corresponding to the polynucleotides of the present invention, along with polynucleotide segments of each template sequence as defined by the indicated “start” and “stop” nucleotide positions. The reading frames of the polynucleotide segments are shown, and the polypeptides encoded by the polynucleotide segments constitute either signal peptide (SP) or transmembrane (TM) domains, as indicated. The membrane topology of the encoded polypeptide sequence is indicated, the N-terminus (N) listed as being oriented to either the cytosolic (in) or non-cytosolic (out) side of the cell membrane or organelle.

[0030] Table 2 shows the sequence identification numbers (SEQ ID NO:s) corresponding to the polynucleotides of the present invention, along with component sequence identification numbers (component IDs) corresponding to each template. The component sequences, which were used to assemble the template sequences, are defined by the indicated “start” and “stop” nucleotide positions along each template.

[0031] Table 3 shows the tissue distribution profiles for the templates of the invention.

[0032] Table 4 summarizes the bioinformatics tools which are useful for analysis of the polynucleotides of the present invention. The first column of Table 4 lists analytical tools, programs, and algorithms, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score, the greater the homology between two sequences).

DETAILED DESCRIPTION OF THE INVENTION

[0033] Before the nucleic acid sequences and methods are presented, it is to be understood that this invention is not limited to the particular machines, methods, and materials described. Although particular embodiments are described, machines, methods, and materials similar or equivalent to these embodiments may be used to practice the invention. The preferred machines, methods, and materials set forth are not intended to limit the scope of the invention which is limited only by the appended claims.

[0034] The singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. All technical and scientific terms have the meanings commonly understood by one of ordinary skill in the art. All publications are incorporated by reference for the purpose of describing and disclosing the cell lines, vectors, and methodologies which are presented and which might be used in connection with the invention. Nothing in the specification is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0035] Definitions

[0036] As used herein, the lower case “sptm” refers to a nucleic acid sequence, while the upper case “SPTM” refers to an amino acid sequence encoded by sptm. A “full-length” sptm refers to a nucleic acid sequence containing the entire coding region of a gene endogenously expressed in human tissue.

[0037] “Adjuvants” are materials such as Freund's adjuvant, mineral gels (aluminum hydroxide), and surface active substances (lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol) which may be administered to increase a host's immunological response.

[0038] “Allele” refers to an alternative form of a nucleic acid sequence. Alleles result from a “mutation,” a change or an alternative reading of the genetic code. Any given gene may have none, one, or many allelic forms. Mutations which give rise to alleles include deletions, additions, or substitutions of nucleotides. Each of these changes may occur alone, or in combination with the others, one or more times in a given nucleic acid sequence. The present invention encompasses allelic sptm.

[0039] “Amino acid sequence” refers to a peptide, a polypeptide, or a protein of either natural or synthetic origin. The amino acid sequence is not limited to the complete, endogenous amino acid sequence and may be a fragment, epitope, variant, or derivative of a protein expressed by a nucleic acid sequence.

[0040] “Amplification” refers to the production of additional copies of a sequence and is carried out using polymerase chain reaction (PCR) technologies well known in the art.

[0041] “Antibody” refers to intact molecules as well as to fragments thereof, such as Fab, F(ab′)2, and Fv fragments, which are capable of binding the epitopic determinant. Antibodies that bind SPTM polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or peptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired. Commonly used carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KLH). The coupled peptide is then used to immunize the animal.

[0042] “Antisense sequence” refers to a sequence capable of specifically hybridizing to a target sequence. The antisense sequence may include DNA, RNA, or any nucleic acid mimic or analog such as peptide nucleic acid (PNA); oligonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides having modified sugar groups such as 2′-methoxyethyl sugars or 2′-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2′-deoxyuracil, or 7-deaza-2′-deoxyguanosine.

[0043] “Antisense sequence” refers to a sequence capable of specifically hybridizing to a target sequence. The antisense sequence can be DNA, RNA, or any nucleic acid mimic or analog.

[0044] “Antisense technology” refers to any technology which relies on the specific hybridization of an antisense sequence to a target sequence.

[0045] A “bin” is a portion of computer memory space used by a computer program for storage of data, and bounded in such a manner that data stored in a bin may be retrieved by the program.

[0046] “Biologically active” refers to an amino acid sequence having a structural, regulatory, or biochemical function of a naturally occurring amino acid sequence.

[0047] “Clone joining” is a process for combining gene bins based upon the bins' containing sequence information from the same clone. The sequences may assemble into a primary gene transcript as well as one or more splice variants.

[0048] “Complementary” describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing (5′-A-G-T-3′ pairs with its complement 3′-T-C-A-5′).

[0049] A “component sequence” is a nucleic acid sequence selected by a computer program such as PHRED and used to assemble a consensus or template sequence from one or more component sequences.

[0050] A “consensus sequence” or “template sequence” is a nucleic acid sequence which has been assembled from overlapping sequences, using a computer program for fragment assembly such as the GELVIEW fragment assembly system (Genetics Computer Group (GCG), Madison Wis.) or using a relational database management system (RDMS).

[0051] “Conservative amino acid substitutions” are those substitutions that, when made, least interfere with the properties of the original protein, i.e., the structure and especially the function of the protein is conserved and not significantly changed by such substitutions. The table below shows amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative substitutions.

1Original ResidueConservative SubstitutionAlaGly, SerArgHis, LysAsnAsp, Gln, HisAspAsn, GluCysAla, SerGlnAsn, Glu, HisGluAsp, Gln, HisGlyAlaHisAsn, Arg, Gln, GluIleLeu, ValLeuIle, ValLysArg, Gln, GluMetLen, IlePheHis, Met, Leu, Trp, TyrSerCys, ThrThrSer, ValTrpPhe, TyrTyrHis, Phe, TrpValIle, Leu, Thr

[0052] Conservative substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.

[0053] “Deletion” refers to a change in either a nucleic or amino acid sequence in which at least one nucleotide or amino acid residue, respectively, is absent.

[0054] “Derivative” refers to the chemical modification of a nucleic acid sequence, such as by replacement of hydrogen by an alkyl, acyl, arino, hydroxyl, or other group.

[0055] The terms “element” and “array element” refer to a polynucleotide, polypeptide, or other chemical compound having a unique and defined position on a microarray.

[0056] “E-value” refers to the statistical probability that a match between two sequences occurred by chance.

[0057] A “fragment” is a unique portion of sptm or SPTM which is identical in sequence to but shorter in length than the parent sequence. A fragment may comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue. For example, a fragment may comprise from 10 to 1000 contiguous amino acid residues or nucleotides. A fragment used as a probe, primer, antigen, therapeutic molecule, or for other purposes, may be at least 5, 10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500 contiguous amino acid residues or nucleotides in length. Fragments may be preferentially selected from certain regions of a molecule. For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or 500 amino acids (or first 25% or 50%) of a polypeptide as shown in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing and the figures, may be encompassed by the present embodiments.

[0058] A fragment of sptm comprises a region of unique polynucleotide sequence that specifically identifies sptm, for example, as distinct from any other sequence in the same genome. A fragment of sptm is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish sptm from related polynucleotide sequences. The precise length of a fragment of sptm and the region of sptm to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.

[0059] A fragment of SPTM is encoded by a fragment of sptm. A fragment of SPTM comprises a region of unique amino acid sequence that specifically identifies SPTM. For example, a fragment of SPTM is useful as an immunogenic peptide for the development of antibodies that specifically recognize SPTM. The precise length of a fragment of SPTM and the region of SPTM to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.

[0060] A “full length” nucleotide sequence is one containing at least a start site for translation to a protein sequence, followed by an open reading frame and a stop site, and encoding a “full length” polypeptide.

[0061] “Hit” refers to a sequence whose annotation will be used to describe a given template. Criteria for selecting the top hit are as follows: if the template has one or more exact nucleic acid matches, the top hit is the exact match with highest percent identity. If the template has no exact matches but has significant protein hits, the top hit is the protein hit with the lowest E-value. If the template has no significant protein hits, but does have significant non-exact nucleotide hits, the top hit is the nucleotide hit with the lowest E-value.

[0062] “Homology” refers to sequence similarity either between a reference nucleic acid sequence and at least a fragment of an sptm or between a reference amino acid sequence and a fragment of an SPTM.

[0063] “Hybridization” refers to the process by which a strand of nucleotides anneals with a complementary strand through base pairing. Specific hybridization is an indication that two nucleic acid sequences share a high degree of identity. Specific hybridization complexes form under defined annealing conditions, and remain hybridized after the “washing” step. The defined hybridization conditions include the annealing conditions and the washing step(s), the latter of which is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i.e., binding between pairs of nucleic acid probes that are not perfectly matched. Permissive conditions for annealing of nucleic acid sequences are routinely determinable and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency.

[0064] Generally, stringency of hybridization is expressed with reference to the temperature under which the wash step is carried out. Generally, such wash temperatures are selected to be about 5° C. to 20° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions for nucleic acid hybridization is well known and can be found in Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold Spring Harbor Press, Plainview N.Y.; specifically see volume 2, chapter 9.

[0065] High stringency conditions for hybridization between polynucleotides of the present invention include wash conditions of 68° C. in the presence of about 0.2×SSC and about 0.1% SDS, for 1 hour. Alternatively, temperatures of about 65° C., 60° C., or 55° C. may be used. SSC concentration may be varied from about 0.2 to 2×SSC, with SDS being present at about 0.1%. Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, denatured salmon sperm DNA at about 100-200 μg/ml. Useful variations on these conditions will be readily apparent to those skilled in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their resultant proteins.

[0066] Other parameters, such as temperature, salt concentration, and detergent concentration may be varied to achieve the desired stringency. Denaturants, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as RNA:DNA hybridizations. Appropriate hybridization conditions are routinely determinable by one of ordinary skill in the art.

[0067] “Immunogenic” describes the potential for a natural, recombinant, or synthetic peptide, epitope, polypeptide, or protein to induce antibody production in appropriate animals, cells, or cell lines.

[0068] “Insertion” or “addition” refers to a change in either a nucleic or amino acid sequence in which at least one nucleotide or residue, respectively, is added to the sequence.

[0069] “Labeling” refers to the covalent or noncovalent joining of a polynucleotide, polypeptide, or antibody with a reporter molecule capable of producing a detectable or measurable signal.

[0070] “Microarray” is any arrangement of nucleic acids, amino acids, antibodies, etc., on a substrate. The substrate may be a solid support such as beads, glass, paper, nitrocellulose, nylon, or an appropriate membrane.

[0071] “Linkers” are short stretches of nucleotide sequence which may be added to a vector or an sptm to create restriction endonuclease sites to facilitate cloning. “Polylinkers” are engineered to incorporate multiple restriction enzyme sites and to provide for the use of enzymes which leave 5′ or 3′ overhangs (e.g., BamHI, EcoRI, and HindIII) and those which provide blunt ends (e.g., EcoRV, SnaBI, and StuI).

[0072] “Naturally occurring” refers to an endogenous polynucleotide or polypeptide that may be isolated from viruses or prokaryotic or eukaryotic cells.

[0073] “Nucleic acid sequence” refers to the specific order of nucleotides joined by phosphodiester bonds in a linear, polymeric arrangement. Depending on the number of nucleotides, the nucleic acid sequence can be considered an oligomer, oligonucleotide, or polynucleotide. The nucleic acid can be DNA, RNA, or any nucleic acid analog, such as PNA, may be of genomic or synthetic origin, may be either double-stranded or single-stranded, and can represent either the sense or antisense (complementary) strand.

[0074] “Oligomer” refers to a nucleic acid sequence of at least about 6 nucleotides and as many as about 60 nucleotides, preferably about 15 to 40 nucleotides, and most preferably between about 20 and 30 nucleotides, that may be used in hybridization or amplification technologies. Oligomers may be used as, e.g., primers for PCR, and are usually chemically synthesized.

[0075] “Operably linked” refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.

[0076] “Peptide nucleic acid” (PNA) refers to a DNA mimic in which nucleotide bases are attached to a pseudopeptide backbone to increase stability. PNAs, also designated antigene agents, can prevent gene expression by targeting complementary messenger RNA.

[0077] The phrases “percent identity” and “% identity”, as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.

[0078] Percent identity between polynucleotide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison Wis.). CLUSTAL V is described in Higgins, D. G. and Sharp, P. M. (1989) CABIOS 5:151-153 and in Higgins, D. G. et al. (1992) CABIOS 8:189-191. For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: Ktuple=2, gap penalty=5, window=4, and “diagonals saved”=4. The “weighted” residue weight table is selected as the default. Percent identity is reported by CLUSTAL V as the “percent similarity” between aligned polyniucleotide sequence pairs.

[0079] Alternatively, a suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403-410), which is available from several sources, including the NCBI, Bethesda, Md., and on the Internet at http://www.ncbi.nlm.nih.gov/BLAST/. The BLAST software suite includes various sequence analysis programs including “blastn,” that is used to determine alignment between a known polynucleotide sequence and other sequences on a variety of databases. Also available is a tool called “BLAST 2 Sequences” that is used for direct pairwise comparison of two nucleotide sequences. “BLAST 2 Sequences” can be accessed and used interactively at http://www.ncbi.rlm nih.gov/gorf/bl2/. The “BLAST 2 Sequences” tool can be used for both blastn and blastp (discussed below). BLAST programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) set at default parameters. Such default parameters may be, for example:

[0080] Matrix: BLOSUM62

[0081] Reward for match: 1

[0082] Penalty for mismatch: −2

[0083] Open Gap: 5 and Extension Gap: 2 penalties

[0084] Gap x drop-off: 50

[0085] Expect: 10

[0086] Word Size: 11

[0087] Filter: on

[0088] Percent identity may be measured over the length of an entire defined sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in figures or Sequence Listings, may be used to describe a length over which percentage identity may be measured.

[0089] Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.

[0090] The phrases “percent identity” and “% identity”, as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the hydrophobicity and acidity of the substituted residue, thus preserving the structure (and therefore function) of the folded polypeptide.

[0091] Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: Ktuple=1, gap penalty=3, window=5, and “diagonals saved”=5. The PAM250 matrix is selected as the default residue weight table. As with polynucleotide alignments, the percent identity is reported by CLUSTAL V as the “percent similarity” between aligned polypeptide sequence pairs.

[0092] Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two polypeptide sequences, one may use the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) with blastp set at default parameters. Such default parameters may be, for example:

[0093] Matrix: BLOSUM62

[0094] Open Gap: 11 and Extension Gap: 1 penalty

[0095] Gap x drop-off: 50

[0096] Expect: 10

[0097] Word Size: 3

[0098] Filter: on

[0099] Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in figures or Sequence Listings, may be used to describe a length over which percentage identity may be measured.

[0100] “Post-translational modification” of an SPTM may involve lipidation, glycosylation, phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu and the SPTM.

[0101] “Probe” refers to sptm or fragments thereof, which are used to detect identical, allelic or related nucleic acid sequences. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule. Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes. “Primers” are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid sequence, e.g., by the polymerase chain reaction (PCR).

[0102] Probes and primers as used in the present invention typically comprise at least 15 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20, 30, 40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Probes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the figures and Sequence Listing, may be used.

[0103] Methods for preparing and using probes and primers are described in the references, for example Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold 30 Spring Harbor Press, Plainview N.Y.; Ausubel et al., 1987, Current Protocols in Molecular Biology, Greene Publ. Assoc. & Wiley-Intersciences, New York N.Y.; Innis et al., 1990, PCR Protocols, A Guide to Methods and Applications, Academic Press, San Diego Calif. PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical Research, Cambridge Mass.).

[0104] Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR primer pairs of up to 100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to 5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases. Similar primer selection programs have incorporated additional features for expanded capabilities. For example, the PrimOU primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas Tex.) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead Institute/MIT Center for Genome Research, Cambridge Mass.) allows the user to input a “mispriming library,” in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful, in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs.) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.

[0105] “Purified” refers to molecules, either polynucleotides or polypeptides that are isolated or separated from their natural environment and are at least 60% free, preferably at least 75% free, and most preferably at least 90% free from other compounds with which they are naturally associated.

[0106] A “recombinant nucleic acid” is a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques such as those described in Sambrook, supra. The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence. Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.

[0107] Alternatively, such recombinant nucleic acids may be part of a viral vector, e.g., based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.

[0108] “Regulatory element” refers to a nucleic acid sequence from nontranslated regions of a gene, and includes enhancers, promoters, introns, and 3+ untranslated regions, which interact with host proteins to carry out or regulate transcription or translation.

[0109] “Reporter” molecules are chemical or biochemical moieties used for labeling a nucleic acid, an amino acid, or an antibody. They include radionuclides; enzymes; fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors; magnetic particles; and other moieties known in the art.

[0110] An “RNA equivalent,” in reference to a DNA sequence, is composed of the same linear sequence of nucleotides as the reference DNA sequence with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.

[0111] “Sample” is used in its broadest sense. Samples may contain nucleic or amino acids, antibodies, or other materials, and may be derived from any source (e.g., bodily fluids including, but not limited to, saliva, blood, and urine; chromosome(s), organelles, or membranes isolated from a cell; genomic DNA, RNA, or cDNA in solution or bound to a substrate; and cleared cells or tissues or blots or imprints from such cells or tissues).

[0112] “Specific binding” or “specifically binding” refers to the interaction between a protein or peptide and its agonist, antibody, antagonist, or other binding partner. The interaction is dependent upon the presence of a particular structure of the protein, e.g., the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope “A,” the presence of a polypeptide containing epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A and the antibody will reduce the amount of labeled A that binds to the antibody.

[0113] “Substitution” refers to the replacement of at least one nucleotide or amino acid by a different nucleotide or amino acid.

[0114] “Substrate” refers to any suitable rigid or semi-rigid support including, e.g., membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles or capillaries. The substrate can have a variety of surface forms, such as wells, trenches, pins, channels and pores, to which polynucleotides or polypeptides are bound.

[0115] A “transcript image” refers to the collective pattern of gene expression by a particular tissue or cell type under given conditions at a given time.

[0116] “Transformation” refers to a process by which exogenous DNA enters a recipient cell. Transformation may occur under natural or artificial conditions using various methods well known in the art. Transformation may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method is selected based on the host cell being transformed.

[0117] “Transformants” include stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as cells which transiently express inserted DNA or RNA.

[0118] A “transgenic organism,” as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, and plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation. Techniques for transferring the DNA of the present invention into such organisms are widely known and provided in references such as Sambrook et al. (1989), supra.

[0119] A “variant” of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 25% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 30%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or even at least 98% or greater sequence identity over a certain defined length. The variant may result in “conservative” amino acid changes which do not affect structural and/or chemical properties. A variant may be described as, for example, an “allelic” (as defined above), “splice,” “species,” or “polymorphic” variant. A splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule. Species variants are polynucleotide sequences that vary from one species to another. The resulting polypeptides generally will have significant amino acid identity relative to each other. A polymorphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants also may encompass “single nucleotide polymorphisms” (SNPs) in which the polynucleotide sequence varies by one base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.

[0120] In an alternative, variants of the polynucleotides of the present invention may be generated through recombinant methods. One possible method is a DNA shuffling technique such as MOLECULTARBREEDING (Maxygen Inc., Santa Clara Calif.; described in U.S. Pat. No. 5,837,458; Chang, C. -C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians, F. C. et al. (1999) Nat. Biotechnol. 17:259-264; and Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-319) to alter or improve the biological properties of SPTM, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through “artificial” breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized. Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occurring genes in a directed and controllable manner.

[0121] A “variant” of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% or greater sequence identity over a certain defined length of one of the polypeptides.

THE INVENTION

[0122] In a particular embodiment, cDNA sequences derived from human tissues and cell lines were aligned based on nucleotide sequence identity and assembled into “consensus” or “template” sequences which are designated by the template identification numbers (template IDs) in column 2 of Table 1. The sequence identification numbers (SEQ ID NO:s) corresponding to the template IDs are shown in column 1. Segments of the template sequences are defined by the “start” and “stop” nucleotide positions listed in columns 3 and 4. These segments, when translated in the reading frames indicated in column 5, have similarity to signal peptide (SP) or transmembrane (TM) domain consensus sequences, as indicated in column 6.

[0123] The invention incorporates the nucleic acid sequences of these templates as disclosed in the Sequence Listing and the use of these sequences in the diagnosis and treatment of disease states characterized by defects in cell signaling. The invention further utilizes these sequences in hybridization and amplification technologies, and in particular, in technologies which assess gene expression patterns correlated with specific cells or tissues and their responses in vivo or in vitro to pharmaceutical agents, toxins, and other treatments. In this manner, the sequences of the present invention are used to develop a transcript image for a particular cell or tissue.

[0124] Derivation of Nucleic Acid Sequences

[0125] cDNA was isolated from libraries constructed using RNA derived from normal and diseased human tissues and cell lines. The human tissues and cell lines used for cDNA library construction were selected from a broad range of sources to provide a diverse population of cDNAs representative of gene transcription throughout the human body. Descriptions of the human tissues and cell lines used for cDNA library construction are provided in the LIFESEQ database (Incyte Genomics, Inc. (Incyte), Palo Alto Calif.). Human tissues were broadly selected from, for example, cardiovascular, dermatologic, endocrine, gastrointestinal, hematopoietic/immune system, musculoskeletal, neural, reproductive, and urologic sources.

[0126] Cell lines used for cDNA library construction were derived from, for example, leukemic cells, teratocarcinomas, neuroepitheliomas, cervical carcinoma, lung fibroblasts, and endothelial cells. Such cell lines include, for example, THP-1, Jurkat, HUVEC, hNT2, WI38, HeLa, and other cell lines commonly used and available from public depositories (American Type Culture Collection, Manassas Va.). Prior to mRNA isolation, cell lines were untreated, treated with a pharmaceutical agent such as 5′-aza-2′-deoxycytidine, treated with an activating agent such as lipopolysaccharide in the case of leukocytic cell lines, or, in the case of endothelial cell lines, subjected to shear stress.

[0127] Sequencing of the cDNAs

[0128] Methods for DNA sequencing are well known in the art. Conventional enzymatic methods employ the Klenow fragment of DNA polymerase I, SEQUENASE DNA polymerase (U.S. Biochemical Corporation, Cleveland Ohio), Taq polymerase (Applied Biosystems, Foster City Calif.), thermostable T7 polymerase (Amersham Pharmacia Biotech, Inc. (Amersham Pharmacia Biotech), Piscataway N.J.), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE amplification system (Life Technologies Inc. (Life Technologies), Gaithersburg Md.), to extend the nucleic acid sequence from an oligonucleotide primer annealed to the DNA template of interest. Methods have been developed for the use of both single-stranded and double-stranded templates. Chain termination reaction products may be electrophoresed on urea-polyacrylamide gels and detected either by autoradiography (for radioisotope-labeled nucleotides) or by fluorescence (for fluorophore-labeled nucleotides). Automated methods for mechanized reaction preparation, sequencing, and analysis using fluorescence detection methods have been developed. Machines used to prepare cDNAs for sequencing can include the MICROLAB 2200 liquid transfer system (Hamilton Company (Hamilton), Reno Nev.), Peltier thermal cycler (PTC200; MJ Research, Inc. (MJ Research), Watertown Mass.), and ABI CATALYST 800 thermal cycler (Applied Biosystems). Sequencing can be carried out using, for example, the ABI 373 or 377 (Applied Biosystems) or MEGABACE 1000 (Molecular Dynamics, Inc. (Molecular Dynamics), Sunnyvale Calif.) DNA sequencing systems, or other automated and manual sequencing systems well known in the art.

[0129] The nucleotide sequences of the Sequence Listing have been prepared by current, state-of-the-art, automated methods and, as such, may contain occasional sequencing errors or unidentified nucleotides. Such unidentified nucleotides are designated by an N. These infrequent unidentified bases do not represent a hindrance to practicing the invention for those skilled in the art. Several methods employing standard recombinant techniques may be used to correct errors and complete the missing sequence information. (See, e.g., those described in Ausubel, F. M. et al. (1997) Short Protocols in Molecular Biology, John Wiley & Sons, New York N.Y.; and Sambrook, J. et al. (1989) Molecular Cloning A Laboratory Manual, Cold Spring Harbor Press, Plainview N.Y.)

[0130] Assembly of cDNA Sequences

[0131] Human polynucleotide sequences may be assembled using programs or algorithms well known in the art. Sequences to be assembled are related, wholly or in part, and may be derived from a single or many different transcripts. Assembly of the sequences can be performed using such programs as PHRAP (Phils Revised Assembly Program) and the GELVIEW fragment assembly system (GCG), or other methods known in the art.

[0132] Alternatively, cDNA sequences are used as “component” sequences that are assembled into “template” or “consensus” sequences as follows. Sequence chromatograms are processed, verified, and quality scores are obtained using PHRED. Raw sequences are edited using an editing pathway known as Block 1 (See, e.g., the LIFESEQ Assembled User Guide, Incyte Genomics, Palo Alto, Calif.). A series of BLAST comparisons is performed and low-information segments and repetitive elements (e.g., dinucleotide repeats, Alu repeats, etc.) are replaced by “n's”, or masked, to prevent spurious matches. Mitochondrial and ribosomal RNA sequences are also removed. The processed sequences are then loaded into a relational database management system (RDMS) which assigns edited sequences to existing templates, if available. When additional sequences are added into the RDMS, a process is initiated which modifies existing templates or creates new templates from works in progress (i.e., nonfinal assembled sequences) containing queued sequences or the sequences themselves. After the new sequences have been assigned to templates, the templates can be merged into bins. If multiple templates exist in one bin, the bin can be split and the templates reannotated.

[0133] Once gene bins have been generated based upon sequence alignments, bins are “clone joined” based upon clone information. Clone joining occurs when the 5′ sequence of one clone is present in one bin and the 3′ sequence from the same clone is present in a different bin, indicating that the two bins should be merged into a single bin. Only bins which share at least two different clones are merged.

[0134] A resultant template sequence may contain either a partial or a full length open reading frame, or all or part of a genetic regulatory element. This variation is due in part to the fact that the full length cDNAs of many genes are several hundred, and sometimes several thousand, bases in length. With current technology, cDNAs comprising the coding regions of large genes cannot be cloned because of vector limitations, incomplete reverse transcription of the mRNA, or incomplete “second strand” synthesis. Template sequences may be extended to include additional contiguous sequences derived from the parent RNA transcript using a variety of methods known to those of skill in the art. Extension may thus be used to achieve the full length coding sequence of a gene.

[0135] Analysis of the cDNA Sequences

[0136] The cDNA sequences are analyzed using a variety of programs and algorithms which are well known in the art. (See, e.g., Ausubel, 1997, supra, Chapter 7.7; Meyers, R. A. (Ed.) (1995) Molecular Biology and Biotechnology, Wiley VCH, New York N.Y., pp. 856-853; and Table 4.) These analyses comprise both reading frame determinations, e.g., based on triplet codon periodicity for particular organisms (Fickett, J. W. (1982) Nucleic Acids Res. 10:5303-5318); analyses of potential start and stop codons; and homology searches.

[0137] Computer programs known to those of skill in the art for performing computer-assisted searches for amino acid and nucleic acid sequence similarity, include, for example, Basic Local Alignment Search Tool (BLAST; Altschul, S. F. (1993) J. Mol. Evol. 36:290-300; Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403-410). BLAST is especially useful in determining exact matches and comparing two sequence fragments of arbitrary but equal lengths, whose alignment is locally maximal and for which the alignment score meets or exceeds a threshold or cutoff score set by the user (Karlin, S. et al. (1988) Proc. Natl. Acad. Sci. USA 85:841-845). Using an appropriate search tool (e.g., BLAST or HMM), GenBank, SwissProt, BLOCKS, PFAM and other databases may be searched for sequences containing regions of homology to a query sptm or SPTM of the present invention.

[0138] Other approaches to the identification, assembly, storage, and display of nucleotide and polypeptide sequences are provided in “Relational Database for Storing Biomolecule Information,” U.S. Ser. No. 08/947,845, filed Oct. 9, 1997; “Project-Based Full-Length Biomolecular Sequence Database,” U.S. Ser. No. 08/811,758, filed Mar. 6, 1997; and “Relational Database and System for Storing Information Relating to Biomolecular Sequences,” U.S. Ser. No. 09/034,807, filed Mar. 4, 1998, all of which are incorporated by reference herein in their entirety.

[0139] Protein hierarchies can be assigned to the putative encoded polypeptide based on, e.g., motif, BLAST, or biological analysis. Methods for assigning these hierarchies are described, for example, in “Database System Employing Protein Function Hierarchies for Viewing Biomolecular Sequence Data,” U.S. Ser. No. 08/812,290, filed Mar. 6, 1997, incorporated herein by reference.

[0140] Human Secretory Sequences

[0141] The sptm of the present invention may be used for a variety of diagnostic and therapeutic purposes. For example, an sptm may be used to diagnose a particular condition, disease, or disorder associated with cell signaling. Such conditions, diseases, and disorders include, but are not limited to, a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, a cancer of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; an immune system disorder such as such as inflammation, actinic keratosis, acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, arteriosclerosis, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, bronchitis, bursitis, cholecystitis, cirrhosis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, paroxysmal nocturnal hemoglobinuria, hepatitis, hypereosinophilia, irritable bowel syndrome, episodic lymphopenia with lymphocytotoxins, mixed connective tissue disease (MCTD), multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, myelofibrosis, osteoarthritis, osteoporosis, pancreatitis, polycythemia vera, polymyositis, psoriasis, Reiter's syndrome, rheumatoid artritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, primary thrombocythemia, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, trauma, and hematopoietic cancer including lymphoma, leukemia, and myeloma; and a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorder of the central nervous system, cerebral palsy, a neuroskeletal disorder, an autonomic nervous system disorder, a cranial nerve disorder, a spinal cord disease, muscular dystrophy and other neuromuscular disorder, a peripheral nervous system disorder, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathy, myasthenia gravis, periodic paralysis, a mental disorder including mood, anxiety, and schizophrenic disorder, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette's disorder. The sptm can be used to detect the presence of, or to quantify the amount of, an sptm-related polynucleotide in a sample. This information is then compared to information obtained from appropriate reference samples, and a diagnosis is established. Alternatively, a polynucleotide complementary to a given sptm can inhibit or inactivate a therapeutically relevant gene related to the sptm.

[0142] Analysis of sptm Expression Patterns

[0143] The expression of sptm may be routinely assessed by hybridization-based methods to determine, for example, the tissue-specificity, disease-specificity, or developmental stage-specificity of sptm expression. For example, the level of expression of sptm may be compared among different cell types or tissues, among diseased and normal cell types or tissues, among cell types or tissues at different developmental stages, or among cell types or tissues undergoing various treatments. This type of analysis is useful, for example, to assess the relative levels of sptm expression in fully or partially differentiated cells or tissues, to determine if changes in sptm expression levels are correlated with the development or progression of specific disease states, and to assess the response of a cell or tissue to a specific therapy, for example, in pharmacological or toxicological studies. Methods for the analysis of sptm expression are based on hybridization and amplification technologies and include membrane-based procedures such as northern blot analysis, high-throughput procedures that utilize, for example, microarrays, and PCR-based procedures.

[0144] Hybridization and Genetic Analysis

[0145] The sptm, their fragments, or complementary sequences, may be used to identify the presence of and/or to determine the degree of similarity between two (or more) nucleic acid sequences. The sptm may be hybridized to naturally occurring or recombinant nucleic acid sequences under appropriately selected temperatures and salt concentrations. Hybridization with a probe based on the nucleic acid sequence of at least one of the sptm allows for the detection of nucleic acid sequences, including genomic sequences, which are identical or related to the sptm of the Sequence Listing. Probes may be selected from non-conserved or unique regions of at least one of the polynucleotides of SEQ ID NO: 1-79 and tested for their ability to identify or amplify the target nucleic acid sequence using standard protocols.

[0146] Polynucleotide sequences that are capable of hybridizing, in particular, to those shown in SEQ ID NO: 1-79 and fragments thereof, can be identified using various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol. 152:399-407; Kimmel, A. R. (1987) Methods Enzymol. 152:507-511.) Hybridization conditions are discussed in “Definitions.”

[0147] A probe for use in Southern or northern hybridization may be derived from a fragment of an sptm sequence, or its complement, that is up to several hundred nucleotides in length and is either single-stranded or double-stranded. Such probes may be hybridized in solution to biological materials such as plasmids, bacterial, yeast, or human artificial chromosomes, cleared or sectioned tissues, or to artificial substrates containing sptm. Microarrays are particularly suitable for identifying the presence of and detecting the level of expression for multiple genes of interest by examining gene expression correlated with, e.g., various stages of development, treatment with a drug or compound, or disease progression. An array analogous to a dot or slot blot may be used to arrange and link polynucleotides to the surface of a substrate using one or more of the following: mechanical (vacuum), chemical, thermal, or UV bonding procedures. Such an array may contain any number of sptm and may be produced by hand or by using available devices, materials, and machines.

[0148] Microarrays may be prepared, used, and analyzed using methods known in the art. (See, e.g., Brennan, T. M. et al. (1995) U.S. Pat. No. 5,474,796; Schena, M. et al. (1996) Proc. Natl. Acad. Sci. USA 93:10614-10619; Baldeschweiler et al. (1995) PCT application WO95/251116; Shalon, D. et al. (1995) PCT application WO95/35505; Heller, R. A. et al. (1997) Proc. Natl. Acad. Sci. USA 94:2150-2155; and Heller, M. J. et al. (1997) U.S. Pat. No. 5,605,662.)

[0149] Probes may be labeled by either PCR or enzymatic techniques using a variety of commercially available reporter molecules. For example, commercial kits are available for radioactive and chemiluminescent labeling (Amersham Pharmacia Biotech) and for alkaline phosphatase labeling (Life Technologies). Alternatively, sptm may be cloned into commercially available vectors for the production of RNA probes. Such probes may be transcribed in the presence of at least one labeled nucleotide (e.g., 32P-ATP, Amersham Pharmacia Biotech).

[0150] Additionally the polynucleotides of SEQ ID NO: 1-79 or suitable fragments thereof can be used to isolate full length cDNA sequences utilizing hybridization and/or amplification procedures well known in the art, e.g., cDNA library screening, PCR amplification, etc. The molecular cloning of such fall length cDNA sequences may employ the method of cDNA library screening with probes using the hybridization, stringency, washing, and probing strategies described above and in Ausubel, supra, Chapters 3, 5, and 6. These procedures may also be employed with genomic libraries to isolate genomic sequences of sptm in order to analyze, e.g., regulatory elements.

[0151] Genetic Mapping

[0152] Gene identification and mapping are important in the investigation and treatment of almost all conditions, diseases, and disorders. Cancer, cardiovascular disease, Alzheimer's disease, arthritis, diabetes, and mental illnesses are of particular interest. Each of these conditions is more complex than the single gene defects of sickle cell anemia or cystic fibrosis, with select groups of genes being predictive of predisposition for a particular condition, disease, or disorder. For example, cardiovascular disease may result from malfunctioning receptor molecules that fail to clear cholesterol from the bloodstream, and diabetes may result when a particular individual's immune system is activated by an infection and attacks the insulin-producing cells of the pancreas. In some studies, Alzheimer's disease has been linked to a gene on chromosome 21; other studies predict a different gene and location. Mapping of disease genes is a complex and reiterative process and generally proceeds from genetic linkage analysis to physical mapping.

[0153] As a condition is noted among members of a family, a genetic linkage map traces parts of chromosomes that are inherited in the same pattern as the condition. Statistics link the inheritance of particular conditions to particular regions of chromosomes, as defined by RFLP or other markers. (See, for example, Lander, E. S. and Botstein, D. (1986) Proc. Natl. Acad. Sci. USA 83:7353-7357.) Occasionally, genetic markers and their locations are known from previous studies. More often, however, the markers are simply stretches of DNA that differ among individuals. Examples of genetic linkage maps can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OMIM) World Wide Web site.

[0154] In another embodiment of the invention, sptm sequences may be used to generate hybridization probes useful in chromosomal mapping of naturally occurring genomic sequences. Either coding or noncoding sequences of sptm may be used, and in some instances, noncoding sequences may be preferable over coding sequences. For example, conservation of an sptm coding sequence among members of a multi-gene family may potentially cause undesired cross hybridization during chromosomal mapping. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e.g., human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial P1 constructions, or single chromosome cDNA libraries. (See, e.g., Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355; Price, C. M. (1993) Blood Rev. 7:127-134; and Trask, B. J. (1991) Trends Genet. 7:149-154.)

[0155] Fluorescent in situ hybridization (FISH) may be correlated with other physical chromosome mapping techniques and genetic map data. (See, e.g., Meyers, supra, pp. 965-968.) Correlation between the location of sptm on a physical chromosomal map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder. The sptm sequences may also be used to detect polymorphisms that are genetically linked to the inheritance of a particular condition, disease, or disorder.

[0156] In situ hybridization of chromosomal preparations and genetic mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending existing genetic maps. Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the number or arm of the corresponding human chromosome is not known. These new marker sequences can be mapped to human chromosomes and may provide valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once a disease or syndrome has been crudely correlated by genetic linkage with a particular genomic region, e.g., ataxia-telangiectasia to 11q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation. (See, e.g., Gatti, R. A. et al. (1988) Nature 336:577-580.) The nucleotide sequences of the subject invention may also be used to detect differences in chromosomal architecture due to translocation, inversion, etc., among normal, carrier, or affected individuals.

[0157] Once a disease-associated gene is mapped to a chromosomal region, the gene must be cloned in order to identify mutations or other alterations (e.g., translocations or inversions) that may be correlated with disease. This process requires a physical map of the chromosomal region containing the disease-gene of interest along with associated markers. A physical map is necessary for determining the nucleotide sequence of and order of marker genes on a particular chromosomal region. Physical mapping techniques are well known in the art and require the generation of overlapping sets of cloned DNA fragments from a particular organelle, chromosome, or genome. These clones are analyzed to reconstruct and catalog their order. Once the position of a marker is determined, the DNA from that region is obtained by consulting the catalog and selecting clones from that region. The gene of interest is located through positional cloning techniques using hybridization or similar methods.

[0158] Diagnostic Uses

[0159] The sptm of the present invention may be used to design probes useful in diagnostic assays. Such assays, well known to those skilled in the art, may be used to detect or confirm conditions, disorders, or diseases associated with abnormal levels of sptm expression. Labeled probes developed from sptm sequences are added to a sample under hybridizing conditions of desired stringency. In some instances, sptm, or fragments or oligonucleotides derived from sptm, may be used as primers in amplification steps prior to hybridization. The amount of hybridization complex formed is quantified and compared with standards for that cell or tissue. If sptm expression varies significantly from the standard, the assay indicates the presence of the condition, disorder, or disease. Qualitative or quantitative diagnostic methods may include northern, dot blot, or other membrane or dip-stick based technologies or multiple-sample format technologies such as PCR, enzyme-linked immunosorbent assay (ELISA)-like, pin, or chip-based assays.

[0160] The probes described above may also be used to monitor the progress of conditions, disorders, or diseases associated with abnormal levels of sptm expression, or to evaluate the efficacy of a particular therapeutic treatment. The candidate probe may be identified from the sptm that are specific to a given human tissue and have not been observed in GenBank or other genome databases. Such a probe may be used in animal studies, preclinical tests, clinical trials, or in monitoring the treatment of an individual patient. In a typical process, standard expression is established by methods well known in the art for use as a basis of comparison, samples from patients affected by the disorder or disease are combined with the probe to evaluate any deviation from the standard profile, and a therapeutic agent is administered and effects are monitored to generate a treatment profile. Efficacy is evaluated by determining whether the expression progresses toward or returns to the standard normal pattern. Treatment profiles may be generated over a period of several days or several months. Statistical methods well known to those skilled in the art may be use to determine the significance of such therapeutic agents.

[0161] The polynucleotides are also useful for identifying individuals from minute biological samples, for example, by matching the RFLP pattern of a sample's DNA to that of an individual's DNA. The polynucleotides of the present invention can also be used to determine 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, an individual can be identified through a unique set of DNA sequences. Once a unique ID database is established for an individual, positive identification of that individual can be made from extremely small tissue samples.

[0162] In a particular aspect, oligonucleotide primers derived from the sptm of the invention may be used to detect single nucleotide polymorphisms (SNPs). SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from sptm are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP (isSNP), are capable of identifying polymorphisms by comparing the sequences of individual overlapping DNA fragments which assemble into a common consensus sequence. These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc., San Diego Calif.).

[0163] DNA-based identification techniques are critical in forensic technology. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, etc., can be amplified using, e.g., PCR, to identify individuals. (See, e.g., Erlich, H. (1992) PCR Technology, Freeman and Co., New York, N.Y.). Similarly, polynucleotides of the present invention can be used as polymorphic markers.

[0164] There is also a need for reagents capable of identifying the source of a particular tissue. Appropriate reagents can comprise, for example, DNA probes or primers prepared from the sequences of the present invention that are specific for particular tissues. 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.

[0165] The polynucleotides of the present invention can also be used as molecular weight markers on nucleic acid gels or Southern blots, as diagnostic probes for the presence of a specific mRNA in a particular cell type, in the creation of subtracted cDNA libraries which aid in the discovery of novel polynucleotides, in selection and synthesis of oligomers for attachment to an array or other support, and as an antigen to elicit an immune response.

[0166] Disease Model Systems Using sptm

[0167] The polynucleotides encoding SPTM or their mammalian homologs may be “knocked out” in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of human disease. (See, e.g., U.S. Pat. No. 5,175,383 and U.S. Pat. No. 5,767,337.) For example, mouse ES cells, such as the mouse 129/SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e.g., the neomycin phosphotransferase gene (neo; Capeechi, M. R. (1989) Science 244:1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-loxP system to knockout a gene of interest in a tissue- or developmental stage-specific manner (Marth, J. D. (1996) Clin. Invest. 97:1999-2002; Wagner, K. U. et al. (1997) Nucleic Acids Res. 25:4323-4330). Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL/6 mouse strain. The blastocysts are surgically transferred to pseudopregnant dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains. Transgenic animals thus generated may be tested with potential therapeutic or toxic agents.

[0168] The polynucleotides encoding SPTM may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J. A. et al. (1998) Science 282:1145-1147).

[0169] The polynucleotides encoding SPTM of the invention can also be used to create “knockin” humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of sptm is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease. Alternatively, a mammal inbred to overexpress sptm, resulting, e.g., in the secretion of SPTM in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol. Annu. Rev. 4:55-74).

[0170] Screening Assays

[0171] SPTM encoded by polynucleotides of the present invention may be used to screen for molecules that bind to or are bound by the encoded polypeptides. The binding of the polypeptide and the molecule may activate (agonist), increase, inhibit (antagonist), or decrease activity of the polypeptide or the bound molecule. Examples of such molecules include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.

[0172] Preferably, the molecule is closely related to the natural ligand of the polypeptide, e.g., a ligand or fragment thereof, a natural substrate, or a structural or functional mimetic. (See, Coligan et al., (1991) Current Protocols in Immunology 1(2): Chapter 5.) Similarly, the molecule can be closely related to the natural receptor to which the polypeptide binds, or to at least a fragment of the receptor, e.g., the active site. In either case, the molecule can be rationally designed using known techniques. Preferably, the screening for these molecules involves producing appropriate cells which express the polypeptide, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E. coli. Cells expressing the polypeptide or cell membrane fractions which contain the expressed polypeptide are then contacted with a test compound and binding, stimulation, or inhibition of activity of either the polypeptide or the molecule is analyzed.

[0173] An assay may simply test binding of a candidate compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. Alternatively, the assay may assess binding in the presence of a labeled competitor.

[0174] Additionally, 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.

[0175] Preferably, an ELISA assay using, e.g., a monoclonal or polyclonal antibody, can measure polypeptide level in a sample. The antibody can measure polypeptide level by either binding, directly or indirectly, to the polypeptide or by competing with the polypeptide for a substrate.

[0176] All of the above assays can be used in a diagnostic or prognostic context. 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 polypeptide from suitably manipulated cells or tissues.

[0177] Transcript Imaging and Toxicological Testing

[0178] Another embodiment relates to the use of sptm to develop a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time. (See Seilhamer et al., “Comparative Gene Transcript Analysis,” U.S. Pat. No. 5,940,484, expressly incorporated by reference herein.) Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity pertaining to cell signaling.

[0179] Transcript images which profile sptm expression may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect sptm expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.

[0180] Transcript images which profile sptm expression may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E. F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S. and Anderson, N. L. (2000) Toxicol. Lett. 112-113:467-71, expressly incorporated by reference herein). If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties. These fingerprints or signatures are most useful and refined when they contain expression information from a large number of genes and gene families. Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data. The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity. (See, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released Feb. 29, 2000, available at http://www.niehs.nih.gov/oc/news/toxchip.htm.) Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.

[0181] In one embodiment, the toxicity of a test compound is assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the polynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biological sample. Differences in the transcript levels between the two samples are indicative of a toxic response caused by the test compound in the treated sample.

[0182] Another particular embodiment relates to the use of SPTM encoded by polynucleotides of the present invention to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type. In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the protein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of the present invention. In some cases, further sequence data may be obtained for definitive protein identification.

[0183] A proteomnic profile may also be generated using antibodies specific for SPTM to quantify the levels of SPTM expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. (1999) Anal. Biochem. 270:103-11; Mendoze, L. G. et al. (1999) Biotechniques 27:778-88). Detection may be performed by a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol- or amino-reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.

[0184] Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level. There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N. L. and Seilhamer, J. (1997) Electrophoresis 18:533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.

[0185] In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the SPTM encoded by polynucleotides of the present invention.

[0186] In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the SPTM encoded by polynucleotides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared with the amount in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.

[0187] Transcript images may be used to profile sptm expression in distinct tissue types. This process can be used to determine cell signaling activity in a particular tissue type relative to this activity in a different tissue type. Transcript images may be used to generate a profile of sptm expression characteristic of diseased tissue. Transcript images of tissues before and after treatment may be used for diagnostic purposes, to monitor the progression of disease, and to monitor the efficacy of drug treatments for diseases which affect cell signaling activity.

[0188] Transcript images of cell lines can be used to assess cell signaling activity and/or to identify cell lines that lack or misregulate this activity. Such cell lines may then be treated with pharmaceutical agents, and a transcript image following treatment may indicate the efficacy of these agents in restoring desired levels of this activity. A similar approach may be used to assess the toxicity of pharmaceutical agents as reflected by undesirable changes in cell signaling activity. Candidate pharmaceutical agents may be evaluated by comparing their associated transcript images with those of pharmaceutical agents of known effectiveness.

[0189] Antisense Molecules

[0190] The polynucleotides of the present invention are useful in antisense technology. Antisense technology or therapy relies on the modulation of expression of a target protein through the specific binding of an antisense sequence to a target sequence encoding the target protein or directing its expression. (See, e.g., Agrawal, S., ed. (1996) Antisense TheraDeutics, Humana Press Inc., Totawa N.J.; Alama, A. et al. (1997) Pharmacol. Res. 36(3):171-178; Crooke, S. T. (1997) Adv. Pharmacol. 40:1-49; Sharma, H. W. and R. Narayanan (1995) Bioessays 17(12):1055-1063; and Lavrosky, Y. et al. (1997) Biochem. Mol. Med. 62(l):11-22.) An antisense sequence is a polynucleotide sequence capable of specifically hybridizing to at least a portion of the target sequence. Antisense sequences bind to cellular mRNA and/or genomic DNA, affecting translation and/or transcription. Antisense sequences can be DNA, RNA, or nucleic acid mimics and analogs. (See, e.g., Rossi, J. J. et al. (1991) Antisense Res. Dev. 1(3):285-288; Lee, R. et al. (1998) Biochemistry 37(3):900-1010; Pardridge, W. M. et al. (1995) Proc. Natl. Acad. Sci. USA 92(12):5592-5596; and Nielsen, P. E. and Haaima, G. (1997) Chem. Soc. Rev. 96:73-78.) Typically, the binding which results in modulation of expression occurs through hybridization or binding of complementary base pairs. Antisense sequences can also bind to DNA duplexes through specific interactions in the major groove of the double helix.

[0191] The polynucleotides of the present invention and fragments thereof can be used as antisense sequences to modify the expression of the polypeptide encoded by sptm. The antisense sequences can be produced ex vivo, such as by using any of the ABI nucleic acid synthesizer series (Applied Biosystems) or other automated systems known in the art. Antisense sequences can also be produced biologically, such as by transforming an appropriate host cell with an expression vector containing the sequence of interest. (See, e.g., Agrawal, supra.)

[0192] In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the cellular sequence encoding the target protein. (See, e.g., Slater, J. E., et al. (1998) J. Allergy Clin. Immunol. 102(3):469-475; and Scanlon, K. J., et al. (1995) 9(13):1288-1296.) Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors. (See, e.g., Miller, A. D. (1990) Blood 76:271; Ausubel, F. M. et al. (1995) Current Protocols in Molecular Biology, John Wiley & Sons, New York N.Y.; Uckert, W. and W. Walther (1994) Pharmacol. Ther. 63(3):323-347.) Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art. (See, e.g., Rossi, J. J. (1995) Br. Med. Bull. 51(1):217-225; Boado, R. J. et al. (1998) J. Pharm. Sci. 87(11):1308-1315; and Morris, M. C. et al. (1997) Nucleic Acids Res. 25(14):2730-2736.)

[0193] Expression

[0194] In order to express a biologically active SPTM, the nucleotide sequences encoding SPTM or fragments thereof may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. Methods which are well known to those skilled in the art may be used to construct expression vectors containing sequences encoding SPTM and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. (See, e.g., Sambrook, supra, Chapters 4, 8, 16, and 17; and Ausubel, supra, Chapters 9, 10, 13, and 16.)

[0195] A variety of expression vector/host systems may be utilized to contain and express sequences encoding SPTM. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e.g., baculovirus); plant cell systems transformed with viral expression vectors (e.g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal (mammalian) cell systems. (See, e.g., Sambrook, supra; Ausubel, 1995, supra, Van Heece, G. and S. M. Schuster (1989) J. Biol. Chem. 264:5503-5509; Bitter, G. A. et al. (1987) Methods Enzymol. 153:516-544; Scorer, C. A. et al. (1994) Bio/Technology 12:181-184; Engelhard, E. K. et al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7:1937-1945; Takamatsu, N. (1987) EMBO J. 6:307-311; Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Broglie, R. et al. (1984) Science 224:838-843; Winter, J. et al. (1991) Results Probl. Cell Differ. 17:85-105; The McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York N.Y., pp. 191-196; Logan, J. and T. Shenk (1984) Proc. Natl. Acad. Sci. USA 81:3655-3659; and Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355.) Expression vectors derived from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of nucleotide sequences to the targeted organ, tissue, or cell population. (See, e.g., Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5(6):350-356; Yu, M. et al., (1993) Proc. Natl. Acad. Sci. USA 90(13):6340-6344; Buller, R. M. et al. (1985) Nature 317(6040):813-815; McGregor, D. P. et al. (1994) Mol. Immunol. 31(3):219-226; and Verma, I. M. and N. Somia (1997) Nature 389:239-242.) The invention is not limited by the host cell employed.

[0196] For long term production of recombinant proteins in mammalian systems, stable expression of SPTM in cell lines is preferred. For example, sequences encoding SPTM can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Any number of selection systems may be used to recover transformed cell lines. (See, e.g., Wigler, M. et al. (1977) Cell 11:223-232; Lowy, I. et al. (1980) Cell 22:817-823.; Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14; Hartman, S. C. and R. C. Mulligan (1988) Proc. Natl. Acad. Sci. USA 85:8047-8051; Rhodes, C. A. (1995) Methods Mol. Biol. 55:121-131.)

[0197] Therapeutic Uses of sptm

[0198] The polynucleotides encoding SPTM of the invention may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e.g., in the cases of severe combined immunodeficiency (SCID)-X1 disease characterized by X-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R. M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995) Science 270:470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6:667-703), thalassemias, familial hypercholesterolemia, and hemophilia resulting from Factor VIII or Factor IX deficiencies (Crystal, R. G. (1995) Science 270:404-410; Verma, I. M. and Somia, N. (1997) Nature 389:239-242)), (ii) express a conditionally lethal gene product (e.g., in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular parasites (e.g., against human retroviruses, such as human immunodeficiency virus (HIV) (Baltimore, D. (1988) Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci. USA. 93:11395-11399), hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis; and protozoan parasites such as Plasmodium falciparum and Trypanosoma cruzi). In the case where a genetic deficiency in sptm expression or regulation causes disease, the expression of sptm from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.

[0199] In a further embodiment of the invention, diseases or disorders caused by deficiencies in sptm are treated by constructing mammalian expression vectors comprising sptm and introducing these vectors by mechanical means into sptm-deficient cells. Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA microinjection into individual cells, (ii) ballistic gold particle delivery, (iii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R. A. and Anderson, W. F. (1993) Annu. Rev. Biochem. 62:191-217;

[0200] Ivics, Z. (1997) Cell 91:501-510; Boulay, J -L. and Récipon, H. (1998) Curr. Opin. Biotechnol. 9:445-450).

[0201] Expression vectors that may be effective for the expression of sptm include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX vectors (Invitrogen, Carlsbad Calif.), PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV (Stratagene, La Jolla Calif.), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto Calif.). The sptm of the invention may be expressed using (i) a constitutively active promoter, (e.g., from cytomegalovirus (CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or β-actin genes), (ii) an inducible promoter (e.g., the tetracycline-regulated promoter (Gossen, M. and Bujard, H. (1992) Proc. Natl. Acad. Sci.

[0202] U.S.A. 89:5547-5551; Gossen, M. et al., (1995) Science 268:1766-1769; Rossi, F. M. V. and Blau, H. M. (1998) Curr. Opin. Biotechnol. 9:451456), commercially available in the T-REX plasmid (Invitrogen); the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND;

[0203] Invitrogen); the FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F. M. V. and Blau, H. M. supra), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding SPTM from a normal individual.

[0204] Commercially available liposome transformation kits (e.g., the PERFECT LIPID TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters. In the alternative, transformation is performed using the calcium phosphate method (Graham, F. L. and Eb, A. J. (1973) Virology 52:456-467), or by electroporation (Neumann, E. et al. (1982) EMBO J. 1:841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.

[0205] In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to sptm expression are treated by constructing a retrovirus vector consisting of (i) sptm under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirus cis-acting RNA sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e.g., PFB and PFBNEO) are commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92:6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al. (1987) J. Virol. 61:1647-1650; Bender, M. A. et al. (1987) J. Virol. 61:1639-1646; Adam, M. A. and Miller, A. D. (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol. 72:8463-8471; Zufferey, R. et al. (1998) J. Virol. 72:9873-9880). U.S. Pat. No. 5,910,434 to Rigg (“Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant”) discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference. Propagation of retrovirus vectors, transduction of a population of cells (e.g., CD4+ T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Ranga, U. et al. (1997) J. Virol. 71:7020-7029; Bauer, G. et al. (1997) Blood 89:2259-2267; Bonyhadi, M. L. (1997) J. Virol. 71:4707-4716; Ranga, U. et al. (1998) Proc. Natl. Acad. Sci. U.S.A. 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).

[0206] In the alternative, an adenovirus-based gene therapy delivery system is used to deliver sptm to cells which have one or more genetic abnormalities with respect to the expression of sptm. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M. E. et al. (1995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Pat. No. 5,707,618 to Armentano (“Adenovirus vectors for gene therapy”), hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P. A. et al. (1999) Annu. Rev. Nutr. 19:511-544 and Verma, I. M. and Somia, N. (1997) Nature 18:389:239-242, both incorporated by reference herein.

[0207] In another alternative, a herpes-based, gene therapy delivery system is used to deliver sptm to target cells which have one or more genetic abnormalities with respect to the expression of sptm. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing sptm to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector has been used to deliver a reporter gene to the eyes of primates (Liu, X. et al. (1999) Exp. Eye Res.169:385-395). The construction of a HSV-1 virus vector has also been disclosed in detail in U.S. Pat. No. 5,804,413 to DeLuca (“Herpes simplex virus strains for gene transfer”), which is hereby incorporated by reference. U.S. Pat. No. 5,804,413 teaches the use of recombinant HSV d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under the control of the appropriate promoter for purposes including human gene therapy. Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22. For HSV vectors, see also Goins, W. F. et al. 1999 J. Virol. 73:519-532 and Xu, H. et al., (1994) Dev. Biol. 163:152-161, hereby incorporated by reference. The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.

[0208] In another alternative, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver sptm to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and Li, K -J. (1998) Curr. Opin. Biotech. 9:464469). During alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full-length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e.g., protease and polymerase). Similarly, inserting sptm into the alphavirus genome in place of the capsid-coding region results in the production of a large number of sptm RNAs and the synthesis of high levels of SPTM in vector transduced cells. While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphavirus can be altered to suit the needs of the gene therapy application (Dryga, S. A. et al. (1997) Virology 228:74-83). The wide host range of alphaviruses will allow the introduction of sptm into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction. The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA and RNA transfections, and performing alphavirus infections, are well known to those with ordinary skill in the art.

[0209] Antibodies

[0210] Anti-SPTM antibodies may be used to analyze protein expression levels. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, and Fab fragments. For descriptions of and protocols of antibody technologies, see, e.g., Pound J. D. (1998) Immunochemical Protocols, Humana Press, Totowa, N.J.

[0211] The amino acid sequence encoded by the sptm of the Sequence Listing may be analyzed by appropriate software (e.g., LASERGENE NAVIGATOR software, DNASTAR) to determine regions of high immunogenicity. The optimal sequences for immunization are selected from the C-terminus, the N-terminus, and those intervening, hydrophilic regions of the polypeptide which are likely to be exposed to the external environment when the polypeptide is in its natural conformation. Analysis used to select appropriate epitopes is also described by Ausubel (1997, supra, Chapter 11.7). Peptides used for antibody induction do not need to have biological activity; however, they must be antigenic. Peptides used to induce specific antibodies may have an amino acid sequence consisting of at least five amino acids, preferably at least 10 amino acids, and most preferably at least 15 amino acids. A peptide which mimics an antigenic fragment of the natural polypeptide may be fused with another protein such as keyhole limpet hemocyanin (KLH; Sigma, St. Louis Mo.) for antibody production. A peptide encompassing an antigenic region may be expressed from an sptm, synthesized as described above, or purified from human cells.

[0212] Procedures well known in the art may be used for the production of antibodies. Various hosts including mice, goats, and rabbits, may be immunized by injection with a peptide. Depending on the host species, various adjuvants may be used to increase immunological response.

[0213] In one procedure, peptides about 15 residues in length may be synthesized using an ABI 431A peptide synthesizer (Applied Biosystems) using fmoc-chemistry and coupled to KLH (Sigma) by reaction with M-maleimidobenzoyl-N-hydroxysuccinimide ester (Ausubel, 1995, supra). Rabbits are immunized with the peptide-KLH complex in complete Freund's adjuvant. The resulting antisera are tested for antipeptide activity by binding the peptide to plastic, blocking with 1% bovine serum albumin (BSA), reacting with rabbit antisera, washing, and reacting with radioiodinated goat anti-rabbit IgG. Antisera with antipeptide activity are tested for anti-SPTM activity using protocols well known in the art, including ELISA, radioimmunoassay (RIA), and immunoblotting.

[0214] In another procedure, isolated and purified peptide may be used to immunize mice (about 100 μg of peptide) or rabbits (about 1 mg of peptide). Subsequently, the peptide is radioiodinated and used to screen the immunized animals' B-lymphocytes for production of antipeptide antibodies. Positive cells are then used to produce hybridomas using standard techniques. About 20 mg of peptide is sufficient for labeling and screening several thousand clones. Hybridomas of interest are detected by screening with radioiodinated peptide to identify those fusions producing peptide-specific monoclonal antibody. In a typical protocol, wells of a multi-well plate (FAST, Becton-Dickinson, Palo Alto, Calif.) are coated with affinity-purified, specific rabbit-anti-mouse (or suitable anti-species IgG) antibodies at 10 mg/ml. The coated wells are blocked with 1% BSA and washed and exposed to supernatants from hybridomas. After incubation, the wells are exposed to radiolabeled peptide at 1 mg/ml.

[0215] Clones producing antibodies bind a quantity of labeled peptide that is detectable above background. Such clones are expanded and subjected to 2 cycles of cloning. Cloned hybridomas are injected into pristane-treated mice to produce ascites, and monoclonal antibody is purified from the ascitic fluid by affinity chromatography on protein A (Amersham Pharmacia Biotech). Several procedures for the production of monoclonal antibodies, including in vitro production, are described in Pound (supra). Monoclonal antibodies with antipeptide activity are tested for anti-SPTM activity using protocols well known in the art, including ELISA, RIA, and immunoblotting.

[0216] Antibody fragments containing specific binding sites for an epitope may also be generated. For example, such fragments include, but are not limited to, the F(ab′)2 fragments produced by pepsin digestion of the antibody molecule, and the Fab fragments generated by reducing the disulfide bridges of the F(ab′)2 fragments. Alternatively, construction of Fab expression libraries in filamentous bacteriophage allows rapid and easy identification of monoclonal fragments with desired specificity (Pound, supra, Chaps. 45-47). Antibodies generated against polypeptide encoded by sptm can be used to purify and characterize full-length SPTM protein and its activity, binding partners, etc.

[0217] Assays Using Antibodies

[0218] Anti-SPTM antibodies may be used in assays to quantify the amount of SPTM found in a particular human cell. Such assays include methods utilizing the antibody and a label to detect expression level under normal or disease conditions. The peptides and antibodies of the invention may be used with or without modification or labeled by joining them, either covalently or noncovalently, with a reporter molecule.

[0219] Protocols for detecting and measuring protein expression using either polyclonal or monoclonal antibodies are well known in the art. Examples include ELISA, RIA, and fluorescent activated cell sorting (FACS). Such immunoassays typically involve the formation of complexes between the SPTM and its specific antibody and the measurement of such complexes. These and other assays are described in Pound (supra).

[0220] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0221] The disclosures of all patents, applications, and publications mentioned above and below, including U.S. Ser. No. 60/205,287, U.S. Ser. No. 60/205,324, U.S. Ser. No. 60/205,286, U.S. Ser. No. 60/205,323, U.S. Ser. No. 60/185,215, U.S. Ser. No. 60/185,216, and U.S. Ser. No. 60/205,232, are hereby expressly incorporated by reference.

EXAMPLES

[0222] I. Construction of cDNA Libraries

[0223] RNA was purchased from CLONTECH Laboratories, Inc. (Palo Alto Calif. ) or isolated from various tissues. Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Life Technologies), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCl cushions or extracted with chloroform. RNA was precipitated with either isopropanol or sodium acetate and ethanol, or by other routine methods.

[0224] Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA purity. In most cases, RNA was treated with DNase. For most libraries, poly(A+) RNA was isolated using oligo d(T)-coupled paramagnetic particles (Promega Corporation (Promega), Madison Wis.), OLIGOTEX latex particles (QIAGEN, Inc. (QIAGEN), Valencia Calif.), or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively, RNA was isolated directly from tissue lysates using other RNA isolation kits, e.g., the POLY(A)PURE mRNA purification kit (Ambion, Inc., Austin Tex.).

[0225] In some cases, Stratagene was provided with RNA and constructed the corresponding cDNA libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP vector system (Stratagene Cloning Systems, Inc. (Stratagene), La Jolla Calif.) or SUPERSCRIPT plasmid system (Life Technologies), using the recommended procedures or similar methods known in the art. (See, e.g., Ausubel, 1997, supra, Chapters 5.1 through 6.6.) Reverse transcription was initiated using oligo d(T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL SI 000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Pharmacia Biotech) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORT1 plasmid (Life Technologies), PCDNA2.1 plasmid (Invitrogen, Carlsbad Calif.), PBK-CMV plasmid (Stratagene), or pINCY (Incyte Genomics, Palo Alto Calif.), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XL1-BlueMRF, or SOLR from Stratagene or DH5α, DH10B, or ElectroMAX DH10B from Life Technologies.

[0226] II. Isolation of cDNA Clones

[0227] Plasmids were recovered from host cells by in vivo excision using the UNIZAP vector system (Stratagene) or by cell lysis. Plasmids were purified using at least one of the following: the Magic or WIZARD Minipreps DNA purification system (Promega); the AGTC Miniprep purification kit (Edge BioSystems, Gaithersburg Md.); and the QIAWELL 8, QIAWELL 8 Plus, and QIAWELL 8 Ultra plasmid purification systems or the R.E.A.L. PREP 96 plasmid purification kit (QIAGEN). Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without lyophilization, at 4° C.

[0228] Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format. (Rao, V. B. (1994) Anal. Biochem. 216:1-14.) Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified plasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Inc. (Molecular Probes), Eugene Oreg.) and a FLUOROSKAN II fluorescence scanner (Labsystems Oy, Helsinki, Finland).

[0229] III. Sequencing and Analysis

[0230] cDNA sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 thermal cycler (Applied Biosystems) or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientific Corp., Sunnyvale Calif.) or the MICROLAB 2200 liquid transfer system (Hamilton). cDNA sequencing reactions were prepared using reagents provided by Amersham Pharmacia Biotech or supplied in ABI sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems). Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Molecular Dynamics); the ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction with standard ABI protocols and base calling software; or other sequence analysis systems known in the art. Reading frames within the cDNA sequences were identified using standard methods (reviewed in Ausubel, 1997, supra, Chapter 7.7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.

[0231] IV. Assembly and Analysis of Sequences

[0232] Component sequences from chromatograms were subject to PHRED analysis and assigned a quality score. The sequences having at least a required quality score were subject to various pre-processing editing pathways to eliminate, e.g., low quality 3′ ends, vector and linker sequences, polyA tails, Alu repeats, mitochondrial and ribosomal sequences, bacterial contamination sequences, and sequences smaller than 50 base pairs. In particular, low-information sequences and repetitive elements (e.g., dinucleotide repeats, Alu repeats, etc.) were replaced by “n's”, or masked, to prevent spurious matches.

[0233] Processed sequences were then subject to assembly procedures in which the sequences were assigned to gene bins (bins). Each sequence could only belong to one bin. Sequences in each gene bin were assembled to produce consensus sequences (templates). Subsequent new sequences were added to existing bins using BLASTn (v. 1.4 WashU) and CROSSMATCH. Candidate pairs were identified as all BLAST hits having a quality score greater than or equal to 150. Alignments of at least 82% local identity were accepted into the bin. The component sequences from each bin were assembled using a version of PHRAP. Bins with several overlapping component sequences were assembled using DEEP PHRAP. The orientation (sense or antisense) of each assembled template was determined based on the number and orientation of its component sequences. Template sequences as disclosed in the sequence listing correspond to sense strand sequences (the “forward” reading frames), to the best determination. The complementary (antisense) strands are inherently disclosed herein. The component sequences which were used to assemble each template consensus sequence are listed in Table 2 along with their positions along the template nucleotide sequences.

[0234] Bins were compared against each other and those having local similarity of at least 82% were combined and reassembled. Reassembled bins having templates of insufficient overlap (less than 95% local identity) were re-split. Assembled templates were also subject to analysis by STITCHER/EXON MAPPER algorithms which analyze the probabilities of the presence of splice variants, alternatively spliced exons, splice junctions, differential expression of alternative spliced genes across tissue types or disease states, etc. These resulting bins were subject to several rounds of the above assembly procedures.

[0235] Once gene bins were generated based upon sequence alignments, bins were clone joined based upon clone information. If the 5′ sequence of one clone was present in one bin and the 3′ sequence from the same clone was present in a different bin, it was likely that the two bins actually belonged together in a single bin. The resulting combined bins underwent assembly procedures to regenerate the consensus sequences.

[0236] The final assembled templates were subsequently annotated using the following procedure. Template sequences were analyzed using BLASTn (v2.0, NCBI) versus gbpri (GenBank version 120). “Hits” were defined as an exact match having from 95% local identity over 200 base pairs through 100% local identity over 100 base pairs, or a homolog match having an E-value, i.e. a probability score, of ≦1×10−8. The hits were subject to frameshift FASTx versus GENPEPT (GenBank version 120). (See Table 4). In this analysis, a homolog match was defined as having an E-value of ≦1×10−8. The assembly method used above was described in “System and Methods for Analyzing Biomolecular Sequences,” U.S. Ser. No. 09/276,534, filed Mar. 25, 1999, and the LIFESEQ Gold user manual (Incyte) both incorporated by reference herein.

[0237] Following assembly, template sequences were subjected to motif, BLAST, and functional analyses, and categorized in protein hierarchies using methods described in, e.g., “Database System Employing Protein Function Hierarchies for Viewing Biomolecular Sequence Data,” U.S. Ser. No. 08/812,290, filed Mar. 6, 1997; “Relational Database for Storing Biomolecule Information,” U.S. Ser. No. 08/947,845, filed Oct. 9, 1997; “Project-Based Full-Length Biomolecular Sequence Database,” U.S. Ser. No. 08/811,758, filed Mar. 6, 1997; and “Relational Database and System for Storing Information Relating to Biomolecular Sequences,” U.S. Ser. No. 09/034,807, filed Mar. 4, 1998, all of which are incorporated by reference herein.

[0238] The template sequences were further analyzed by translating each template in all three forward reading frames and searching each translation against the Pfam database of hidden Markov model-based protein families and domains using the HMMER software package (available to the public from Washington University School of Medicine, St. Louis Mo.). (See also World Wide Web site http://pfam.wustl.edu/ for detailed descriptions of Pfam protein domains and families.)

[0239] Additionally, the template sequences were translated in all three forward reading frames, and each translation was searched against hidden Markov models for signal peptides using the HMMER software package. Construction of hidden Markov models and their usage in sequence analysis has been described. (See, for example, Eddy, S. R. (1996) Curr. Opin. Str. Biol. 6:361-365.) Only those signal peptide hits with a cutoff score of 11 bits or greater are reported. A cutoff score of 11 bits or greater corresponds to at least about 91-94% true-positives in signal peptide prediction. Template sequences were also translated in all three forward reading frames, and each translation was searched against TMAP, a program that uses weight matrices to delineate transmembrane segments on protein sequences and determine orientation, with respect to the cell cytosol (Persson, B. and Argos, P. (1994) J. Mol. Biol. 237:182-192, and Persson, B. and Argos, P. (1996) Protein Sci. 5:363-371.) Regions of templates which, when translated, contain similarity to signal peptide or transmembrane consensus sequences are reported in Table 1.

[0240] Template sequences are further analyzed using the bioinformatics tools listed in Table 4, or using sequence analysis software known in the art such as MACDNASIS PRO software (Hitachi Software Engineering, South San Francisco Calif.) and LASERGENE software (DNASTAR). Template sequences may be further queried against public databases such as the GenBank rodent, mammalian, vertebrate, prokaryote, and eukaryote databases.

[0241] V. Analysis of Polynucleotide Expression

[0242] Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound. (See, e.g., Sambrook, supra, ch. 7; Ausubel, 1995, supra, ch. 4 and 16.)

[0243] Analogous computer techniques applying BLAST were used to search for identical or related molecules in cDNA databases such as GenBank or LIFESEQ (Incyte Genomics). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as exact or similar. The basis of the search is the product score, which is defined as:

\frac{BLAST Score \times Percent Identity}{5 \times minimum {length (Seq . 1), length (Seq . 2)}}

[0244] The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows: the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 times the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and −4 for every mismatch. Two sequences may share more than one HSP (separated by gaps). If there is more than one HSP, then the pair with the highest BLAST score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST alignment. For example, a product score of 100 is produced only for 100% identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100% identity and 70% overlap at one end, or by 88% identity and 100% overlap at the other. A product score of 50 is produced either by 100% identity and 50% overlap at one end, or 79% identity and 100% overlap.

[0245] Alternatively, polynucleotide sequences encoding SPTM are analyzed with respect to the tissue sources from which they were derived. Polynucleotide sequences encoding SPTM were assembled, at least in part, with overlapping Incyte cDNA sequences. Each cDNA sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organ/tissue categories: cardiovascular system; connective tissue; digestive system; embryonic structures; endocrine system; exocrine glands; genitalia, female; genitalia, male; germ cells; hemic and immune system; liver; musculoskeletal system; nervous system; pancreas; respiratory system; sense organs; skin; stomatognathic system; unclassified/mixed; or urinary tract. The number of libraries in each category for each polynucleotide sequence encoding SPTM is counted and divided by the total number of libraries across all categories for each polynucleotide sequence encoding SPTM. Similarly, each human tissue is classified into one of the following disease/condition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category for each polynucleotide sequence encoding SPTM is counted and divided by the total number of libraries across all categories for each polynucleotide sequence encoding SPTM. The resulting percentages reflect the tissue-specific and disease-specific expression of cDNA encoding SPTM. Percentage values of tissue-specific expression are reported in Table 3. cDNA sequences and cDNA library/tissue information are found in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto Calif.).

[0246] VI. Tissue Distribution Profiling

[0247] A tissue distribution profile is determined for each template by compiling the cDNA library tissue classifications of its component cDNA sequences. Each component sequence, is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following categories: cardiovascular system; connective tissue; digestive system; embryonic structures; endocrine system; exocrine glands; genitalia, female; genitalia, male; germ cells; hemic and immune system; liver; musculoskeletal system; nervous system; pancreas; respiratory system; sense organs; skin; stomatognathic system; unclassified/mixed; or urinary tract. Template sequences, component sequences, and cDNA library/tissue information are found in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto Calif.).

[0248] Table 3 shows the tissue distribution profile for the templates of the invention. For each template, the three most frequently observed tissue categories are shown in column 2, along with the percentage of component sequences belonging to each category. Only tissue categories with percentage values of ≧10% are shown. A tissue distribution of “widely distributed” in column 2 indicates percentage values of <10% in all tissue categories.

[0249] VII. Transcript Image Analysis

[0250] Transcript images are generated as described in Seilhamer et al., “Comparative Gene Transcript Analysis,” U.S. Pat. No. 5,840,484, incorporated herein by reference.

[0251] VIII. Extension of Polynucleotide Sequences and Isolation of a Full-length cDNA

[0252] Oligonucleotide primers designed using an sptm of the Sequence Listing are used to extend the nucleic acid sequence. One primer is synthesized to initiate 5′ extension of the template, and the other primer, to initiate 3′ extension of the template. The initial primers may be designed using OLIGO 4.06 software (National Biosciences, Inc. (National Biosciences), Plymouth Minn.), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68° C. to about 72° C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations are avoided. Selected human cDNA libraries are used to extend the sequence. If more than one extension is necessary or desired, additional or nested sets of primers are designed.

[0253] High fidelity amplification is obtained by PCR using methods well known in the art. PCR is performed in 96-well plates using the PTC-200 thermal cycler (MJ Research). The reaction mix contains DNA template, 200 nmol of each primer, reaction buffer containing Mg2+, (NH4)2SO4, and β-mercaptoethanol, Taq DNA polymerase (Amersham Pharmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerase (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 60° C., 1 min; Step 4: 68° C., 2 min; Step 5: Steps 2,3, and4 repeated 20 times; Step 6: 68° C., 5 min; Step 7: storage at 4° C. In the alternative, the parameters for primer pair T7 and SK+ are as follows: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 57° C., 1 min; Step 4: 68° C., 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68° C., 5 min; Step 7: storage at 4° C.

[0254] The concentration of DNA in each well is determined by dispensing 100 μl PICOGREEN quantitation reagent (0.25% (v/v); Molecular Probes) dissolved in 1×Tris-EDTA (TE) and 0.5 μl of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Incorporated (Corning), Corning N.Y.), allowing the DNA to bind to the reagent. The plate is scanned in a FLUOROSKAN II (Labsystems Oy) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 μl to 10 μl aliquot of the reaction mixture is analyzed by electrophoresis on a 1% agarose mini-gel to determine which reactions are successful in extending the sequence.

[0255] The extended nucleotides are desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease (Molecular Biology Research, Madison Wis.), and sonicated or sheared prior to religation into pUC 18 vector (Amersham Pharmacia Biotech). For shotgun sequencing, the digested nucleotides are separated on low concentration (0.6 to 0.8%) agarose 25 gels, fragments are excised, and agar digested with AGAR ACE (Promega). Extended clones are religated using T4 ligase (New England Biolabs, Inc., Beverly Mass.) into pUC 18 vector (Amersham Pharmacia Biotech), treated with Pfu DNA polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells are selected on antibiotic-containing media, individual colonies are picked and cultured overnight at 37° C. in 384-well plates in LB/2×carbenicillin liquid media.

[0256] The cells are lysed, and DNA is amplified by PCR using Taq DNA polymerase (Amershain Pharmacia Biotech) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 60° C., 1 min; Step 4: 72° C., 2 min; Step 5: steps 2, 3, and 4 repeated 29 times; Step 6: 72° C., 5 min; Step 7: storage at 4° C. DNA is quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA recoveries are reamplified using the same conditions as described above. Samples are diluted with 20% dimethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Pharmacia Biotech) or the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).

[0257] In like manner, the sptm is used to obtain regulatory sequences (promoters, introns, and enhancers) using the procedure above, oligonucleotides designed for such extension, and an appropriate genomic library.

[0258] IX. Labeling of Probes and Southern Hybridization Analyses

[0259] Hybridization probes derived from the sptm of the Sequence Listing are employed for screening cDNAs, mRNAs, or genomic DNA. The labeling of probe nucleotides between 100 and 1000 nucleotides in length is specifically described, but essentially the same procedure may be used with larger cDNA fragments. Probe sequences are labeled at room temperature for 30 minutes using a T4 polynucleotide kinase, γ32P-ATP, and 0.5×One-Phor-All Plus (Amersham Pharmacia Biotech) buffer and purified using a ProbeQuant G-50 Microcolumn (Amersham Pharmacia Biotech). The probe mixture is diluted to 107 dpm/μg/ml hybridization buffer and used in a typical membrane-based hybridization analysis.

[0260] The DNA is digested with a restriction endonuclease such as Eco RV and is electrophoresed through a 0.7% agarose gel. The DNA fragments are transferred from the agarose to nylon membrane (NYTRAN Plus, Schleicher & Schuell, Inc., Keene N.H.) using procedures specified by the manufacturer of the membrane. Prehybridization is carried out for three or more hours at 68° C., and hybridization is carried out overnight at 68° C. To remove non-specific signals, blots are sequentially washed at room temperature under increasingly stringent conditions, up to 0.1×saline sodium citrate (SSC) and 0.5% sodium dodecyl sulfate. After the blots are placed in a PHOSPHORIMAGER cassette (Molecular Dynamics) or are exposed to autoradiography film, hybridization patterns of standard and experimental lanes are compared. Essentially the same procedure is employed when screening RNA.

[0261] X. Chromosome Mapping of sptm

[0262] The cDNA sequences which were used to assemble SEQ ID NO: 1-79 are compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that match SEQ ID NO: 1-79 are assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as PHRAP (Table 4). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for Genome Research (WIGR), and Genethon are used to determine if any of the clustered sequences have been previously mapped. Inclusion of a mapped sequence in a cluster will result in the assignment of all sequences of that cluster, including its particular SEQ ID NO:, to that map location. The genetic map locations of SEQ ID NO: 1-79 are described as ranges, or intervals, of human chromosomes. The map position of an interval, in centiMorgans, is measured relative to the terminus of the chromosome's p-arm. (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination.) The cM distances are based on genetic markers mapped by Gendthon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters.

[0263] XI. Microarray Analysis

[0264] Probe Preparation from Tissue or Cell Samples

[0265] Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and polyA+ RNA is purified using the oligo (dT) cellulose method. Each polyA+ RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/μl oligo-dT primer (21 mer), 1×first strand buffer, 0.03 units/μl RNase inhibitor, 500 μM dATP, 500 μM dGTP, 500 μM dTTP, 40 μM dCTP, 40 μM dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Pharmacia Biotech). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng polyA+ RNA with GEMBRIGHT kits (Incyte). Specific control polyA+ RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA (W. Lei, unpublished). As quantitative controls, the control mRNAs at 0.002 ng, 0.02 ng, 0.2 ng, and 2 ng are diluted into reverse transcription reaction at ratios of 1:100,000, 1:10,000, 1:1000, 1:100 (w/w) to sample mRNA respectively. The control mRNAs are diluted into reverse transcription reaction at ratios of 1:3, 3:1,1:10, 10:1,1:25, 25:1 (w/w) to sample mRNA differential expression patterns. After incubation at 37° C. for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of 0.5M sodium hydroxide and incubated for 20 minutes at 85° C. to the stop the reaction and degrade the RNA. Probes are purified using two successive CHROMA SPIN 30 gel filtration spin columns (CLONTECH Laboratories, Inc. (CLONTECH), Palo Alto Calif.) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100% ethanol. The probe is then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook N.Y.) and resuspended in 14 μl 5×SSC/0.2% SDS.

[0266] Microarray Preparation

[0267] Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts. PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert. Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 μg. Amplified array elements are then purified using SEPHACRYL-400 (Amersham Pharmacia Biotech).

[0268] Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0.1% SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4% hydrofluoric acid (VWR Scientific Products Corporation (VWR), West Chester, Pa.), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are cured in a 110° C. oven.

[0269] Array elements are applied to the coated glass substrate using a procedure described in U.S. Pat. No. 5,807,522, incorporated herein by reference. 1 μl of the array element DNA, at an average concentration of 100 ng/μl, is loaded into the open capillary printing element by a high-speed robotic apparatus. The apparatus then deposits about 5 ml of array element sample per slide.

[0270] Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene). Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water. Non-specific binding sites are blocked by incubation of microarrays in 0.2% casein in phosphate buffered saline (PBS) (Tropix, Inc., Bedford, Mass.) for 30 minutes at 60° C. followed by washes in 0.2% SDS and distilled water as before.

[0271] Hybridization

[0272] Hybridization reactions contain 9 μl of probe mixture consisting of 0.2 μg each of Cy3 and Cy5 labeled cDNA synthesis products in 5×SSC, 0.2% SDS hybridization buffer. The probe mixture is heated to 65° C. for 5 minutes and is aliquoted onto the microarray surface and covered with an 1.8 cm2 coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 μl of 5×SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60° C. The arrays are washed for 10 min at 45° C. in a first wash buffer (1×SSC, 0.1% SDS), three times for 10 minutes each at 45° C. in a second wash buffer (0.1×SSC), and dried.

[0273] Detection

[0274] Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara Calif.) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of Cy5. The excitation laser light is focused on the array using a 20×microscope objective (Nikon, Inc., Melville N.Y.). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster-scanned past the objective. The 1.8 cm×1.8 cm array used in the present example is scanned with a resolution of 20 micrometers.

[0275] In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially. Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT R1477, Hamamatsu Photonics Systems, Bridgewater N.J.) corresponding to the two fluorophores. Appropriate filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for Cy5. Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.

[0276] The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the probe mix at a known concentration. A specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1:100,000. When two probes from different sources (e.g., representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.

[0277] The output of the photomultiplier tube is digitized using a 12-bit RTI-835H analog-to-digital (AID) conversion board (Analog Devices, Inc., Norwood, Mass.) installed in an IBM-compatible PC computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simultaneously, the data are first corrected for optical crosstalk (due to overlapping emission spectra) between the fluorophores using each fluorophore's emission spectrum.

[0278] A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte).

[0279] XII. Complementary Nucleic Acids

[0280] Sequences complementary to the sptm are used to detect, decrease, or inhibit expression of the naturally occurring nucleotide. The use of oligonucleotides comprising from about 15 to 30 base pairs is typical in the art. However, smaller or larger sequence fragments can also be used. Appropriate oligonucleotides are designed from the sptm using OLIGO 4.06 software (National Biosciences) or other appropriate programs and are synthesized using methods standard in the art or ordered from a commercial supplier. To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5′ sequence and used to prevent transcription factor binding to the promoter sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding and processing of the transcript.

[0281] XIII. Expression of SPTM

[0282] Expression and purification of SPTM is accomplished using bacterial or virus-based expression systems. For expression of SPTM in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the T5 or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21(DE3). Antibiotic resistant bacteria express SPTM upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of SPTM in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Autographica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding SPTM by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Snodoptera frugiperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases. Infection of the latter requires additional genetic modifications to baculovirus. (See e.g., Engelhard, supra; and Sandig, supra.)

[0283] In most expression systems, SPTM is synthesized as a fusion protein with, e.g., glutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysates. GST, a 26-kilodalton enzyme from Schistosoma japonicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Pharmacia Biotech). Following purification, the GST moiety can be proteolytically cleaved from SPTM at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG antibodies (Eastman Kodak Company, Rochester N.Y.). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN). Methods for protein expression and purification are discussed in Ausubel (1995, supra, Chapters 10 and 16). Purified SPTM obtained by these methods can be used directly in the following activity assay.

[0284] XIV. Demonstration of SPTM Activity

[0285] An assay for SPTM activity measures the expression of SPTM on the cell surface. cDNA encoding SPTM is subcloned into an appropriate mammalian expression vector suitable for high levels of cDNA expression. The resulting construct is transfected into a nonhuman cell line such as NIH3T3. Cell surface proteins are labeled with biotin using methods known in the art. Immunoprecipitations are performed using SPTM-specific antibodies, and immunoprecipitated samples are analyzed using SDS-PAGE and immunoblotting techniques. The ratio of labeled immunoprecipitant to unlabeled immunoprecipitant is proportional to the amount of SPTM expressed on the cell surface.

[0286] Alternatively, an assay for SPTM activity measures the amount of SPTM in secretory, membrane-bound organelles. Transfected cells as described above are harvested and lysed. The lysate is fractionated using methods known to those of skill in the art, for example, sucrose gradient ultracentrifugation. Such methods allow the isolation of subcellular components such as the Golgi apparatus, ER, small membrane-bound vesicles, and other secretory organelles. Immunoprecipitations from fractionated and total cell lysates are performed using SPTM-specific antibodies, and immunoprecipitated samples are analyzed using SDS-PAGE and immunoblotting techniques. The concentration of SPTM in secretory organelles relative to SPTM in total cell lysate is proportional to the amount of SPTM in transit through the secretory pathway.

[0287] XV. Functional Assays

[0288] SPTM function is assessed by expressing sptm at physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA expression. Vectors of choice include pCMV SPORT (Life Technologies) and pCR3.1 (Invitrogen Corporation, Carlsbad Calif.), both of which contain the cytomegalovirus promoter. 5-10 μg of recombinant vector are transiently transfected into a human cell line, preferably of endothelial or hematopoietic origin, using either liposonme formulations or electroporation. 1-2 μg of an additional plasmid containing sequences encoding a marker protein are co-transfected.

[0289] Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector. Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP; CLONTECH), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated laser optics-based technique, is used to identity transfected cells expressing GFP or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties.

[0290] FCM detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA with propidium iodide; changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake; alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M. G. (1994) Flow Cytometry, Oxford, New York N.Y.

[0291] The influence of SPTM on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding SPTM and either CD64 or CD64-GFP. CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human immunoglobulin G (IgG). Transfected cells ate efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 (DYNAL, Inc., Lake Success N.Y.). mRNA can be purified from the cells using methods well known by those of skill in the art. Expression of mRNA encoding SPTM and other genes of interest can be analyzed by northern analysis or microarray techniques.

[0292] XVI. Production of Antibodies

[0293] SPTM substantially purified using polyacrylamide gel electrophoresis (PAGE; see, e.g., Harrington, M. G. (1990) Methods Enzymol. 182:488-495), or other purification techniques, is used to immunize rabbits and to produce antibodies using standard protocols.

[0294] Alternatively, the SPTM amino acid sequence is analyzed using LASERGENE software (DNASTAR) to determine regions of high immunogenicity, and a corresponding peptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art. (See, e.g., Ausubel, 1995, supra, Chapter 11.)

[0295] Typically, peptides 15 residues in length are synthesized using an ABI 431A peptide synthesizer (Applied Biosystems) using fmoc-chemistry and coupled to KLH (Sigma) by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity. (See, e.g., Ausubel, supra.) Rabbits are immunized with the peptide-KLH complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide activity by, for example, binding the peptide to plastic, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG. Antisera with antipeptide activity are tested for anti-SPTM activity using protocols well known in the art, including ELISA, RIA, and immunoblotting.

[0296] XVII. Purification of Naturally Occurring SPTM Using Specific Antibodies

[0297] Naturally occurring or recombinant SPTM is substantially purified by immunoaffinity chromatography using antibodies specific for SPTM. An immunoaffinity column is constructed by covalently coupling anti-SPTM antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.

[0298] Media containing SPTM are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of SPTM (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/SPTM binding (e.g., a buffer of pH 2 to pH 3, or a high concentration of a chaotrope, such as urea or thiocyanate ion), and SPTM is collected.

[0299] XVIII. Identification of Molecules Which Interact with SPTM

[0300] SPTM, or biologically active fragments thereof, are labeled with 125I Bolton-Hunter reagent. (See, e.g., Bolton, A. E. and W. M. Hunter (1973) Biochem. J. 133:529-539.) Candidate molecules previously arrayed in the wells of a multi-well plate are incubated with the labeled SPTM, washed, and any wells with labeled SPTM complex are assayed. Data obtained using different concentrations of SPTM are used to calculate values for the number, affinity, and association of SPTM with the candidate molecules.

[0301] Alternatively, molecules interacting with SPTM are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989) Nature 340:245-246, or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (CLONTECH). SPTM may also be used in the PATHCALLING process (CuraGen Corp., New Haven Conn.) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K. et al. (2000) U.S. Pat. No. 6,057,101).

[0302] All publications and patents mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention which are obvious to those skilled in the field of molecular biology or related fields are intended to be within the scope of the following claims.

2TABLE 1SEQDomainID NO:Template IDStartStopFrameTypeTopology1LG:223939.1:2000FEB18202288forward 1TMN in2LG:397140.1:2000FEB18508588forward 1TM2LG:397140.1:2000FEB18236319forward 2TMN out2LG:397140.1:2000FEB18377463forward 2TMN out2LG:397140.1:2000FEB18288374forward 3TM2LG:397140.1:2000FEB18480566forward 3TM3LG:1094205.1:2000FEB18826912forward 1TMN in3LG:1094205.1:2000FEB18867953forward 3TMN out4LG:481361.5:2000FEB18115201forward 1TMN out4LG:481361.5:2000FEB18295354forward 1TMN out4LG:481361.5:2000FEB18373459forward 1TMN out4LG:481361.5:2000FEB18101187forward 2TMN out4LG:481361.5:2000FEB18369443forward 3TMN out5LG:981170.1:2000FEB181078forward 1TMN out5LG:981170.1:2000FEB18598648forward 1TMN out5LG:981170.1:2000FEB18790876forward 1TMN out5LG:981170.1:2000FEB1810571143forward 1TMN out5LG:981170.1:2000FEB1813721458forward 1TMN out5LG:981170.1:2000FEB1816781764forward 1TMN out5LG:981170.1:2000FEB1818851959forward 1TMN out5LG:981170.1:2000FEB181182forward 2TMN out5LG:981170.1:2000FEB18731817forward 2TMN out5LG:981170.1:2000FEB1810251105forward 2TMN out5LG:981170.1:2000FEB1813641450forward 2TMN out5LG:981170.1:2000FEB1816431696forward 2TMN out5LG:981170.1:2000FEB1818951954forward 2TMN out5LG:981170.1:2000FEB1824110forward 3TMN out5LG:981170.1:2000FEB18843899forward 3TMN out5LG:981170.1:2000FEB1810681136forward 3TMN out5LG:981170.1:2000FEB1815991655forward 3TMN out5LG:981170.1:2000FEB1817071793forward 3TMN out5LG:981170.1:2000FEB1818751961forward 3TMN out6LI:197613.1:2000FEB01140226forward 2TMN out6LI:197613.1:2000FEB01269355forward 2TMN out7LI:902682.1:2000FEB01225311forward 3TMN out8LI:212029.1:2000FEB0120872149forward 2TMN out8LI:212029.1:2000FEB0121622224forward 2TMN out9LI:249170.1:2000FEB01208282forward 1TMN in10LI:813218.1:2000FEB01466552forward 1TMN out10LI:813218.1:2000FEB01137202forward 2TMN out10LI:813218.1:2000FEB01356436forward 2TMN out10LI:813218.1:2000FEB01452520forward 2TMN out11LI:902522.3:2000FEB0199158forward 3TMN out12LI:474304.1:2000FEB0164147forward 1TMN in12LI:474304.1:2000FEB01217285forward 1TMN in12LI:474304.1:2000FEB01298372forward 1TMN in12LI:474304.1:2000FEB012688forward 2TMN out12LI:474304.1:2000FEB01110172forward 2TMN out12LI:474304.1:2000FEB01200271forward 2TMN out12LI:474304.1:2000FEB01332418forward 2TMN out12LI:474304.1:2000FEB01890952forward 2TMN out12LI:474304.1:2000FEB0172158forward 3TMN out12LI:474304.1:2000FEB01273332forward 3TMN out12LI:474304.1:2000FEB01330383forward 3TMN out12LI:474304.1:2000FEB01606674forward 3TMN out13LI:027320.1:2000FEB01544603forward 1TMN out13LI:027320.1:2000FEB01694768forward 1TMN out13LI:027320.1:2000FEB0111021182forward 1TMN out13LI:027320.1:2000FEB0111801236forward 1TMN out13LI:027320.1:2000FEB01545604forward 2TM13LI:027320.1:2000FEB01851913forward 2TM13LI:027320.1:2000FEB01932994forward 2TM13LI:027320.1:2000FEB0110131075forward 2TM13LI:027320.1:2000FEB0111721228forward 2TM13LI:027320.1:2000FEB01579665forward 3TMN in13LI:027320.1:2000FEB01720806forward 3TMN in13LI:027320.1:2000FEB01828908forward 3TMN in13LI:027320.1:2000FEB0110201103forward 3TMN in13LI:027320.1:2000FEB0111161202forward 3TMN in14LI:228319.1:2000FEB0176162forward 1TMN out14LI:228319.1:2000FEB01119187forward 2TMN in14LI:228319.1:2000FEB01506592forward 2TMN in14LI:228319.1:2000FEB0163149forward 3TMN in14LI:228319.1:2000FEB01369455forward 3TMN in14LI:228319.1:2000FEB01708770forward 3TMN in14LI:228319.1:2000FEB01786848forward 3TMN in15LG:197267.2:2000MAY191188forward 2TMN in15LG:197267.2:2000MAY19200271forward 2TMN in16LG:403332.1:2000MAY19352417forward 1TMN in16LG:403332.1:2000MAY19490552forward 1TMN in16LG:403332.1:2000MAY19562624forward 1TMN in16LG:403332.1:2000MAY19721783forward 1TMN in16LG:403332.1:2000MAY19796858forward 1TMN in16LG:403332.1:2000MAY19871948forward 1TMN in16LG:403332.1:2000MAY1910121098forward 1TMN in16LG:403332.1:2000MAY1911381188forward 1TMN in16LG:403332.1:2000MAY1911921278forward 1TMN in16LG:403332.1:2000MAY1914531530forward 1TMN in16LG:403332.1:2000MAY19365427forward 2TMN in16LG:403332.1:2000MAY19521607forward 2TMN in16LG:403332.1:2000MAY19644727forward 2TMN in16LG:403332.1:2000MAY19800886forward 2TMN in16LC:403332.1:2000MAY19911973forward 2TMN in16LG:403332.1:2000MAY199861048forward 2TMN in16LG:403332.1:2000MAY1912111297forward 2TMN in16LG:403332.1:2000MAY1914451504forward 2TMN in16LG:403332.1:2000MAY19375461forward 3TM16LG:403332.1:2000MAY19495557forward 3TM16LG:403332.1:2000MAY19594656forward 3TM16LG:403332.1:2000MAY19681767forward 3TM16LG:403332.1:2000MAY199901052forward 3TM16LG:403332.1:2000MAY1910771139forward 3TM16LG:403332.1:2000MAY1912031274forward 3TM16LG:403332.1:2000MAY1913321385forward 3TM17LG:983076.3:2000MAY19479565forward 2TMN in17LG:983076.3:2000MAY19704790forward 2TMN in17LG:983076.3:2000MAY19114200forward 3TMN out17LG:983076.3:2000MAY19261317forward 3TMN out17LG:983076.3:2000MAY19501587forward 3TMN out17LG:983076.3:2000MAY19738794forward 3TMN out18LG:216612.3:2000MAY19120206forward 3TMN in18LG:216612.3:2000MAY19234284forward 3TMN in18LG:216612.3:2000MAY19327413forward 3TMN in18LG:216612.3:2000MAY19444530forward 3TMN in18LG:216612.3:2000MAY19810887forward 3TMN in19LG:322465.1:2000MAY19239319forward 2TMN out19LG:322465.1:2000MAY19276329forward 3TMN out20LG:093477.1:2000MAY1925111forward 1TMN out20LG:093477.1:2000MAY191185forward 2TMN out20LG:093477.1:2000MAY19242295forward 2TMN out20LG:093477.1:2000MAY1924110forward 3TMN in20LG:093477.1:2000MAY19657719forward 3TMN in21LG:222880.1:2000MAY19211297forward 1TM21LG:222880.1:2000MAY1916631749forward 1TM21LG:222880.1:2000MAY1918011863forward 1TM21LG:222880.1:2000MAY1919061968forward 1TM21LG:222880.1:2000MAY1922692316forward 1TM21LG:222880.1:2000MAY19425487forward 2TMN in21LG:222880.1:2000MAY19506568forward 2TMN in21LG:222880.1:2000MAY19611691forward 2TMN in21LG:222880.1:2000MAY19698784forward 2TMN in21LG:222880.1:2000MAY19875961forward 2TMN in21LG:222880.1:2000MAY1910161078forward 2TMN in21LG:222880.1:2000MAY1911061168forward 2TMN in21LG:222880.1:2000MAY1915441630forward 2TMN in21LG:222880.1:2000MAY1916911774forward 2TMN in21LG:222880.1:2000MAY1919402026forward 2TMN in21LG:222880.1:2000MAY1923152395forward 2TMN in21LG:222880.1:2000MAY1917101784forward 3TMN out21LG:222880.1:2000MAY1918091895forward 3TMN out21LG:222880.1:2000MAY1919262009forward 3TMN out21LG:222880.1:2000MAY1920642129forward 3TMN out22LG:898320.3:2000MAY19151237forward 1TMN out22LG:898320.3:2000MAY19478534forward 1TMN out22LG:898320.3:2000MAY19736822forward 1TMN out22LG:898320.3:2000MAY1915281599forward 1TMN out22LG:898320.3:2000MAY1916631710forward 1TMN out22LG:898320.3:2000MAY1920172088forward 1TMN out22LG:898320.3:2000MAY1921312184forward 1TMN out22LG:898320.3:2000MAY19719796forward 2TMN in22LG:898320.3:2000MAY1913341420forward 2TMN in22LG:898320.3:2000MAY1915981681forward 2TMN in22LG:898320.3:2000MAY1917331819forward 2TMN in22LG:898320.3:2000MAY1919191984forward 2TMN in22LG:898320.3:2000MAY1920782140forward 2TMN in22LG:898320.3:2000MAY1921592245forward 2TMN in22LG:898320.3:2000MAY1990176forward 3TMN out22LG:898320.3:2000MAY19411485forward 3TMN out22LG:898320.3:2000MAY19501578forward 3TMN out22LG:898320.3:2000MAY19600686forward 3TMN out22LG:898320.3:2000MAY19783854forward 3TMN out22LG:898320.3:2000MAY19912989forward 3TMN out22LG:898320.3:2000MAY1910231097forward 3TMN out22LG:898320.3:2000MAY1911641226forward 3TMN out22LG:898320.3:2000MAY1912361298forward 3TMN out22LG:898320.3:2000MAY1913351421forward 3TMN out22LG:898320.3:2000MAY1920162093forward 3TMN out22LG:898320.3:2000MAY1921512237forward 3TMN out23LG:1327047.1:2000MAY19466552forward 1TMN out23LG:1327047.1:2000MAY19137202forward 2TMN out23LG:1327047.1:2000MAY19356436forward 2TMN out23LG:1327047.1:2000MAY19452520forward 2TMN out23LG:1327047.1:2000MAY1911311217forward 3TM24LG:235157.21:2000MAY191191forward 2TMN out24LG:235157.21:2000MAY19161247forward 2TMN out24LG:235157.21:2000MAY19467529forward 2TMN out24LG:235157.21:2000MAY19551613forward 2TMN out24LG:235157.21:2000MAY19686760forward 2TMN out24LG:235157.21:2000MAY19785862forward 2TMN out25LG:085713.1:2000MAY1997183forward 1TMN out25LG:085713.1:2000MAY1914891575forward 1TMN out25LG:085713.1:2000MAY1917861854forward 1TMN out25LG:085713.1:2000MAY1922752361forward 1TMN out25LG:085713.1:2000MAY1924072493forward 1TMN out25LG:085713.1:2000MAY19134211forward 2TMN in25LG:085713.1:2000MAY1914811528forward 2TMN in25LG:085713.1:2000MAY1920992164forward 2TMN in25LG:085713.1:2000MAY1923872449forward 2TMN in25LG:085713.1:2000MAY1924742536forward 2TMN in25LG:085713.1:2000MAY1972158forward 3TMN out25LG:085713.1:2000MAY1914881574forward 3TMN out25LG:085713.1:2000MAY1920372108forward 3TMN out25LG:085713.1:2000MAY1921842270forward 3TMN out25LG:085713.1:2000MAY1923462432forward 3TMN out26LG:482421.1:2000MAY19385456forward 1TMN out26LG:482421.1:2000MAY19715777forward 1TMN out26LG:482421.1:2000MAY19841909forward 1TMN out26LG:482421.1:2000MAY1997011056forward 1TMN out26LG:482421.1:2000MAY1912221284forward 1TMN out26LG:482421.1:2000MAY1914231491forward 1TMN out26LG:482421.1:2000MAY1921852271forward 1TMN out26LG:482421.1:2000MAY1925182604forward 1TMN out26LG:482421.1:2000MAY1926742760forward 1TMN out26LG:482421.1:2000MAY191164forward 2TMN out26LG:482421.1:2000MAY19260346forward 2TMN out26LG:482421.1:2000MAY19416502forward 2TMN out26LG:482421.1:2000MAY19506586forward 2TMN out26LG:482421.1:2000MAY19857943forward 2TMN out26LG:482421.1:2000MAY199651021forward 2TMN out26LG:482421.1:2000MAY1919341987forward 2TMN out26LG:482421.1:2000MAY1921202206forward 2TMN out26LG:482421.1:2000MAY1925492635forward 2TMN out26LG:482421.1:2000MAY1926932773forward 2TMN out26LG:482421.1:2000MAY191265forward 3TMN out26LG:482421.1:2000MAY19258332forward 3TMN out26LG:482421.1:2000MAY19603689forward 3TMN out26LG:482421.1:2000MAY19690773forward 3TMN out26LG:482421.1:2000MAY19822905forward 3TMN out26LG:482421.1:2000MAY199721028forward 3TMN out26LG:482421.1:2000MAY1910741130forward 3TMN out26LG:482421.1:2000MAY1924032489forward 3TMN out26LG:482421.1:2000MAY1925502636forward 3TMN out26LG:482421.1:2000MAY1926732753forward 3TMN out27LG:330944.4:2000MAY19389475forward 2TMN out28LI:223060.1:2000MAY01433519forward 1TMN in28LI:223060.1:2000MAY0112671353forward 1TMN in28LI:223060.1:2000MAY0116391704forward 1TMN in28LI:223060.1:2000MAY0117591842forward 1TMN in28LI:223060.1:2000MAY01260334forward 2TMN out28LI:223060.1:2000MAY019381003forward 2TMN out28LI:223060.1:2000MAY0115531639forward 2TMN out28LI:223060.1:2000MAY0114281514forward 3TMN out29LI:213087.1:2000MAY01732818forward 3TMN in30LI:405330.1:2000MAY01103165forward 1TM30LI:405330.1:2000MAY01406492forward 1TM30LI:405330.1:2000MAY0112761362forward 1TM30LI:405330.1:2000MAY0113961449forward 1TM30LI:405330.1:2000MAY0116151674forward 1TM30LI:405330.1:2000MAY0118641917forward 1TM30LI:405330.1:2000MAY0119662016forward 1TM30LI:405330.1:2000MAY0120172097forward 1TM30LI:405330.1:2000MAY0122572319forward 1TM30LI:405330.1:2000MAY0123292397forward 1TM30LI:405330.1:2000MAY0124162478forward 1TM30LI:405330.1:2000MAY01485550forward 2TMN out30LI:405330.1:2000MAY01671757forward 2TMN out30LI:405330.1:2000MAY0112831357forward 2TMN out30LI:405330.1:2000MAY0115111579forward 2TMN out30LI:405330.1:2000MAY0118771933forward 2TMN out30LI:405330.1:2000MAY0123392395forward 2TMN out30LI:405330.1:2000MAY0124112473forward 2TMN out30LI:405330.1:2000MAY01249320forward 3TMN in30LI:405330.1:2000MAY01678764forward 3TMN in30LI:405330.1:2000MAY019901070forward 3TMN in30LI:405330.1:2000MAY0116501721forward 3TMN in30LI:405330.1:2000MAY0122652351forward 3TMN in30LI:405330.1:2000MAY0124332513forward 3TMN in31LI:350243.2:2000MAY0137993852forward 1TM31LI:350243.2:2000MAY0144534533forward 1TM31LI:350243.2:2000MAY0153925460forward 1TM31LI:350243.2:2000MAY0159446030forward 1TM31LI:350243.2:2000MAY0162566333forward 1TM31LI:350243.2:2000MAY0170037071forward 1TM31LI:350243.2:2000MAY0173337398forward 1TM31LI:350243.2:2000MAY0175527626forward 1TM31LI:350243.2:2000MAY0177807845forward 1TM31LI:350243.2:2000MAY0178677923forward 1TM31LI:350243.2:2000MAY0179548025forward 1TM31LI:350243.2:2000MAY0184078490forward 1TM31LI:350243.2:2000MAY0143614447forward 2TMN out31LI:350243.2:2000MAY0147244807forward 2TMN out31LI:350243.2:2000MAY0154025488forward 2TMN out31LI:350243.2:2000MAY0156185668forward 2TMN out31LI:350243.2:2000MAY0156875767forward 2TMN out31LI:350243.2:2000MAY0162636334forward 2TMN out31LI:350243.2:2000MAY0164886574forward 2TMN out31LI:350243.2:2000MAY0176107696forward 2TMN out31LI:350243.2:2000MAY0178147900forward 2TMN out31LI:350243.2:2000MAY0179918047forward 2TMN out31LI:350243.2:2000MAY0185018587forward 2TMN out31LI:350243.2:2000MAY0186998785forward 2TMN out31LI:350243.2:2000MAY0139754052forward 3TMN in31LI:350243.2:2000MAY0150375108forward 3TMN in31LI:350243.2:2000MAY0160906155forward 3TMN in31LI:350243.2:2000MAY0162766338forward 3TMN in31LI:350243.2:2000MAY0163576419forward 3TMN in31LI:350243.2:2000MAY0164926557forward 3TMN in31LI:350243.2:2000MAY0170057055forward 3TMN in31LI:350243.2:2000MAY0171857271forward 3TMN in31LI:350243.2:2000MAY0173657439forward 3TMN in31LI:350243.2:2000MAY0176507727forward 3TMN in31LI:350243.2:2000MAY0178187868forward 3TMN in31LI:350243.2:2000MAY0178817949forward 3TMN in31LI:350243.2:2000MAY0184458507forward 3TMN in31LI:350243.2:2000MAY0185268585forward 3TMN in32LI:445188.1:2000MAY011063forward 1TMN in32LI:445188.1:2000MAY01169240forward 1TMN in32LI:445188.1:2000MAY01337408forward 1TMN in32LI:445188.1:2000MAY01406471forward 1TMN in32LI:445188.1:2000MAY01796861forward 1TMN in32LI:445188.1:2000MAY019671041forward 1TMN in32LI:445188.1:2000MAY0111351209forward 1TMN in32LI:445188.1:2000MAY0112281314forward 1TMN in32LI:445188.1:2000MAY0113961473forward 1TMN in32LI:445188.1:2000MAY01131217forward 2TMN in32LI:445188.1:2000MAY01335421forward 2TMN in32LI:445188.1:2000MAY019801042forward 2TMN in32LI:445188.1:2000MAY0111361189forward 2TMN in32LI:445188.1:2000MAY0114451522forward 2TMN in32LI:445188.1:2000MAY011259forward 3TMN out32LI:445188.1:2000MAY01135221forward 3TMN out32LI:445188.1:2000MAY01258344forward 3TMN out32LI:445188.1:2000MAY01351431forward 3TMN out32LI:445188.1:2000MAY01573650forward 3TMN out32LI:445188.1:2000MAY01819893forward 3TMN out32LI:445188.1:2000MAY0110081094forward 3TMN out32LI:445188.1:2000MAY0111491235forward 3TMN out32LI:445188.1:2000MAY0116951763forward 3TMN out33LI:244378.1:2000MAY0128114forward 1TMN out33LI:244378.1:2000MAY01403462forward 1TMN out33LI:244378.1:2000MAY01466549forward 1TMN out33LI:244378.1:2000MAY0119722058forward 1TMN out33LI:244378.1:2000MAY011176forward 2TMN in33LI:244378.1:2000MAY01401487forward 2TMN in33LI:244378.1:2000MAY01533619forward 2TMN in33LI:244378.1:2000MAY0113131369forward 2TMN in33LI:244378.1:2000MAY0119852035forward 2TMN in33LI:244378.1:2000MAY012486forward 3TMN 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in58LI:474069.7:2000MAY0114871537forward 2TMN in58LI:474069.7:2000MAY0120302107forward 2TMN in58LI:474069.7:2000MAY012792forward 3TMN in58LI:474069.7:2000MAY01699785forward 3TMN in58LI:474069.7:2000MAY019361001forward 3TMN in58LI:474069.7:2000MAY0119292003forward 3TMN in59LI:245193.3:2000MAY0111951275forward 1TMN in59LI:245193.3:2000MAY0115791656forward 1TMN in59LI:245193.3:2000MAY0117891860forward 1TMN in59LI:245193.3:2000MAY0120292091forward 1TMN in59LI:245193.3:2000MAY0115621621forward 2TMN in59LI:245193.3:2000MAY0118801957forward 2TMN in59LI:245193.3:2000MAY0121562206forward 2TMN in59LI:245193.3:2000MAY0125132575forward 2TMN in59LI:245193.3:2000MAY0125912653forward 2TMN in59LI:245193.3:2000MAY0126692731forward 2TMN in59LI:245193.3:2000MAY0115481634forward 3TMN in59LI:245193.3:2000MAY0116591745forward 3TMN in59LI:245193.3:2000MAY0121542231forward 3TMN in59LI:245193.3:2000MAY0123642450forward 3TMN in59LI:245193.3:2000MAY0125712618forward 3TMN in59LI:245193.3:2000MAY0126492735forward 3TMN in60LI:403872.1:2000MAY01562624forward 1TM60LI:403872.1:2000MAY01730780forward 1TM60LI:403872.1:2000MAY0114981575forward 1TM60LI:403872.1:2000MAY0116481722forward 1TM60LI:403872.1:2000MAY0123592433forward 1TM60LI:403872.1:2000MAY01371454forward 2TMN in60LI:403872.1:2000MAY01731781forward 2TMN in60LI:403872.1:2000MAY019561012forward 2TMN in60LI:403872.1:2000MAY0111061192forward 2TMN in60LI:403872.1:2000MAY0115411600forward 2TMN in60LI:403872.1:2000MAY0116611747forward 2TMN in60LI:403872.1:2000MAY0119942050forward 2TMN in60LI:403872.1:2000MAY0122612332forward 2TMN in60LI:403872.1:2000MAY0123572443forward 2TMN in60LI:403872.1:2000MAY01543629forward 3TMN out60LI:403872.1:2000MAY01708782forward 3TMN out60LI:403872.1:2000MAY0115301601forward 3TMN out60LI:403872.1:2000MAY0116561715forward 3TMN out60LI:403872.1:2000MAY0119832069forward 3TMN out60LI:403872.1:2000MAY0121452225forward 3TMN out60LI:403872.1:2000MAY0122262309forward 3TMN out60LI:403872.1:2000MAY0123492426forward 3TMN out61LI:1086294.1:2000MAY01748834forward 1TMN out61LI:1086294.1:2000MAY0122782352forward 1TMN out61LI:1086294.1:2000MAY0123062356forward 2TMN out62LI:337514.3:2000MAY0119061992forward 1TMN in62LI:337514.3:2000MAY0115121598forward 3TMN out63LI:230711.1:2000MAY01898978forward 1TMN out63LI:230711.1:2000MAY0113271389forward 1TMN out63LI:230711.1:2000MAY0120592145forward 1TMN out63LI:230711.1:2000MAY01134220forward 2TMN out63LI:230711.1:2000MAY0115171591forward 2TMN out63LI:230711.1:2000MAY0116311708forward 2TMN out63LI:230711.1:2000MAY0120332119forward 2TMN out63LI:230711.1:2000MAY01114188forward 3TMN in63LI:230711.1:2000MAY01570620forward 3TMN in63LI:230711.1:2000MAY01648716forward 3TMN in63LI:230711.1:2000MAY0111011160forward 3TMN in64LI:040338.2:2000MAY01794880forward 2TMN in64LI:040338.2:2000MAY01162233forward 3TMN out64LI:040338.2:2000MAY01708791forward 3TMN out65LI:399174.2:2000MAY01622693forward 1TM65LI:399174.2:2000MAY019581008forward 1TM65LI:399174.2:2000MAY0110271080forward 1TM65LI:399174.2:2000MAY0113031377forward 1TM65LI:399174.2:2000MAY019651018forward 2TMN in65LI:399174.2:2000MAY01126200forward 3TMN out66LI:197275.5:2000MAY01211285forward 1TMN out66LI:197275.5:2000MAY01761811forward 2TMN out66LI:197275.5:2000MAY01210281forward 3TMN out66LI:197275.5:2000MAY01537623forward 3TMN out67LI:336872.1:2000MAY01175231forward 1TMN out67LI:336872.1:2000MAY0110991185forward 1TMN out67LI:336872.1:2000MAY0114501536forward 1TMN out67LI:336872.1:2000MAY01182247forward 2TMN in67LI:336872.1:2000MAY0110011072forward 2TMN in67LI:336872.1:2000MAY0111691246forward 2TMN in67LI:336872.1:2000MAY0113731447forward 2TMN in67LI:336872.1:2000MAY01171224forward 3TMN out67LI:336872.1:2000MAY0110891175forward 3TMN out67LI:336872.1:2000MAY0113021364forward 3TMN out68LI:1092901.1:2000MAY01172258forward 1TMN out68LI:1092901.1:2000MAY01299379forward 2TMN out68LI:1092901.1:2000MAY01425511forward 2TMN out69LI:022387.5:2000MAY0111951281forward 1TMN out69LI:022387.5:2000MAY01710796forward 2TMN out69LI:022387.5:2000MAY0112141276forward 2TMN out69LI:022387.5:2000MAY01675743forward 3TMN out69LI:022387.5:2000MAY0110921175forward 3TMN out69LI:022387.5:2000MAY0112151301forward 3TMN out70LI:1188334.1:2000MAY01208294forward 1TMN out70LI:1188334.1:2000MAY01370456forward 1TMN out70LI:1188334.1:2000MAY011182forward 2TMN out70LI:1188334.1:2000MAY01131190forward 2TMN out70LI:1188334.1:2000MAY011280forward 3TMN in70LI:1188334.1:2000MAY01123194forward 3TMN in71LI:1188664.1:2000MAY01274348forward 1TMN in71LI:1188664.1:2000MAY01607657forward 1TMN in71LI:1188664.1:2000MAY01254304forward 2TMN in71LI:1188664.1:2000MAY01494580forward 2TMN in72LI:247388.1:2000MAY0111261212forward 1TMN out72LI:247388.1:2000MAY01134220forward 2TMN in72LI:247388.1:2000MAY01389448forward 2TMN in72LI:247388.1:2000MAY019681033forward 2TMN in72LI:247388.1:2000MAY01741812forward 3TMN in72LI:247388.1:2000MAY0112001277forward 3TMN in73LI:816339.4:2000MAY01466534forward 1TMN in73LI:816339.4:2000MAY01562648forward 1TMN in73LI:816339.4:2000MAY019371017forward 1TMN in73LI:816339.4:2000MAY0111621248forward 1TMN in73LI:816339.4:2000MAY0113061368forward 1TMN in73LI:816339.4:2000MAY0113901452forward 1TMN in73LI:816339.4:2000MAY01407487forward 2TMN out73LI:816339.4:2000MAY01575652forward 2TMN out73LI:816339.4:2000MAY01698784forward 2TMN out73LI:816339.4:2000MAY019501012forward 2TMN out73LI:816339.4:2000MAY0110431105forward 2TMN out73LI:816339.4:2000MAY0111361198forward 2TMN out73LI:816339.4:2000MAY0112441306forward 2TMN out73LI:816339.4:2000MAY0113341396forward 2TMN out73LI:816339.4:2000MAY0114241486forward 2TMN out73LI:816339.4:2000MAY01468554forward 3TMN out73LI:816339.4:2000MAY01591644forward 3TMN out73LI:816339.4:2000MAY019331010forward 3TMN out73LI:816339.4:2000MAY0111821244forward 3TMN out73LI:816339.4:2000MAY0112571319forward 3TMN out74LI:1188967.1:2000MAY011467forward 2TMN out74LI:1188967.1:2000MAY01272325forward 2TMN out75LI:236230.3:2000MAY0110811149forward 1TMN in75LI:236230.3:2000MAY0111951281forward 1TMN in75LI:236230.3:2000MAY0113301416forward 1TMN in75LI:236230.3:2000MAY01182253forward 2TMN out75LI:236230.3:2000MAY0110161102forward 2TMN out75LI:236230.3:2000MAY0111541240forward 2TMN out75LI:236230.3:2000MAY0113461432forward 2TMN out75LI:236230.3:2000MAY0163149forward 3TMN out75LI:236230.3:2000MAY01396449forward 3TMN out75LI:236230.3:2000MAY01567644forward 3TMN out75LI:236230.3:2000MAY0111071181forward 3TMN out75LI:236230.3:2000MAY0113201382forward 3TMN out75LI:236230.3:2000MAY0114101472forward 3TMN out76LI:246728.3:2000MAY0116331695forward 1TMN out76LI:246728.3:2000MAY0117831854forward 1TMN out76LI:246728.3:2000MAY0124922566forward 2TMN out76LI:246728.3:2000MAY01792854forward 3TMN in76LI:246728.3:2000MAY0123252375forward 3TMN in77LI:1190057.1:2000MAY01646696forward 1TMN in77LI:1190057.1:2000MAY0111951263forward 1TMN in77LI:1190057.1:2000MAY0115911668forward 1TMN in77LI:1190057.1:2000MAY0121042169forward 1TMN in77LI:1190057.1:2000MAY0122332295forward 1TMN in77LI:1190057.1:2000MAY0123202382forward 1TMN in77LI:1190057.1:2000MAY0126232703forward 1TMN in77LI:1190057.1:2000MAY0131243207forward 1TMN in77LI:1190057.1:2000MAY0112171270forward 2TMN out77LI:1190057.1:2000MAY0115951681forward 2TMN out77LI:1190057.1:2000MAY0122672353forward 2TMN out77LI:1190057.1:2000MAY0124202491forward 2TMN out77LI:1190057.1:2000MAY0126242698forward 2TMN out77LI:1190057.1:2000MAY0127202785forward 2TMN out77LI:1190057.1:2000MAY0130143067forward 2TMN out77LI:1190057.1:2000MAY0131163202forward 2TMN out77LI:1190057.1:2000MAY0119051991forward 3TMN in77LI:1190057.1:2000MAY0122172297forward 3TMN in77LI:1190057.1:2000MAY0126012657forward 3TMN in77LI:1190057.1:2000MAY0130723143forward 3TMN in78LI:221836.3:2000MAY01775846forward 1TMN out78LI:221836.3:2000MAY0120502106forward 1TMN out78LI:221836.3:2000MAY0121972265forward 1TMN out78LI:221836.3:2000MAY0125392613forward 1TMN out78LI:221836.3:2000MAY0122162302forward 2TM78LI:221836.3:2000MAY0125822668forward 2TM78LI:221836.3:2000MAY0118991976forward 3TMN out78LI:221836.3:2000MAY0120342120forward 3TMN out78LI:221836.3:2000MAY0121992261forward 3TMN out78LI:221836.3:2000MAY0122832345forward 3TMN out78LI:221836.3:2000MAY0124902564forward 3TMN out79LI:334047.3:2000MAY01115201forward 1TMN out79LI:334047.3:2000MAY0156142forward 2TMN in79LI:334047.3:2000MAY01497577forward 2TMN in

[0303]

3

TABLE 2

SEQ

ID NO:
Component ID
Start
Stop

1
2079155F6
1
474

1
2079155H1
1
287

1
6485024H1
30
531

1
269086H1
55
416

1
g4194935
215
662

1
g3174230
294
608

2
g3405927
511
865

2
4061048T8
213
755

2
5961372H1
1
539

3
4318348F6
361
482

3
g4739876
483
760

3
g5637692
483
760

3
g5392945
603
1049

3
5338818H1
827
1078

3
6484158H1
1
544

3
5792010H1
36
340

3
5785018H1
36
336

3
5793390H1
36
306

3
6555681H1
125
694

3
3903879H1
156
435

3
g4850881
306
759

4
g2411092
1
241

4
7104605H1
1
533

4
4699688T6
146
533

5
6440110H1
1
71

5
5406681H1
1
122

5
6953084H1
63
615

5
5373405H1
63
285

5
5373405F8
83
602

5
3942701H1
190
481

5
4340882H1
392
586

5
4340882F6
392
865

5
3323337H1
449
716

5
1479486F6
453
867

5
1479486H1
453
688

5
4774836H1
1896
2149

5
4229676H1
1940
2149

5
4254348H1
2050
2148

5
1993010H1
483
763

5
3471007H1
681
951

5
3915086H1
718
875

5
2708491F6
775
1111

5
2708491H1
776
1069

5
6307323H1
845
1181

5
551890H1
939
1121

5
4492287H1
940
1315

5
3783242H1
1095
1382

5
1479372H1
1229
1476

5
2761062H1
1232
1497

5
2761062R6
1232
1489

5
6001120H1
1289
1774

5
6977932H1
1468
1665

5
7033269H1
1506
2033

5
3466972H1
1516
1770

5
2788543H1
1517
1748

5
5858122H1
1588
1848

5
2705868F6
1617
1980

5
5022301H1
1617
1884

5
2705868H1
1618
1886

5
5373405T6
1620
2144

5
1479486T6
1623
2109

5
2761062T6
1622
2108

5
2705868T6
1635
2107

5
3468165H1
1631
1895

5
1993688T6
1696
2108

5
1993688F6
1703
2147

5
1993688H1
1703
1950

5
666099H1
1721
1946

5
g3423957
1776
2148

5
g3241592
1821
2154

5
4340882T6
1846
2111

5
5016835H1
1893
2144

6
6206710H1
1
518

6
1632421H1
231
457

6
3255825H1
242
491

6
1951956T6
1
423

6
g1099892
61
470

6
1356903H1
545
744

6
4987735H1
279
444

6
4987835H1
279
444

7
3170506F6
176
241

7
6387831H1
334
463

7
5607909H1
1
243

7
3558469F6
14
444

7
3558469H1
14
293

7
g2006934
14
114

7
6109819H1
33
325

7
g2464233
46
103

7
3170506H1
176
452

8
g2069455
1
404

8
1597036H1
1
218

8
6429759H1
68
471

8
4013148H1
178
462

8
g2064597
256
604

8
3296932F6
312
950

8
3296932H1
312
563

8
5839392H1
315
545

8
1254055H1
421
639

8
3527901H1
434
704

8
3402996H1
549
697

8
3503954F6
615
1002

8
3503954H1
616
915

8
3985708H1
623
812

8
6117978H1
729
1018

8
3620240H1
767
976

8
5912238H1
872
1066

8
1961296H1
965
1237

8
3406891F6
1026
1582

8
3406891H1
1026
1266

8
6196163H1
1193
1793

8
6196263H1
1193
1660

8
6059105H1
1200
1336

8
3296932T6
1249
1867

8
4367370H2
1253
1496

8
1908946F6
1257
1607

8
1908946H1
1257
1499

8
g1958480
1311
1530

8
2270984R6
1377
1831

8
2270975H1
1377
1613

8
2270984H1
1377
1605

8
g850966
1497
1759

8
5028068H1
1499
1786

8
1808792T6
1564
2151

8
987831H1
1575
1772

8
3406891T6
1593
2149

8
3410491H1
1602
1683

8
3503954T6
1606
2156

8
1808792F6
1606
2061

8
1808792H1
1606
1852

8
2270984T6
1688
2209

8
g3231619
1764
2196

8
1908946T6
1856
2139

8
g851209
1874
2177

8
g3765675
1877
2174

8
g3755028
1885
2189

8
g1153884
1912
2174

8
5511650H1
2088
2271

9
g2016674
1
372

9
6147645H1
830
1263

9
6338012H1
1
401

9
6336313H1
22
565

9
6577916H1
22
400

9
g907436
1
324

9
6146280H1
39
573

9
g1556832
14
174

9
6334269H1
187
736

9
6147106H1
189
743

9
g2180097
1
381

9
6145722H1
314
826

9
g1969671
44
388

9
6147235H1
444
987

9
g1109940
188
316

9
6146408H1
530
954

9
6149660H1
543
1006

9
6144394H1
586
1189

9
g1970587
1
235

10
g993188
793
1107

10
g3752938
851
1199

10
3070204H1
595
886

10
4420032H1
906
1146

10
3448504T6
187
819

10
4401644H1
1029
1282

10
5092611H1
1
214

10
5092611F6
1
621

10
1667402H1
159
214

10
3410836H1
533
781

10
3448604H1
535
785

10
3448504R6
535
884

10
5955967H1
566
794

10
g2367695
570
959

10
5499560R6
579
1009

10
g2629724
594
1046

10
g4089777
675
993

10
g1440904
708
1042

10
g1941334
715
940

10
g2078942
715
957

10
g2901697
748
1048

11
2967428H1
1
284

12
3002696H1
1
285

12
3002696F6
1
394

12
1356974F6
109
495

12
1356974H1
109
353

12
3694703H1
215
496

12
1241180H1
253
311

12
5432511H1
253
362

12
5864554H1
391
666

12
4959207H1
409
524

12
5641442H1
415
654

12
g2163443
423
741

12
2923379H1
430
686

12
4699556H1
430
683

12
040379H1
431
592

12
3032206H1
430
716

12
2509521H1
434
662

12
2509521F6
434
665

12
1703965H1
437
682

12
5605693H1
437
697

12
5546287H1
474
665

12
3801120H1
653
948

12
4878230H1
661
910

12
60135211B1
810
1213

12
60135113V1
834
1227

12
60135211V1
834
1227

13
70319065D1
190
589

13
70320239D1
212
793

13
70320883D1
212
645

13
70318969D1
213
774

13
70317969D1
398
791

13
70318139D1
398
931

13
70317613D1
398
857

13
70318020D1
398
856

13
70317863D1
398
791

13
70319554D1
398
791

13
70318409D1
398
695

13
70319562D1
398
741

13
70317555D1
398
635

13
70318235D1
399
928

13
70320237D1
399
852

13
70318920D1
399
812

13
70320035D1
411
741

13
70318273D1
417
856

13
4120208H1
332
571

13
70320719D1
447
856

13
3882715H1
1
312

13
2797803F6
1
452

13
2797803H1
1
245

13
2788120H1
4
256

13
70317458D1
481
876

13
70318194D1
481
856

13
70320117D1
521
856

13
70319709D1
559
988

13
70319736D1
639
1133

13
70319869D1
715
856

13
2797803T6
97
633

13
70320906D1
743
1133

13
70320282D1
743
856

13
3873636H1
291
586

13
70319282D1
877
1310

13
70319385D1
904
1133

13
g2329469
121
408

13
3873636T6
1
336

13
70321152D1
466
931

13
70317918D1
466
930

13
70320713D1
466
856

13
70320635D1
466
856

13
70320227D1
466
855

13
70317509D1
466
856

13
70320434D1
466
876

13
70320694D1
468
856

13
70320790D1
466
838

13
70318744D1
466
880

13
70318259D1
467
930

13
70318517D1
481
931

14
g982879
1
359

14
g1039681
62
330

14
1850733F6
165
655

14
1850733H1
165
450

14
5962837H1
290
797

14
g1040085
419
732

14
g982880
468
732

14
70060347V1
660
1048

15
g1855688
706
918

15
g2464352
752
910

15
g1471158
757
906

15
2127070H1
769
901

15
g2836064
779
901

15
g3665793
787
901

15
g2969091
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331
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466
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563
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636
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684
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695
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22
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22
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22
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22
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1190
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25
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1358
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25
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25
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1235
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25
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25
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25
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25
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25
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25
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1288
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25
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1341
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25
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226
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226
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379
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381
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455
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530
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646
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25
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653
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25
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653
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25
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655
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25
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667
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667
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25
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25
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25
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768
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25
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806
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25
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847
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850
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25
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969
1188

25
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979
1207

25
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996
1477

25
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1007
1342

25
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1020
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25
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1
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25
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1
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25
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39
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25
3801333H1
46
327

25
6146685H1
131
608

25
3021452H1
203
499

25
2655535H1
226
520

25
g867230
2483
2783

25
g1477035
2519
2783

25
6158466H1
2530
2692

25
646057H1
2530
2784

25
3535428H1
2550
2782

25
g1479354
2562
2781

25
g3095823
2573
2706

25
2878073H1
2577
2784

25
g944173
2582
2679

25
3702759H1
2594
2782

25
g5325988
2594
2782

25
g969343
2630
2782

25
2043940H1
2651
2782

25
661586H1
2658
2813

25
5056769H1
2702
2789

25
6332343H1
1960
2520

25
5327933H1
1964
2225

25
g3658839
1983
2394

25
g39274l4
1988
2423

25
5275308H1
2005
2238

25
2673389H1
2047
2295

25
g274328
2457
2782

25
7237473H1
2048
2569

25
5333974H1
2054
2302

25
1982603H1
2091
2315

25
2044369H1
2192
2427

25
g4196655
2192
2327

25
4726834H1
2192
2469

25
1772731H1
2244
2461

25
4266001H1
2279
2468

25
4730142H1
2304
2558

25
g2555947
2309
2616

25
840781H1
2310
2582

25
4492313H1
2310
2757

25
4593969H1
2310
2579

25
4492214H1
2315
2782

25
g5109339
2326
2784

25
613645H1
2337
2571

25
2132842H1
2376
2617

25
g4073710
2384
2785

25
g1527498
2413
2783

25
g2184179
2453
2785

25
2721848H1
2456
2707

25
2637714H1
2456
2709

25
g2569732
1382
1794

25
3042074H1
1471
1786

25
4714518H1
1907
1991

25
4261452H1
1474
1733

25
2773951H1
1488
1742

25
g3050704
1508
1703

25
6023537H1
1527
1763

25
2653867H1
1534
1820

25
g4522739
1927
2326

25
g3960542
1580
1841

25
g1119058
1591
1716

25
6411539H1
1616
2116

25
g5369593
1952
2423

25
2097957H1
1626
1902

25
3769037H1
1634
1888

25
3509114H1
1638
1908

25
3927329H1
1656
1922

25
2593752H1
1679
1869

25
g1981200
1681
1968

25
1683135H1
1757
1897

25
5832853H1
1792
2069

25
806178H1
1796
2022

25
3558496H1
1804
2073

25
2795155H1
1843
2089

25
1982603R6
1867
2315

25
2876519H1
1883
2138

25
g3804453
1895
2327

25
g5812417
1896
2308

25
5563230H1
1959
2187

26
3719577H1
1538
1698

26
g2166727
1572
1672

26
g1259102
2007
2205

26
693434H1
2012
2270

26
6021316H1
2013
2538

26
2605880H1
2014
2246

26
2605880F6
2014
2595

26
4132607F6
1614
2100

26
g2166556
1633
1729

26
g2013024
1983
2258

26
g1321421
2014
2246

26
1258355F6
2015
2225

26
1258355F1
2015
2511

26
1258355H1
2015
2216

26
4584658H1
2019
2164

26
2211736H1
2025
2282

26
2956194H1
2026
2103

26
5853223H1
2026
2227

26
3597053H1
1993
2297

26
6718635H1
2026
2279

26
4728680H1
2026
2159

26
3210462H1
2026
2225

26
g707728
2026
2234

26
g727700
2038
2283

26
2228104H1
2043
2111

26
3597053F7
1997
2600

26
2839674H2
2043
2159

26
2932162H1
2043
2135

26
6096855H1
2043
2204

26
3717718H1
2043
2155

26
g1294859
2046
2640

26
3448635H1
2048
2289

26
3900947R8
2055
2678

26
2814661H1
1998
2286

26
3901994H1
2055
2321

26
2604117H1
2069
2314

26
4538547H1
2069
2325

26
g789232
2070
2294

26
g1677967
2093
2316

26
g1783925
2101
2388

26
g4690089
2125
2583

26
g4685239
2125
2332

26
g858499
2138
2459

26
5725860H2
2176
2244

26
123421H1
2177
2318

26
g777923
2177
2289

26
g789198
2203
2454

26
g781495
2204
2455

26
2667384H1
2205
2433

26
g1697403
2230
2531

26
g3933029
2237
2737

26
2939915H1
2235
2393

26
4643005H1
2235
2484

26
4704174F9
1
569

26
3122989H1
273
555

26
4704174H1
322
569

26
4777379H1
348
606

26
2834749F6
405
694

26
2834749H1
420
694

26
5911946H1
436
722

26
4721035H1
446
695

26
1601324H1
453
599

26
g4876168
456
887

26
5372175H1
456
681

26
1992918H1
466
560

26
2782119H1
516
746

26
g1628776
669
1024

26
6256994H1
670
928

26
g1312588
674
886

26
2101267H1
697
941

26
g1948843
762
1091

26
7076736H1
791
1279

26
2135134F6
816
1213

26
2135134H1
816
1077

26
2792758H1
907
1221

26
5151110H1
1175
1353

26
6529106H1
1196
1624

26
3136230H1
1206
1482

26
3136230F6
1206
1635

26
7041019H1
1218
1660

26
178010H1
1249
1493

26
4109878H1
1348
1617

26
2135134T6
1388
1727

26
g434268
1404
1671

26
2809378T6
1477
1727

26
g707734
1513
1698

26
2900195H1
1510
1714

26
7088770H1
2241
2784

26
2688875H1
2289
2543

26
g1688483
2301
2695

26
3126776H1
2302
2574

26
4132607T6
2348
2933

26
3900947T8
2378
2822

26
g3924091
2375
2772

26
764214H1
2380
2661

26
g1697306
2396
2775

26
g5589502
2398
2775

26
g2210147
2404
2787

26
2900195T6
2417
2907

26
1262991R1
2417
2917

26
1262991H1
2417
2655

26
4978404H1
2446
2697

26
4508011H1
2457
2720

26
3735710H1
2461
2698

26
6217351H1
2472
2933

26
g2524340
2476
2948

26
2117643T6
2489
2846

26
g3645213
2494
2955

26
g4372648
2495
2775

26
g3596913
2496
2958

26
g4372672
2500
2951

26
g3674408
2514
2955

26
g4310744
2515
2963

26
723560H1
2516
2722

26
g3595253
2521
2964

26
g2525244
2522
2770

26
4160050T6
2527
2934

26
g4665502
2536
2964

26
2743458H1
2544
2802

26
2738862H1
2544
2790

26
2743458F7
2544
2949

26
g5637396
2548
2955

26
g3432798
2549
2950

26
g5369924
2550
2979

26
g4310271
2552
2949

26
g3841661
2554
2953

26
g4888429
2557
2949

26
4620145H1
2558
2805

26
2605880T6
2563
2848

26
3207727H1
2565
2825

26
g1783745
2570
2949

26
g1677968
2571
2950

26
3980476H1
2573
2751

26
3966076H1
2572
2704

26
3966076F7
2572
2963

26
3966076T7
2572
2859

26
g5445604
2583
2959

26
6494640H1
2583
2945

26
g4622298
2586
2949

26
g6439089
2592
2960

26
1258355T6
2592
2910

26
g5540648
2607
2960

26
2273680H1
2614
2887

26
g4620011
2619
2949

26
1711022H1
2630
2844

26
6587024H1
2633
2749

26
1472231H1
2634
2836

26
1472231T1
2634
2906

26
5177089H1
2643
2915

26
1711022F7
2646
2964

26
g1860279
2645
2949

26
g3837895
2646
2958

26
g1644779
2650
2945

26
5645429H1
2650
2902

26
g858397
2651
2926

26
g4107761
2656
2949

26
g839957
2659
2950

26
g657066
2662
2963

26
g5325849
2682
2956

26
g727611
2687
2950

26
1413430H1
2685
2938

26
2887585H1
2686
2946

26
g1242496
2689
2949

26
1796886H1
2696
2945

26
g1688397
2697
2945

26
1711022T7
2706
2842

26
g2941734
2711
2965

26
3022288H1
2725
2949

26
g777818
2734
2959

26
g434265
2732
2949

26
g789233
2736
2941

26
g789199
2741
2954

26
g3144224
2745
2949

26
2737665H1
2751
2945

26
g4195279
2774
2953

26
4718419H1
2784
2980

26
g1948844
2803
2958

26
g2524323
2860
2949

26
g2106662
2878
2948

27
6506033H1
273
426

27
6506133H1
273
434

27
5742229H1
319
613

27
6334334H1
237
643

27
3388613F6
1
485

27
3388613H1
1
291

27
g1815060
33
488

27
6941841H1
79
525

28
5372512H1
1
156

28
3481951H1
1
300

28
086514H1
116
324

28
6773036J1
136
255

28
3228141H1
256
535

28
469821H1
427
664

28
4323062H1
454
579

28
g6131888
498
919

28
2997736H1
585
872

28
648674H1
723
978

28
g6474252
755
1175

28
2720552F6
824
1376

28
2720552H1
824
1055

28
3731554H1
848
1141

28
g1294839
880
1372

28
g1294842
880
1336

28
5837915H1
1008
1273

28
5598427H1
1063
1333

28
7060462H1
1093
1625

28
2925401H1
1115
1340

28
3147672H1
1212
1519

28
7353404H1
1216
1753

28
g2018589
1262
1572

28
5290315H1
1344
1593

28
2720552T6
1402
1736

28
g570734
1437
1695

28
999643H1
1449
1694

28
6805084J1
1475
1968

28
1631088F6
1521
1966

28
2092882H1
1521
1721

28
g1242302
1550
1775

28
g2955269
1564
1775

28
139470H1
1620
1736

28
2072462H1
1639
1906

28
4286166H1
1641
1911

28
g1242305
1660
1775

28
085524H1
1714
1911

28
g1210407
1752
1950

28
g1196175
1753
1950

28
4287958H1
1768
1911

28
1631088H1
1789
1966

29
g5446946
632
897

29
g3075841
221
576

29
g2767512
248
577

29
g2818989
248
593

29
3394790H1
353
636

29
g2901002
453
708

29
804254H1
569
849

29
2906845H1
1
78

29
2741409T6
1
548

29
2741409F6
7
488

29
2741409H1
7
269

29
658133H1
12
268

29
3836585H1
31
316

29
4796210H1
129
412

29
6205209H1
154
370

29
1447527H1
218
457

30
7189828H2
1
573

30
7031283H1
176
699

30
g4406653
255
2784

30
5594735H1
403
643

30
4858522H1
468
592

30
5151418H1
659
780

30
6440827H1
673
1152

30
3817033H1
949
1206

30
5007439H1
954
1182

30
5187677H1
997
1255

30
5003069H1
1121
1381

30
6838881H1
1261
1723

30
g772660
1266
1605

30
g769304
1267
1535

30
g564397
1267
1459

30
g900136
1342
1684

30
5077690H1
1399
1642

30
6742827H1
1434
1983

30
1398653H1
1574
1839

30
1398653F6
1574
1819

30
5085840H1
1578
1764

30
5188226H1
1630
1896

30
1429039H1
1640
1909

30
5390274H1
1752
2017

30
5719068H1
1774
2172

30
1926364H1
1778
2016

30
4987108F8
2070
2609

30
4986308H1
2070
2366

30
4643979H1
2083
2337

30
4987108T8
2105
2606

30
4987108T9
2118
2684

30
7351533H1
2126
2615

30
2073148T6
2288
2745

30
607997H1
2302
2551

30
1625327T6
2305
2743

30
1398653T6
2312
2756

30
1625327F6
2312
2753

30
1625327H1
2312
2521

30
2073148F6
2312
2787

30
g5235046
2312
2790

30
2073148H1
2312
2565

30
g4988528
2313
2787

30
g3238921
2317
2785

30
g5850283
2319
2784

30
g5233757
2323
2787

30
g4688102
2337
2784

30
2606717H1
2337
2597

30
g5451665
2363
2784

30
g6473523
2372
2789

30
1689007H1
2390
2605

30
g2883211
2398
2787

30
g6471739
2401
2788

30
g3765856
2401
2784

30
2840911H1
2418
2684

30
g5445474
2428
2784

30
g6199495
2432
2784

30
g2817078
2436
2793

30
g5367496
2437
2784

30
g900137
2445
2791

30
g3254684
2451
2790

30
g821905
2459
2792

30
g816772
2543
2792

30
g560418
2544
2784

30
g3051927
2582
2790

30
g2358712
2597
2784

30
g796532
2689
2791

31
6111576H1
9012
9325

31
5158913H1
9018
9313

31
5159112H1
9018
9178

31
6100031H1
9056
9341

31
70405514D1
9077
9213

31
70333057D1
9083
9540

31
70321671D1
9083
9258

31
70404961D1
9124
9213

31
6112811H1
9200
9519

31
70337581D1
9209
9540

31
70337708D1
9209
9540

31
70347673D1
9209
9540

31
70337784D1
9215
9521

31
6107901H1
9218
9540

31
6116727H1
9225
9517

31
5442124H1
9226
9473

31
70337937D1
9235
9540

31
70339709D1
9243
9540

31
70322912D1
9243
9521

31
70346838D1
9243
9361

31
70346734D1
9243
9361

31
70338406D1
9258
9657

31
70346872D1
9262
9521

31
g4325928
8675
8909

31
2874640H1
8718
8904

31
6019242H1
8727
8917

31
70404974D1
8821
9213

31
3387504H1
8840
8897

31
6299464H1
8898
9207

31
6300602H1
8898
9216

31
6343373H1
8905
9205

31
4570393H1
8939
9203

31
70340823D1
8943
9202

31
6602501H1
8954
9535

31
6080143H1
8956
9450

31
70406005D1
8957
9207

31
3903264H1
8957
9192

31
70405554D1
8957
9122

31
3171665H1
8957
9054

31
6576424H1
8962
9187

31
6731345H1
8964
9514

31
5177674H2
8964
9233

31
5605333H1
8964
9106

31
6823919H1
8969
9510

31
6823919J1
8969
9505

31
6859476H1
8985
9421

31
6855538H1
8985
9515

31
5752336H1
8989
9520

31
5756348H1
8990
9549

31
6604143H1
8989
9547

31
5296001H1
8992
9145

31
7220264H1
9007
9505

31
7313036H1
9006
9503

31
g3399851
8504
8903

31
g1939318
8504
8895

31
g3150717
8508
8904

31
1978921H1
8533
8804

31
g3427618
8559
8904

31
g1885652
8614
8904

31
2917437F6
8632
9171

31
2917437H1
8633
8895

31
1242917H1
7364
7579

31
1887279F6
7369
7953

31
1887279H1
7369
7448

31
6873590H1
7384
7978

31
1904771H1
7463
7736

31
1594587T6
7476
7994

31
2158441H1
7477
7745

31
1434154H1
7497
7745

31
388880H1
7499
7757

31
347519H1
7502
7737

31
1922153T6
7506
7994

31
038495H1
7515
7757

31
038806H1
7515
7797

31
1922153R6
7530
7991

31
039364H1
7529
7762

31
1922153H1
7530
7801

31
1645260H1
7572
7680

31
g3052905
7573
8094

31
3714030H1
7598
7910

31
g3146667
7603
8097

31
2880781T6
7616
7992

31
g4187707
7634
8100

31
1887279T6
7636
7992

31
g3897482
7653
8095

31
g4969820
7654
8097

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31
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31
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31
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31
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31
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31
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31
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31
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31
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31
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2039

31
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1932

31
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1725

31
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2041

31
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1832

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31
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31
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31
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2037

31
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31
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31
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1685
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31
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31
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31
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1748
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1748
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31
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31
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1836
2079

31
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31
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1899
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31
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1913
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1914
2329

31
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2138

31
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1922
2510

31
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1921
2184

31
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1921
2366

31
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1952
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31
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1972
2379

31
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1978
2213

31
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1990
2241

31
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1991
2369

32
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1
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32
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1
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32
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1
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32
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4
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32
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4
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32
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13
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32
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32
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32
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358
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32
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401
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32
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421
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32
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477
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32
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32
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626
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32
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633
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32
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678
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32
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32
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32
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32
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32
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32
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32
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32
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32
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32
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32
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452
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33
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33
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33
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33
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33
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33
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33
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1507

33
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33
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33
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33
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1621

33
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1524

33
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1290
1411

33
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1301
1535

33
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33
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33
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1884

33
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1752

33
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1376
1882

33
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1381
2019

33
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1407
2011

33
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1406
1705

33
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1410
1852

33
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1411
2028

33
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1447
1605

33
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1468
1724

33
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1486
2036

33
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1488
1831

33
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1500
1741

33
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1503
1772

33
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1536
1699

33
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1544
1934

33
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1543
1843

33
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1548
2003

33
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1548
1658

33
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1558
2009

33
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1578
2068

33
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1581
2055

33
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1597
1884

33
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1599
2026

33
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1606
2066

33
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1651
2061

33
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1647
2029

33
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1668
2072

33
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1670
2067

33
506569H1
1707
1938

33
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1710
2067

33
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1765
2074

33
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1781
1980

33
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1790
2067

33
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1793
2052

33
1638111F6
1809
2198

33
71156557V1
1820
1960

33
g765481
1866
2070

33
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1869
2074

33
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1900
2198

33
g6197210
1917
2072

33
g3805642
1940
2070

33
g2368950
1945
2069

33
g2183586
1957
2020

33
g2541498
1994
2067

33
1638111H1
1999
2198

33
2756125H1
2094
2198

33
1635764H1
2099
2198

33
1632232H1
1610
1822

33
g6200220
1636
2068

34
5804093H1
1
177

34
2684902H1
8
257

34
5833363H1
27
136

34
g3280141
29
431

34
4203938H1
100
374

34
2563955H1
179
402

35
70408909D1
1832
2372

35
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1839
2338

35
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1835
2338

35
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1845
2338

35
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1839
2339

35
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1840
2338

35
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1848
2338

35
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1854
2338

35
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1854
2338

35
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1865
2338

35
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1865
2337

35
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1869
2338

35
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1870
2338

35
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1872
2337

35
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1879
2338

35
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1883
2338

35
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1899
2338

35
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1906
2338

35
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1903
2338

35
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1909
2338

35
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1908
2338

35
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1908
2338

35
70409112D1
1911
2427

35
70401329D1
1910
2427

35
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1917
2338

35
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1919
2338

35
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1923
2338

35
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1925
2338

35
3021378H1
1931
2239

35
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1935
2338

35
70410219D1
1938
2338

35
70403042D1
1941
2338

35
70401079D1
1942
2338

35
70409409D1
1942
2337

35
70403961D1
1943
2338

35
70409163D1
1947
2427

35
70402796D1
1950
2338

35
3700809H1
1951
2251

35
70402339D1
1963
2338

35
3475377H1
1965
2116

35
5640458H1
1965
2103

35
70400757D1
1967
2338

35
70403528D1
1969
2338

35
70403542D1
1974
2426

35
70408826D1
1978
2337

35
70400431D1
1993
2654

35
70403190D1
1999
2427

35
70408542D1
2001
2337

35
70410141D1
2005
2338

35
70401284D1
2002
2338

35
71220096V1
2021
2742

35
7262840H1
2031
2527

35
3277490H1
2025
2282

35
4806444H1
2027
2305

35
5464475H1
2039
2303

35
70410172D1
2029
2427

35
4725604H1
2044
2327

35
g1010563
2062
2431

35
2744790H1
2075
2336

35
g1766452
2086
2417

35
70401307D1
2099
2441

35
6507755H1
2109
2637

35
70831953V1
2115
2668

35
3987571H1
2119
2384

35
70401747D1
2124
2360

35
3426754H1
2130
2401

35
485095H1
2143
2396

35
3492396H1
2150
2434

35
3931556H1
2156
2448

35
3930720H1
2156
2466

35
3934202H1
2158
2442

35
4889738H1
2172
2465

35
4906569H2
2195
2471

35
7272031H1
2200
2720

35
71219448V1
2202
2828

35
5468686H1
2207
2384

35
4914352H1
2208
2502

35
g1636142
2209
2466

35
6160218H1
2219
2480

35
3873766H1
2234
2528

35
70403069D1
2234
2337

35
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2245
2514

35
3643322H1
2257
2528

35
2123362F6
2257
2701

35
2123362H1
2257
2585

35
033931H1
2257
2335

35
4615229H1
2260
2522

35
3212960H1
2260
2557

35
6729709H1
2268
2832

35
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2283
2592

35
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2289
2737

35
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2289
2738

35
4199572H1
2313
2480

35
2795091H1
2323
2571

35
1389192H1
2325
2575

35
g1628772
2328
2690

35
70403666D1
2340
2804

35
2501716H1
2341
2567

35
3562675H1
2344
2655

35
3229405H1
2346
2449

35
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2346
2604

35
2207651H1
2350
2546

35
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2352
2625

35
6553789H1
2361
2831

35
3370548H1
2359
2635

35
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2361
2837

35
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2361
2624

35
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2370
2620

35
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2374
2618

35
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2384
2614

35
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2404
2706

35
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2406
2691

35
6361886H1
2430
2806

35
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2444
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35
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2447
2654

35
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2451
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35
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2457
2667

35
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2458
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35
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1804
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1804
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1804
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1803
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1803
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1803
2321

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1803
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1803
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1803
2304

35
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1803
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1803
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1803
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1803
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35
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1803
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1804
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35
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1803
2304

35
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1803
2277

35
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1803
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1803
2296

35
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1803
2304

35
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1805
2338

35
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1803
2266

35
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1803
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35
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1803
2324

35
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1803
2338

35
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1803
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35
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1803
2251

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1803
2252

35
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1803
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1803
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1803
2251

35
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1803
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35
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1803
2254

35
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1803
2226

35
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1803
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35
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1803
2194

35
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1803
2194

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1803
2251

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1803
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1803
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1803
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1803
2162

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1804
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1804
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1803
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1803
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1804
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1804
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1803
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1804
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1804
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1804
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1803
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1803
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1803
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1804
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1804
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1803
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1803
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1804
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1804
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1803
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1803
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1804
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1803
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1803
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1803
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1804
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1803
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1803
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1803
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1803
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1803
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1803
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1803
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1803
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1803
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1803
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1804
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1803
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1804
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1803
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2512
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44
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3665
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44
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3825

44
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3692
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44
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44
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3739
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44
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3740
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44
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44
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44
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3826

44
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3769
4031

44
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44
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44
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3812
4278

44
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3830
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44
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3847
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44
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3851
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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44
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4171
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44
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44
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44
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44
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4214
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44
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44
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44
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1
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44
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164
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44
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288
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44
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294
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44
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308
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44
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341
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44
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435
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44
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504
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44
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607
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44
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1064

44
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762
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44
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775
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44
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788
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44
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798
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44
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802
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44
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801
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44
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44
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820
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44
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825
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44
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825
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44
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846
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44
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880
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44
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889
1175

44
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900
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44
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44
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993
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44
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1013
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44
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1017
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44
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1069
1330

44
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1069
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44
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1097
1370

44
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1119
1401

44
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1125
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44
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1149
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44
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1160
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44
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1203
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44
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1215
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44
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1235
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44
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1257
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44
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1265
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44
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1288
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44
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1303
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44
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1315
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44
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1356
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44
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1367
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44
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1395
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44
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1469
1999

44
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1503
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44
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1575
1956

44
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1580
2183

44
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1580
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44
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1580
1826

44
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1580
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44
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1580
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44
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1588
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44
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1592
2173

44
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1614
1907

44
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1614
1877

44
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1628
1875

44
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1632
1886

44
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1633
1891

44
688318H1
1634
1905

44
2445716H1
1664
1914

44
6044677H1
1665
1972

44
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1665
1891

44
2005094H1
1670
1929

44
6329762H1
1714
2197

44
2898215H1
1710
2021

44
2243695H1
1728
1968

44
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1731
1996

44
5826773H1
1740
2266

44
518068H1
1739
1966

44
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1745
2323

44
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1748
2290

44
6332331H1
1747
2192

44
6420565H1
1756
2147

44
70741619V1
3350
3955

44
6773924H1
1756
2263

44
3490671H1
1759
1926

44
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1760
2016

44
2171658H1
1759
1959

44
4840412H1
1770
2029

44
5639607H1
1839
1967

44
2512143H1
1858
2174

44
3243167H1
1970
2205

44
2371305H1
1981
2202

44
71303275V1
2021
2416

44
71130980V1
2217
2338

44
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2222
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44
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2329
2863

44
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2375
2634

44
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2397
2598

44
1932345H1
2461
2718

44
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2467
2747

44
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2720

44
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2468
2655

44
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2472
2763

44
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2478
2745

44
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2483
2621

44
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2488
2742

44
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2488
2948

44
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2488
2753

44
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2488
3017

44
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2490
2745

44
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2502
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44
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2505
2721

44
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2507
2780

44
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2527
2743

44
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2598
2832

44
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2605
2877

44
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2620
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44
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2631
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44
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3351
3875

44
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2638
2911

44
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2641
2874

44
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2641
2863

44
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2652
2922

44
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2700
3010

44
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2706
2957

44
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2723
2985

44
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2728
2988

44
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2738
2984

44
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2748
3194

44
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2780
3041

44
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2796
3066

44
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2819
3075

44
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2832
3168

44
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2844
3007

44
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2846
3059

44
4140731H1
2864
3170

44
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2874
3188

44
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2935
3169

44
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2981
3180

44
3223084H1
2993
3290

44
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2999
3085

44
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3028
3310

44
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3070
3289

44
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3075
3277

44
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3091
3328

44
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3292
3552

44
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3312
3923

45
6572570J1
1
436

45
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1
380

45
4345534F6
21
269

45
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72
231

45
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105
269

45
7204038H1
148
663

45
6981431H1
294
825

45
2630960F6
730
1090

45
2630960H1
730
965

45
609082H1
802
1065

45
g564302
805
1003

45
g1139137
837
1181

45
2554584H1
957
1231

45
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957
1233

45
6990332H1
984
1308

45
g781616
1020
1332

45
5904340H1
1041
1335

45
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1041
1283

45
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1042
1343

45
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1057
1609

45
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1070
1684

45
6092295H1
1129
1391

45
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1133
1551

45
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1143
1733

45
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1278
1440

45
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1279
1701

45
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1317
1751

45
5099033H1
1339
1615

45
4147460H1
1349
1541

45
3142603T6
1395
1863

45
3689942H1
1434
1717

45
g4394682
1460
1909

45
g3418148
1462
1908

45
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1472
1885

45
6197152H1
1476
1923

45
2630960T6
1491
1867

45
g3424422
1526
1906

45
5638207H1
1551
1833

45
g827423
1566
1771

45
1299193F6
1583
1900

45
6073452T6
1583
1862

45
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1583
1777

45
1299193T6
1583
1857

45
2107254H1
1590
1866

45
g560355
1684
1900

45
g1784513
1726
1848

45
2223448H1
1760
1896

45
g6505941
1763
2406

45
2660260H1
1785
2032

45
4857157H1
1816
2022

45
3242659H1
1933
2154

45
g823764
2079
2417

45
6572570H1
2278
2762

45
6924120H1
2500
3013

45
6168506H1
2644
2967

45
6987381H1
2657
3220

45
3508325H1
2828
3116

46
7061915H1
1
477

46
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172
658

46
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353
4979

46
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794
1156

46
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827
1154

46
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1845
2143

46
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1888
2061

46
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2289
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46
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2289
2532

46
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2438
2801

46
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2447
2779

46
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2615
3003

46
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2628
2914

46
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2745
2961

47
6772168H1
1565
2062

47
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1463
1697

47
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1534
1797

47
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1563
1929

47
5022301H1
1563
1833

47
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1564
1835

47
4340882T6
1795
2060

47
1479486T6
1569
2058

47
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1568
2057

47
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1581
2056

47
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1577
1844

47
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1645
2057

47
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1652
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47
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1652
1899

47
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1670
1895

47
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1725
2098

47
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1770
2104

47
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1175
1422

47
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1178
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47
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1178
1435

47
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1235
1723

47
6977932H1
1414
1612

47
7033269H1
1452
1982

47
3466972H1
1462
1719

47
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1842
2094

47
4774836H1
1845
2099

47
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1889
2098

47
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1999
2098

47
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715
1057

47
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1
555

47
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1
224

47
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21
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47
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129
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47
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331
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47
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331
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47
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389
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47
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393
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47
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393
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47
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423
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47
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621
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47
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658
817

47
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1566
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47
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1041
1328

47
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716
1011

47
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787
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47
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881
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47
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882
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48
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884
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48
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955
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48
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754
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48
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745
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48
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826
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48
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48
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48
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855
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48
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556
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48
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559
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48
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584
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48
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571
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48
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620
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48
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635
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48
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639
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48
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657
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48
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704
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48
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729
1123

48
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947
1323

48
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960
1527

48
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969
1601

48
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983
1631

48
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984
1298

48
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993
1269

48
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1028
1312

48
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1
224

48
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1
135

48
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5
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48
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20
596

48
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363
650

48
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378
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48
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387
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48
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416
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48
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24
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48
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210
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48
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426
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48
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438
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48
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440
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48
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440
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48
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475
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48
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248
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48
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250
912

48
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259
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48
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355
1012

48
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363
1033

48
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363
725

48
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1091
1408

48
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1109
1378

48
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1137
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48
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1137
1471

48
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1137
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48
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1137
1396

48
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1149
1704

48
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1149
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48
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1176
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48
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1168
1666

48
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1222
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48
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1248
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48
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1250
1538

48
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489
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48
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490
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48
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500
1181

48
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505
1145

48
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528
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49
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1
542

49
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23
287

49
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77
411

49
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77
655

49
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77
277

49
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193
497

49
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230
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49
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229
502

49
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396
581

49
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491
1020

49
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564
798

49
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603
866

49
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670
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49
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678
737

49
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679
753

49
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712
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49
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712
1114

49
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765
832

49
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765
832

49
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765
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49
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807
1469

49
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814
1176

49
4080269H1
870
1146

49
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897
1445

49
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949
1215

49
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950
1206

49
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962
1540

49
1386487H1
1074
1292

49
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1082
1334

49
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1121
1403

49
1313052H1
1130
1364

49
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1179
1465

49
1578741H1
1199
1411

49
6521182H1
1240
1806

49
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1243
1449

49
3905468H1
1244
1490

49
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1246
1761

49
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1251
1517

49
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1435
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49
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1449
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49
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1449
1668

49
6942236H1
1467
2063

49
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1488
1811

49
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1488
1668

49
1974505F6
1535
1853

49
1974505H1
1535
1668

49
6978865H1
1547
1936

49
g1856293
1557
1943

49
6839538H1
1559
2161

49
6073945H1
1564
1765

49
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1605
1892

49
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1753
2232

49
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1759
2243

49
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1775
2271

49
2364406H1
1776
1931

49
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1787
2267

49
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1794
2267

49
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1794
2272

49
1974505T6
1795
2231

49
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1802
2269

49
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1815
2271

49
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1829
2269

49
1781695H1
1833
2127

49
1781695R6
1833
2266

49
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1843
2267

49
4243158H1
1857
2235

49
1514627F6
1888
2269

49
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1879
2269

49
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1910
2274

49
g1550011
1918
2269

49
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1920
2273

49
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1923
2269

49
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1926
2272

49
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1928
2260

49
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1929
2276

49
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1929
2271

49
g4392501
1929
2260

49
1971904T6
1930
2232

49
g1856294
1940
2269

49
g3095415
1941
2271

49
g5630271
1944
2272

49
546355H1
1961
2220

49
g3896543
1970
2269

49
1781695T6
1983
2229

49
g2219452
2007
2269

49
g6463319
2010
2273

49
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2038
2269

49
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2077
2269

49
652012H1
2089
2352

49
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2122
2272

49
1312172H1
2140
2324

49
1514627H1
2190
2269

50
2638422T6
1
140

50
2638422F6
1
373

50
6981422H1
7
572

50
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53
490

50
2638422H1
113
373

50
6768020J1
195
727

50
7359784H1
207
757

50
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365
749

50
5900048H1
409
699

50
6989532H1
559
1155

50
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1122

56
5044068R6
519
939

56
70565572V1
549
1013

56
70563167V1
589
1157

56
4414516H1
597
862

56
70564872V1
599
1148

56
2187472H1
651
928

56
70563453V1
669
1239

56
70564150V1
678
1265

56
70564317V1
705
1376

56
70562729V1
718
1328

56
70562680V1
726
1288

56
70564226V1
742
1421

56
g4988332
2176
2411

56
g564908
2177
2411

56
3590745H1
2330
2634

56
476150H1
2331
2602

56
1577439H1
2440
2654

56
g2347702
2176
2413

56
g4124357
2097
2417

56
g882958
2124
2419

56
3791454H1
2139
2415

56
4905965H2
2176
2361

56
g6473997
2176
2415

56
6141362H1
1555
1901

56
4597106H1
1559
1853

56
70564268V1
1362
1678

56
70564413V1
1378
1930

56
3553956H1
1381
1537

56
70669318V1
1404
1644

56
1241441H1
1429
1701

56
1297330H1
1489
1643

56
70565761V1
1509
2000

56
4857906H1
1550
1860

57
g5664193
1
377

57
g2619178
5
333

57
6441247H1
12
543

57
453769H1
184
377

57
3762476H1
235
538

57
6729757H1
348
910

57
3116387F6
383
761

57
3116387H1
384
664

57
5661301H1
391
644

57
g1977456
394
782

57
3496148F6
397
981

57
70139347V1
397
887

57
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397
675

57
1008165H1
455
761

57
6518018H1
464
1031

57
4177624H1
490
696

57
826356H1
517
846

57
6441415H1
554
1059

57
4539787H1
619
878

57
70142580V1
634
1044

57
6710170H1
649
1209

57
6203306H1
668
1199

57
70131575V1
692
1096

57
7362891H1
712
1260

57
2798030F6
720
1287

57
2798030H1
720
971

57
2659046H1
723
968

57
g1748057
740
899

57
1832131H1
748
960

57
4822509H1
763
1012

57
6980545H1
771
1103

57
5219156H1
843
1062

57
5767782H1
859
1315

57
5644717H1
859
1095

57
6917456H1
880
1413

57
3788651H1
923
1087

57
4571245H1
925
1203

57
3436728H1
928
1087

57
2231388F6
953
1455

57
2231388H1
953
1202

57
5040546H1
956
1087

57
70133707V1
976
1464

57
2113640H1
977
1226

57
6583623H1
1015
1355

57
g2004410
1019
1322

57
4314146H1
1020
1302

57
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1020
1353

57
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1027
1229

57
70131494V1
1104
1537

57
2737895H1
1123
1333

57
6443615H1
1123
1627

57
666344H1
1123
1300

57
70143472V1
1128
1500

57
4112076H1
1170
1444

57
469801H1
1232
1464

57
469801R6
1232
1464

57
70138703V1
1237
1803

57
817498H1
1266
1558

57
817306R1
1266
1836

57
817306H1
1266
1484

57
6440332H1
1269
1829

57
4226121H1
1286
1563

57
2888006H1
1291
1565

57
5326773H1
1333
1512

57
4827817H1
1343
1622

57
2837990H1
1343
1585

57
181567H1
1351
1537

57
064652H1
1351
1526

57
1566979H1
1353
1562

57
5489077H1
1372
1494

57
70132097V1
1377
1687

57
g853275
1388
1725

57
6132302H1
1388
1663

57
2744049H1
1388
1648

57
826818H1
1400
1733

57
3467063H1
1437
1705

57
70133770V1
1439
1833

57
3449015H1
1463
1629

57
3121922H1
1463
1773

57
2538144H1
1485
1813

57
70136427V1
1488
1931

57
2008648H1
1506
1685

57
3145660T6
1511
2119

57
70136864V1
1526
1925

57
469801T6
1526
2094

57
3116387T6
1579
2142

57
4760891H1
1610
1891

57
1572810T6
1637
2138

57
3917658H1
1652
1962

57
g5764969
1660
2134

57
6752149H1
1663
2144

57
g5232494
1668
2138

57
g3835399
1696
2137

57
g3804418
1702
2137

57
1814612T6
1704
2141

57
3879011H1
1725
2014

57
g3145312
1767
2184

57
g5658515
1767
2183

57
g4896513
1777
2189

57
g3041462
1783
2183

57
1268321F6
1789
2170

57
1268321H1
1789
2040

57
2798030T6
1790
2144

57
4855273H1
1844
2031

57
3947216H1
1844
2020

57
2232569H1
1859
2088

57
g6507253
1866
2134

57
2244523H1
1863
2114

57
2044580H1
1880
2159

57
g4088814
1891
2181

57
1268321T6
1903
2130

57
4850944H1
1927
2158

57
1492447H1
1928
2134

57
g5658077
1940
2134

57
g1211221
1951
2196

57
621406H1
1954
2171

57
g852913
1962
2111

57
2231388T6
1974
2142

57
g1155579
2012
2197

57
2245140H1
2088
2172

57
3496148T7
1537
2094

57
6175211H1
1541
1824

57
1814612F6
1548
2013

57
1814612H1
1548
1801

57
2370362H1
1551
1807

57
2372634H1
1551
1793

57
70131661V1
1563
1852

58
2174866H1
1
146

58
2698567H1
1
197

58
5541622H1
1
194

58
2930567F6
33
479

58
2930567H1
33
338

58
4982447H1
269
540

58
6255850H1
303
576

58
6258186H1
303
577

58
5721674H1
321
908

58
4152487H1
322
596

58
4028078H1
339
611

58
7279087H1
343
928

58
3097754H1
343
649

58
5668252H1
343
574

58
5538912H2
342
416

58
2816646H1
349
612

58
2816646F6
349
871

58
2610076H1
349
585

58
2777845H1
349
580

58
3293887H1
350
593

58
g1753994
350
559

58
3355981H1
351
608

58
g29167
376
691

58
2476803H1
387
650

58
2476803F6
387
595

58
g1646650
406
767

58
3796918H1
778
1068

58
7217683H1
812
1267

58
5608991H1
821
1011

58
1811369F6
853
1303

58
1811369H1
853
1163

58
71041470V1
943
1602

58
4514405H1
957
1207

58
3860484H1
982
1279

58
6708640H1
1017
1588

58
207612H1
1015
1241

58
3461827H1
1088
1182

58
6753368J1
1105
1745

58
g1629548
1195
1610

58
7156421J1
1209
1390

58
7156421H1
1209
1374

58
7202481H1
1235
1816

58
653612R6
1252
1492

58
6325601H1
1252
1547

58
653612H1
1252
1494

58
653612T6
1253
1462

58
2667659H1
1309
1395

58
2206550H1
1293
1492

58
6598025H1
1340
1850

58
3928253H1
1315
1633

58
3928196H1
1316
1628

58
5039319T9
1355
1949

58
3414970H1
1347
1620

58
1743113H1
1381
1664

58
g2115578
1382
1750

58
71042069V1
1422
2060

58
5691992H1
1409
1710

58
2816646T6
1435
2011

58
71041726V1
1509
2118

58
4689116H1
1522
1787

58
2936253H1
1524
1803

58
3528601T6
1552
2014

58
5203894H1
1559
1823

58
3415070T6
1578
2015

58
5423080H1
1583
1854

58
5422280H1
1583
1828

58
g434100
1753
2008

58
1811369T6
1780
2215

58
6489437H1
1800
2249

58
g1751419
1841
2048

58
g2541732
1845
2055

58
g5530419
1870
2049

58
3212650T6
1875
2026

58
3118422H1
1882
2049

58
3002323F6
1882
2047

58
3118368T6
1885
2009

58
830827R1
1897
2249

58
830827H1
1897
2160

58
997447H1
1899
2151

58
6506368H1
1903
2249

58
g1977012
1938
2287

58
1811076T6
1938
2221

58
2589380H1
1968
2238

58
2552865H1
1968
2215

58
g2631458
1972
2243

58
5573308H1
1982
2232

58
g6439334
2088
2250

58
3732638H1
2100
2243

58
3736212H1
2116
2249

58
g1629446
2143
2250

58
g3891127
2146
2250

58
6131388H1
2153
2243

59
3625376H1
2752
2845

59
g5675476
2517
2963

59
g3146172
2594
2958

59
3274786H1
2616
2858

59
1953692H1
111
344

59
6539166H1
198
716

59
2133241F6
229
647

59
2133241H1
229
494

59
6365336H1
335
613

59
1676569H1
375
591

59
g2881893
461
513

59
6812474H1
525
1081

59
4934590H1
525
609

59
045505H1
526
755

59
2670704F6
598
980

59
2670704H1
598
846

59
003688H1
628
941

59
6812474J1
792
1344

59
2185753H1
923
1155

59
1665259H1
1333
1552

59
5193614H1
1718
1967

59
4378244H1
1994
2271

59
70742391V1
2036
2610

59
419872H1
2167
2379

59
171741R1
2186
2661

59
171741H1
2186
2362

59
g2009473
2197
2490

59
g2189171
2227
2329

59
g6330101
1
2954

59
2669204T6
5
463

59
5951559H1
34
348

59
3942253H1
2231
2521

59
042842H1
2237
2480

59
2656261H1
2243
2497

59
1971006F6
2319
2789

59
1971006H1
2319
2583

59
2667143T6
2341
2911

59
001227H1
2373
2728

59
3716845H1
2374
2648

59
6514287H1
2382
2935

59
4120983H1
2404
2640

59
g4189206
2487
2958

59
g2278337
2503
2957

60
71229143V1
621
1253

60
6983112H1
624
904

60
g570318
633
919

60
7046749H1
452
1052

60
70868787V1
465
1132

60
753174H1
355
544

60
4318873H1
153
369

60
71230534V1
162
657

60
7322168H1
165
793

60
6992614H1
233
746

60
g778569
676
1011

60
744829H1
675
915

60
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1
478

60
3335250F6
28
397

60
70870096V1
657
1340

60
70869315V1
674
1384

60
744829R1
675
1254

60
3335250H1
28
270

60
7077668H1
130
662

60
g518739
2296
2520

60
60202000D1
2303
2520

60
g3230679
2327
2520

60
g717890
2461
2535

60
60201999D1
2508
2561

60
750787H1
2258
2510

60
667235H1
2263
2515

60
g561290
2289
2520

60
g714831
2246
2557

60
70818421V1
673
1279

60
g869715
675
1023

60
4745248H1
1
238

60
748982H1
675
914

60
70869543V1
746
1291

60
70838362V1
773
900

60
70837422V1
778
1013

60
71229105V1
787
1469

60
70870484V1
807
1465

60
70869894V1
829
1508

60
70839431V1
828
1138

60
70837620V1
868
1305

60
g565684
918
1102

60
71221539V1
985
1416

60
70869173V1
992
1418

60
71229615V1
1005
1492

60
70867752V1
1053
1804

60
70870784V1
1013
1466

60
71229687V1
1038
1742

60
70870712V1
1032
1587

60
70870207V1
1036
1656

60
g1025621
1047
1385

60
g1059514
1047
1284

60
71229437V1
1156
1803

60
g714830
1131
1442

60
70870012V1
1147
1778

60
4311224H1
1231
1528

60
70869086V1
1284
1849

60
2292421R6
1498
1606

60
71229131V1
1473
2098

60
2292254R6
1506
1988

60
2291932H1
1506
1759

60
530715H1
1531
1754

60
7090888H1
1628
1769

60
g3086021
1626
2047

60
71228809V1
1628
2200

60
60202364B1
1657
2134

60
60202363B1
1657
2096

60
2291932T6
1669
2269

60
60202367B1
1665
2041

60
3335250T6
1672
2184

60
70870682V1
1770
2476

60
70869072V1
1785
2476

60
70867264V1
1828
2445

60
70868309V1
1828
2491

60
6841962H1
1858
2421

60
70870157V1
1978
2569

60
6855669H1
2008
2520

60
6885209J1
2001
2441

60
746910R6
2044
2520

60
746910T6
2045
2516

60
746910H1
2044
2281

60
6844175H1
2075
2520

60
2568562H1
2123
2362

60
g4393425
2130
2563

60
g4109519
2140
2520

60
g2694947
2170
2520

60
g2703845
2174
2520

60
g3884077
2176
2520

60
g3278030
2179
2569

60
4705947H1
2239
2398

60
5266308H1
635
795

61
6803748H1
1
281

61
6803748J1
185
681

61
7179441H1
281
837

61
6993211H1
431
958

61
990041H1
585
938

61
2647312H1
2235
2464

61
5303648H2
2242
2538

61
7236332H1
2251
2534

61
3606921H1
2256
2543

61
4423382H1
2269
2538

61
1976495H1
2269
2526

61
g6400732
2279
2543

61
6538345H1
2292
2509

61
1942829H1
2284
2540

61
1929606H1
2292
2537

61
1794859H1
2312
2543

61
6912812H1
961
1221

61
1602952F6
691
1143

61
3436025H1
691
925

61
3025993H1
921
1218

61
954323H1
2326
2529

61
954323R1
2326
2529

61
954323T1
2326
2483

61
g395758
2345
2528

61
5393045H1
2354
2470

61
1602953H1
691
793

61
1602952H1
691
779

61
1602953F6
691
909

61
1568974H1
1974
2177

61
6950168H1
1976
2470

61
6951183H1
1988
2470

61
1510868H1
1997
2126

61
5511854H1
2007
2266

61
g2017578
2021
2249

61
2225061H1
2036
2295

61
5685115H1
2039
2313

61
5503829H1
2046
2302

61
6736816H1
2051
2433

61
6914591J1
1587
2103

61
7267538H1
1622
1800

61
6559545H1
1677
2237

61
7287559H1
1703
2171

61
6912812J1
1719
2352

61
6714578H1
1791
2351

61
6384321H1
1791
2017

61
7124412H1
1803
2268

61
g650235
1811
2087

61
3934148H1
1829
1983

61
6914591H1
1830
2173

61
3934148F6
1838
2178

61
5950691H1
1874
2208

61
5950591H1
1874
1946

61
7336402H1
1901
2467

61
4000559H1
1959
2238

61
1570912F6
1974
2307

61
1570912H1
1974
2184

61
7152207H1
1328
1863

61
7152523H1
1375
1863

61
684121H1
1431
1674

61
1998986H1
1449
1545

61
598762H1
1472
1718

61
2227505H1
1546
1793

61
3393621H1
1557
1854

61
3441995H1
1570
1822

61
g5528672
2232
2527

61
6992150H1
1037
1416

61
4514493H1
1075
1162

61
1622836H1
1163
1292

61
2864609H1
1208
1358

61
7259857H1
1220
1855

61
3551930H1
1220
1512

61
1379503H1
1223
1458

61
7154005H1
1283
1863

61
5297140H1
2150
2448

61
3984036H1
2152
2347

61
g3048902
2160
2538

61
5297634H1
2177
2469

61
5297140F8
2180
2460

61
g5367334
2217
2545

61
2569168H1
2218
2485

61
g3842534
2219
2536

61
2449539H1
2228
2458

61
4947830H1
2067
2189

61
5345386H1
2069
2260

61
g4244699
2071
2541

61
3934148T6
2072
2496

61
3480660H1
2078
2301

61
576039H1
2079
2319

61
g650236
2084
2482

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2100
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61
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320
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1197
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1
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1436
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863
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4
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1342
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1702
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1912
2054

62
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1980
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1996
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590
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1008
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1021
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63
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1935
2253

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1966
2392

63
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1968
2496

63
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1989
2503

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2014
2458

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2021
2417

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1
359

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1
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63
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1
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270
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2021
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391

72
183176R6
27
491

72
183176H1
27
251

72
2733388H1
110
339

72
5616358H1
120
396

72
71238219V1
165
770

72
g4762579
398
832

72
71020348V1
429
1029

72
71019924V1
467
918

72
7104793H1
478
998

72
71019186V1
519
967

72
4004284H1
525
792

72
71020080V1
771
1365

72
71238694V1
772
1352

72
71237183V1
791
1317

72
71019222V1
822
1224

72
71240267V1
868
1118

72
71240088V1
868
1118

72
71237170V1
1030
1386

72
g2358498
1
382

72
183176R1
27
640

73
277677H1
1431
1536

73
3873445H1
946
1227

73
6448059H1
968
1478

73
000843H1
1046
1539

73
867412H1
1039
1238

73
160137T6
1041
1517

73
1928767T6
1083
1496

73
1928767R6
1099
1542

73
1928767H1
1099
1376

73
2937207H1
1099
1339

73
5001393H1
1100
1297

73
g5631970
1101
1539

73
5989817H1
1102
1292

73
g5747028
1103
1536

73
6074562H1
1113
1412

73
6074662H1
1113
1338

73
g2719198
1477
1539

73
5902113H1
1501
1728

73
4931449H1
1501
1770

73
g673993
182
474

73
g1267101
196
545

73
4826378H1
262
524

73
556057H1
270
478

73
556041H1
270
479

73
3449244H1
1427
1651

73
3521301H1
1274
1416

73
6511601H1
1280
1531

73
7060576H1
1283
1718

73
g1424041
1315
1536

73
g4523497
1231
1652

73
g1193170
1237
1536

73
3051747H1
1272
1562

73
3996830H1
1513
1643

73
453660H1
1653
1728

73
355514H1
1212
1424

73
g2899582
1156
1536

73
3802944H1
1179
1451

73
g5862645
1187
1536

73
4001379H1
1198
1339

73
4819034H1
45
131

73
3725796H1
76
160

73
g1273189
87
309

73
g2141610
1148
1539

73
g4224292
1149
1536

73
g1861043
1153
1541

73
6074694H1
1113
1357

73
g2969771
1116
1536

73
2877117H1
1
139

73
g1934264
1321
1728

73
816059R1
1351
1728

73
816059R6
1351
1549

73
816059H1
1351
1589

73
6716201H1
1400
1664

73
4439494H1
1412
1548

73
2417379F6
342
682

73
2417379H1
342
509

73
433802H1
342
509

73
g1640167
342
492

73
3723919H1
360
471

73
4443121H1
401
705

73
6309581H1
458
948

73
2779428H1
473
715

73
4829932H2
595
840

73
g1891400
596
1068

73
6368954H1
647
926

73
160137H1
660
901

73
160137R6
664
1020

73
1968940H1
726
989

73
3899549H1
785
1048

73
2667776H1
815
1045

73
4871959H1
830
1026

73
2608521H1
904
1097

73
5433362H1
913
1091

73
g2963571
1473
1662

73
g2910204
1121
1536

73
g5592759
1126
1537

73
1227022H1
1139
1269

73
795156H1
1140
1383

73
g748850
11
227

73
g678626
24
445

73
556041R6
270
622

73
6717668H1
277
609

74
5947068H1
65
379

74
g673182
66
311

74
70585819V1
66
223

74
g784700
81
171

74
4071087H1
84
393

74
g3401588
316
738

74
g3412723
338
732

74
g6038772
338
732

74
g784495
365
732

74
3346654H1
49
339

74
70585937V1
67
573

74
2198034H1
54
310

74
6559467H1
53
662

74
2554485H1
55
292

74
3213289H1
55
220

74
7154394H1
56
646

74
999535H1
55
245

74
2446468H1
58
303

74
138735H1
61
441

74
70576514V1
117
242

74
5529836H1
83
260

74
2642157H1
83
233

74
2854411H1
84
281

74
3394115H1
84
265

74
2457270H1
84
217

74
7246868H2
85
171

74
5467726H1
91
265

74
5048151H1
112
277

74
4055118T9
1
653

74
2571441H1
11
258

74
6297876H1
49
332

74
g1389377
68
470

74
4621236H1
70
366

74
2718503H1
69
184

74
g813048
71
501

74
g570365
71
376

74
5478847H1
74
317

74
g613447
81
330

74
70589118V1
67
741

74
7344794H1
68
664

74
1649902F6
67
377

74
1384494H1
67
331

74
1649839H1
67
311

74
1649902H1
67
310

74
6389250H1
68
379

74
2729287T6
122
700

74
4055118T7
124
624

74
906915H1
132
286

74
5621907H1
135
475

74
g1281834
137
550

74
3773136H1
160
490

74
70588034V1
182
477

74
70588682V1
186
734

74
1649902T6
192
689

74
70590189V1
243
734

74
g2908534
249
701

74
70573192V1
282
565

74
g4070388
291
730

74
70578389V1
295
439

74
2584982H1
299
556

74
g3924424
317
650

74
g4896209
440
747

74
70590586V1
409
565

74
4171532H1
427
728

75
g864641
472
730

75
g854955
498
853

75
7018723H1
526
1079

75
1634405F6
537
1019

75
1634405H1
537
753

75
2135762H1
598
889

75
6754472H1
666
1291

75
1573637F6
689
1107

75
1573637H1
689
906

75
000132H1
691
1122

75
g1164431
695
972

75
2893510H1
729
1003

75
5687323H1
796
1064

75
4369688H1
854
1120

75
6130274H1
858
971

75
g778259
940
1189

75
5076483H1
1055
1318

75
3926443F6
1083
1488

75
3926443H1
1084
1284

75
439597T6
1142
1776

75
1634405T6
1166
1762

75
2530791F6
1225
1590

75
2530791H1
1225
1466

75
3926443T6
1285
1789

75
567711T6
1298
1783

75
567711R6
1298
1759

75
567703H1
1298
1551

75
g2785236
1315
1793

75
g3649430
1318
1747

75
g2779890
1324
1813

75
1573637T6
1340
1773

75
g4176290
1343
1817

75
g3765500
1344
1814

75
5032276H1
1380
1620

75
g2569759
1383
1814

75
g3433438
1386
1804

75
g2903602
1395
1814

75
2530791T6
1411
1773

75
2994433H1
1433
1644

75
g1148705
1461
1817

75
g2903846
1465
1793

75
g1880344
1474
1588

75
g777248
1484
1755

75
g6450447
1495
1793

75
g3753249
1527
1813

75
g863905
1529
1804

75
g778854
1529
1795

75
g854914
1530
1773

75
g5365595
1535
1816

75
g778166
1662
1796

75
g2269957
1680
1813

75
g3056293
1703
1814

75
7341877H1
194
778

75
6092377H1
332
608

75
3074534H1
1
263

75
3293881H1
38
284

75
439597R6
177
719

75
439597H1
177
404

75
6558204H1
182
612

75
062726H1
374
548

75
062712H1
374
541

75
5565196H1
413
626

76
1375031F6
785
1262

76
1375031F1
784
1041

76
2133064H1
763
1041

76
6827035J1
1
659

76
3507907H1
885
1175

76
114238H1
915
988

76
128209H1
915
1030

76
6530747H1
1096
1708

76
5291702H1
1127
1366

76
1375031H1
784
1034

76
684570H1
829
1046

76
g2786676
2256
2677

76
g959893
2259
2671

76
g6033820
2259
2666

76
2180264T6
2265
2625

76
g6074973
2269
2673

76
g1507095
2273
2669

76
g5741986
2275
2672

76
g4004471
2278
2672

76
g1201567
2280
2668

76
g2786837
2282
2677

76
g6086742
2293
2671

76
70091053V1
2301
2666

76
70092520V1
2230
2635

76
600490H1
2233
2502

76
70090081V1
2238
2676

76
g4985261
2241
2670

76
g3047609
2241
2666

76
g898301
2240
2666

76
g1194822
2242
2669

76
g697708
2249
2675

76
g3245902
2242
2672

76
g3778060
2242
2672

76
g3675008
2247
2672

76
g3700953
2253
2680

76
70090551V1
2252
2654

76
70088450V1
2252
2654

76
g4987033
2306
2666

76
7346532H1
2315
2669

76
g1195921
2333
2667

76
g3307378
2351
2673

76
g1424265
2356
2666

76
g1994824
2368
2666

76
70092273V1
2369
2666

76
70088685V1
2434
2683

76
g1489884
2497
2667

76
g4298447
2503
2666

76
g1227527
2522
2669

76
g2836709
2227
2666

76
404342H1
2229
2497

76
401524H1
2229
2445

76
402039H1
2229
2426

76
401524F1
2229
2666

76
70093923V1
2230
2654

76
6912204J1
189
491

76
6912204H1
191
490

76
g1146598
386
763

76
7338712H1
426
1013

76
4951401H2
596
877

76
3225692H1
728
993

76
2133064F6
763
1210

76
g2657310
41
563

76
2081047F6
1132
1650

76
2081047H1
1132
1375

76
g2969649
1175
1525

76
873831H1
1198
1406

76
5187690H1
1219
1495

76
4089635H1
1236
1369

76
6596535H1
1272
1417

76
2581130F6
1301
1702

76
2581130H1
1301
1552

76
g1994825
1382
1595

76
7040047H1
1449
1702

76
6630452U1
1468
1702

76
6630374U1
1578
2150

76
4143678H1
1593
1692

76
g959892
1613
1702

76
6903811H1
1646
2243

76
4332838H1
1648
1702

76
g697795
1774
2119

76
g704969
1774
2043

76
2888581H1
1951
2236

76
70089240V1
1973
2539

76
70090145V1
1973
2674

76
70089170V1
1973
2538

76
70092550V1
1973
2489

76
70092490V1
1973
2499

76
70089927V1
1973
2437

76
70092932V1
1973
2447

76
70091424V1
1973
2516

76
70090074V1
1973
2480

76
70090511V1
1973
2426

76
70092562V1
1973
2452

76
70090451V1
1973
2487

76
70093155V1
1973
2333

76
70093381V1
1973
2335

76
2180264F6
1973
2319

76
70091927V1
1973
2286

76
2180264H1
1973
2143

76
70091191V1
1974
2497

76
2956706H1
1982
2065

76
g1239260
1989
2120

76
g3658694
1993
2448

76
g2369409
1995
2221

76
g1489980
1995
2193

76
2915268H1
1995
2189

76
5103731H1
1995
2143

76
5083588H1
1995
2127

76
g2036913
2011
2270

76
1375031T1
2047
2289

76
70090620V1
2054
2455

76
1006083H1
2056
2329

76
g1315008
2071
2546

76
70090041V1
2079
2597

76
2275715H1
2082
2355

76
70089944V1
2092
2664

76
g1507094
2121
2366

76
2503051T6
2138
2254

76
2871614H1
2143
2443

76
2081047T6
2151
2289

76
1543664H1
2164
2375

76
g3734766
2174
2672

76
2133064T6
2177
2289

76
g4175843
2179
2669

76
g2705950
2190
2669

76
70092616V1
2190
2680

76
6017144H1
2186
2462

76
g1424317
2192
2665

76
70092373V1
2191
2664

76
70091541V1
2202
2654

76
920317H1
2208
2457

76
920309H1
2208
2455

76
70091726V1
2216
2666

76
g1317327
2225
2673

76
70089181V1
2228
2655

76
4592652H1
2227
2372

77
5386182H1
2434
2533

77
5929032F6
2513
3092

77
5929032H1
2513
2807

77
5928821H1
2513
2602

77
2404117R6
2533
2936

77
2247162H1
2533
2802

77
5845721H1
2532
2686

77
2404117H1
2533
2717

77
6274929H2
2557
3085

77
4839303H1
2572
2867

77
70936812V1
2588
3163

77
6559464H1
2597
3142

77
2404117T6
2613
3183

77
2424729H1
2630
2886

77
6557735H1
2666
3250

77
70936842V1
2716
3372

77
1414767T6
2737
3276

77
g5768528
2761
3225

77
g1212489
2763
3057

77
659884H1
2764
3006

77
3331210T6
2779
3276

77
4942039H1
2778
3048

77
3331210F6
2781
3196

77
3331210H1
2781
2955

77
2043050H1
2878
3139

77
g678229
2896
3222

77
g4186860
2906
3322

77
g561452
2927
3226

77
g817283
2954
3237

77
g1242796
3055
3317

77
g678324
3120
3276

77
g671188
3142
3276

77
5821129H1
3194
3328

77
1414767F6
1261
1693

77
70407644D1
901
1138

77
71042670V1
1006
1659

77
71039461V1
1032
1644

77
7290781H1
1077
1648

77
71039094V1
1110
1784

77
71039976V1
1157
1628

77
71040172V1
1160
1738

77
71042825V1
1179
1788

77
71042505V1
1191
1806

77
71041242V1
1224
1881

77
70938142V1
1261
1803

77
g574829
1615
1881

77
g767565
1616
1876

77
70937073V1
1646
2215

77
71041370V1
1653
2311

77
g947001
1665
2012

77
3334355H1
1666
1945

77
g705805
1704
1982

77
6763269H1
1740
2365

77
71041012V1
1745
2398

77
1254953H1
1759
1993

77
6507931H1
1798
2269

77
1833479R6
1771
2216

77
1833479H1
1771
2075

77
6271456H2
1777
2341

77
3332037H1
1779
2041

77
59241921H1
1784
2080

77
7292851H1
1788
2312

77
1833479T6
1796
2354

77
70935438V1
1825
2345

77
5205918H1
1835
2094

77
4710070H1
1851
2150

77
71040258V1
1855
2399

77
70936878V1
1868
2349

77
g876649
1880
2293

77
g570326
1880
2195

77
g792017
1880
1970

77
7252042H1
1893
2490

77
5918594H1
1898
2195

77
4308614H1
1922
2266

77
5775902H1
1951
2547

77
900678T6
1952
2320

77
1267888F1
1965
2533

77
1267888H1
1965
2211

77
g1991900
1988
2282

77
g946386
2032
2371

77
g891688
2079
2407

77
70947602V1
2088
2333

77
70947760V1
2095
2333

77
2524117H1
2129
2395

77
g943716
2133
2371

77
70935414V1
2153
2809

77
70938201V1
2175
2740

77
g953501
2230
2370

77
70937638V1
2264
2847

77
5207284H1
2273
2516

77
g823406
2281
2415

77
6747059H1
2291
2882

77
5108466H1
2305
2395

77
750487H1
556
782

77
6983706H1
37
535

77
g2000717
382
570

77
6855956H1
517
998

77
g953502
1
212

77
g2331234
1
2384

77
7359814H1
27
485

77
5351059H1
2335
2472

77
70942966V1
2341
2513

77
2152647H1
2383
2636

77
70941613V1
2429
2567

77
1414767H1
1261
1503

77
g769023
1271
1589

77
71039996V1
1278
1834

77
71041640V1
1276
1859

77
661243H1
1311
1572

77
70845562V1
1318
1677

77
g891480
1320
1516

77
71042682V1
1370
2012

77
6437672H1
1366
1900

77
g705704
1384
1755

77
71040965V1
1418
1876

77
4695010H1
1441
1721

77
70938843V1
1447
1894

77
71041816V1
1463
2053

77
71040541V1
1463
2021

77
4178826H1
1494
1762

77
2525545H1
1496
1726

77
70936642V1
1550
2202

77
71243429V1
1557
1786

77
6124654H1
1590
2086

77
6560433H1
1614
2187

77
g389618
1615
1914

77
960213H1
814
1101

77
g774455
786
1139

77
962582R6
795
1260

77
962582H1
795
849

77
g879553
796
1117

77
4028250H1
574
833

77
g572875
750
1009

78
1504601F6
383
747

78
1258447H1
1616
1755

78
71225337V1
1618
2089

78
982079R6
2378
2741

78
982079H1
2378
2691

78
982079T6
2378
2744

78
4859367H1
1503
1670

78
g1056444
1527
1812

78
2881063H1
1478
1786

78
4546751H1
1485
1761

78
6219786H1
2241
2558

78
5044584H1
1072
1352

78
5731888H1
1086
1332

78
2668983H1
1013
1254

78
5869109H1
1423
1674

78
4175935F6
1476
2104

78
71287876V1
1476
2061

78
71286863V1
1476
2009

78
70995743V1
1476
1941

78
4175935H1
1476
1769

78
70175363V1
1478
2039

78
2881063F6
1478
1993

78
1405756H1
1101
1358

78
6212807H1
1168
1473

78
6789736H1
1286
1749

78
g866161
2297
2612

78
4933985H1
2263
2430

78
g865342
2297
2641

78
70961841V1
2250
2783

78
6843570H1
124
268

78
5447930H2
212
443

78
6819333H1
375
837

78
063360H1
575
793

78
2717804H1
736
995

78
1336510H1
542
798

78
1336565H1
542
794

78
2260777H1
522
781

78
6819333J1
525
1141

78
1504601H1
383
641

78
6935560H1
497
997

78
2260777R6
522
929

78
2417475H1
1999
2100

78
70858537V1
2011
2620

78
70962120V1
2020
2649

78
g5595178
2416
2791

78
g2569464
2421
2792

78
g2848983
2422
2790

78
g1507026
2424
2792

78
g1645469
2491
2786

78
70962041V1
2226
2750

78
2805557T6
2240
2753

78
6307990H1
2241
2695

78
g3701921
2399
2789

78
70856260V1
1659
2200

78
71287735V1
1680
2356

78
71226071V1
1619
2077

78
70960213V1
1653
2205

78
1258447F6
1616
2083

78
5886340H1
1960
2108

78
5880788H1
1959
2089

78
5883358H1
1960
2230

78
5882287H1
1960
2207

78
70996202V1
1968
2079

78
5884261H1
1959
2100

78
5886308H1
1959
2238

78
70172850V1
1547
2052

78
70172946V1
1554
1896

78
5109345H1
1773
1894

78
70858458V1
1829
2390

78
70861427V1
1872
2034

78
g1645468
2153
2569

78
70857537V1
2132
2748

78
70961205V1
2134
2784

78
6465155H1
817
1387

78
3737993H1
865
1101

78
2805557F6
888
1348

78
2805557H1
888
1199

78
7166418H1
1
544

78
6845517H1
18
576

78
7216754H1
109
637

78
g3895948
2405
2789

78
g1506843
2407
2792

78
g3934604
2413
2783

78
71362378V1
1586
1776

78
71288334V1
1613
2200

78
71288102V1
2182
2787

78
70858569V1
2361
2790

78
981508H1
2378
2661

78
g3280794
2348
2786

78
g4900509
2359
2783

78
858094H1
2047
2315

78
71288239V1
2117
2721

78
2056939R6
2154
2463

78
2056939H1
2154
2430

78
1641318H1
2168
2384

78
1298674H1
2174
2448

78
1298674F1
2174
2342

78
70172181V1
1769
2279

78
56995561H1
1678
1913

78
7027634H1
1695
1971

78
71225035V1
1707
2313

78
71225177V1
1746
2398

78
70961047V1
1745
2324

78
1692282F6
1749
2316

78
1692282H1
1749
1985

78
1305007H1
1754
2002

78
5887009H1
1958
2240

78
5889943H1
1958
2243

78
5888977H1
1958
2176

78
5884968H1
1959
2101

78
g2347469
1895
2202

78
2727193H1
1942
2100

78
2083456H1
1955
2102

78
70856801V1
1881
2488

78
2408695H1
2219
2334

78
1504601T6
2211
2755

78
1692282T6
2211
2740

78
71287317V1
2192
2816

78
6376946H1
2205
2491

78
3408549H1
2215
2526

78
2461537H1
982
1199

78
2056939T6
2523
2754

78
3819114H1
2568
2764

78
767808H1
2576
2783

78
g3871569
2579
2783

78
g5638296
2585
2789

78
g2969829
2618
2783

78
6368851H1
2678
2783

79
4404143T6
1
604

79
3566814H1
199
382

79
5639354R6
465
918

[0304]

4

TABLE 3

SEQ

ID NO:
Tissue Distribution

1
Unclassified/Mixed - 71%, Endocrine System - 16%

2
Embryonic Structures - 82%, Nervous System - 18%

3
Germ Cells - 62%, Connective Tissue - 17%, Unclassified/Mixed - 16%

4
Endocrine System - 71%, Nervous System - 29%

5
Nervous System - 76%, Endocrine System - 18%

6
Endocrine System - 63%, Liver - 23%

7
Endocrine System - 29%, Hemic and Immune System - 24%, Exocrine

Glands - 19%

8
Endocrine System - 42%, Germ Cells - 19%

9
Endocrine System - 66%, Sense Organs - 21%, Nervous System - 11%

10
Germ Cells - 30%, Sense Organs - 24%, Nervous System - 17%

11
Nervous System - 100%

12
Embryonic Structures - 18%, Pancreas - 17%, Hemic and Immune

System - 17%

13
Exocrine Glands - 42%, Cardiovascular System - 21%, Respiratory

System - 16%

14
Nervous System - 86%

15
Unclassified/Mixed - 17%, Sense Organs - 12%

16
Unclassified/Mixed - 28%, Embryonic Structures - 20%, Liver - 16%

17
Endocrine System - 100%

18
Digestive System - 57%, Hemic and Immune System - 29%, Nervous

System - 14%

19
Unclassified/Mixed - 90%

20
Exocrine Glands - 50%, Respiratory System - 38%, Nervous System - 13%

21
Unclassified/Mixed - 20%, Connective Tissue - 10%

22
Sense Organs - 17%

23
Female Genitalia - 32%, Hemic and Immune System - 24%, Endocrine

System - 20%

24
Sense Organs - 15%, Embryonic Structures - 13%

25
Sense Organs - 43%, Unclassified/Mixed - 11%

26
Unclassified/Mixed - 16%, Embryonic Structures - 13%, Germ Cells - 13%

27
Respiratory System - 43%, Nervous System - 21%, Female Genitalia - 21%

28
Liver - 33%, Germ Cells - 12%

29
Endocrine System - 31%, Germ Cells - 25%, Liver - 12%

30
Exocrine Glands - 29%, Germ Cells - 28%

31
Exocrine Glands - 18%, Cardiovascular System - 10%

32
Sense Organs - 23%, Embryonic Structures - 15%, Endocrine System - 15%

33
Sense Organs - 17%, Endocrine System 11%, Skin - 10%

34
Musculoskeletal System - 86%

35
Connective Tissue - 16%, Embryonic Structures - 14%, Digestive

System - 11%

36
Pancreas - 40%, Female Genitalia - 20%, Cardiovascular System - 16%

37
Respiratory System - 12%, Urinary Tract - 12%

38
Embryonic Structures - 53%, Digestive System - 17%, Nervous System - 12%

39
Digestive System - 40%, Nervous System - 32%, Nervous System - 28%

40
Exocrine Glands - 47%, Sense Organs - 21%

41
Connective Tissue - 60%, Unclassified/Mixed - 22%

42
Hemic and Immune System - 15%

43
Sense Organs - 21%, Female Genitalia - 13%

44
Hemic and Immune System - 18%, Female Genitalia - 17%

45
Embryonic Structures - 32%, Female Genitalia - 17%

46
Male Genitalia - 49%, Skin - 32%

47
Nervous System - 42%, Nervous System - 40%, Endocrine System - 14%

48
Digestive System - 41%, Nervous System - 15%, Liver - 14%

49
Exocrine Glands - 34%, Unclassified/Mixed - 22%

50
Nervous System - 57%, Unclassified/Mixed - 11%

51
Nervous System - 52%, Digestive System - 25%, Connective Tissue - 10%

52
Digestive System - 24%, Germ Cells - 22%, Exocrine Glands - 11%

53
Endocrine System - 32%, Digestive System - 19%

54
Embryonic Structures - 58%, Nervous System - 37%

55
Female Genitalia - 18%, Nervous System - 18%, Embryonic Structures - 18%

56
Connective Tissue - 29%, Germ Cells - 22%, Liver - 13%

57
Musculoskeletal System - 15%, Embryonic Structures - 11%

58
Stomatognathic System - 27%, Urinary Tract - 11%

59
Sense Organs - 25%, Endocrine System - 16%

60
Exocrine Glands - 33%, Urinary Tract - 27%, Nervous System - 14%

61
Endocrine System - 16%, Musculoskeletal System - 13%

62
Exocrine Glands - 27%, Skin - 15%, Female Genitalia - 15%

63
Female Genitalia - 36%, Urinary Tract - 22%, Digestive System - 22%

64
Germ Cells - 16%, Endocrine System - 11%, Liver - 11%

65
Pancreas - 24%, Unclassified/Mixed - 21%, Male Genitalia - 17%

66
Endocrine System - 43%, Embryonic Structures - 14%,

Unclassified/Mixed - 12%

67
Embryonic Structures - 42%, Male Genitalia - 19%, Female Genitalia - 19%

68
Male Genitalia - 67%, Nervous System - 33%

69
Urinary Tract - 50%, Endocrine System - 18%

70
Respiratory System - 100%

71
Skin - 43%, Nervous System - 19%, Nervous System - 19%

72
Cardiovascular System - 35%, Nervous System - 27%, Male Genitalia - 19%

73
Female Genitalia - 12%, Germ Cells - 11%

74
Male Genitalia - 28%

75
Embryonic Structures - 30%, Urinary Tract - 22%, Respiratory

System - 16%

76
Musculoskeletal System - 16%, Respiratory System - 12%

77
Nervous System - 35%, Male Genitalia - 31%, Germ Cells - 11%

78
Stomatognathic System - 19%, Liver - 12%, Exocrine Glands - 11%

79
Respiratory System - 38%, Female Genitalia - 38%, Male Genitalia - 25%

[0305]

5

TABLE 4

Program
Description
Reference
Parameter Threshold

ABI
A program that removes vector sequences and masks
Applied Biosystems, Foster City, CA.

FACTURA
ambiguous bases in nucleic acid sequences.

ABI/
A Fast Data Finder useful in comparing and annotating
Applied Biosystems, Foster City, CA;
Mismatch <50%

PARACEL
amino acid or nucleic acid sequences.
Paracel Inc., Pasadena, CA.

FDF

ABI
A program that assembles nucleic acid sequences.
Applied Biosystems, Foster City, CA.

Auto-

Assembler

BLAST
A Basic Local Alignment Search Tool useful in sequence
Altschul, S. F. et al. (1990) J. Mol. Biol.
ESTs: Probability

similarity search for amino acid and nucleic acid
215: 403-410; Altschul, S. F. et al. (1997)
value = 1.0E−8

sequences. BLAST includes five functions: blastp, blastn,
Nucleic Acids Res. 25: 3389-3402.
or less Full Length

blastx, tblastn, and tblastx.

sequences: Probability

value = 1.0E−10

or less

FASTA
A Pearson and Lipman algorithm that searches for
Pearson, W. R. and D. J. Lipman (1988) Proc.
ESTs: fasta E

similarity between a query sequence and a group of
Natl Acad Sci. USA 85: 2444-2448; Pearson,
value = 1.06E−6

sequences of the same type. FASTA comprises as least
W. R. (1990) Methods Enzymol. 183: 63-98;
Assembled ESTs:

five functions: fasta, tfasta, fastx, tfastx, and ssearch.
and Smith, T. F. and M. S. Waterman (1981)
fasta Identity = 95%

Adv. Appl. Math. 2: 482-489.
or greater and Match

length = 200

bases or greater;

fastx E value =

1.0E−8 or less

Full Length sequences:

fastx score = 100

or greater

BLIMPS
A BLocks IMProved Searcher that matches a sequence
Henikoff, S. and J. G. Henikoff (1991) Nucleic
Probability value =

against those in BLOCKS, PRINTS, DOMO, PRODOM,
Acids Res. 19: 6565-6572; Henikoff, J. G. and
1.0E−3 or less

and PFAM databases to search for gene families,
S. Henikoff (1996) Methods Enzymol.

sequence homology, and structural
266: 88-105; and Attwood, T. K. et al. (1997) .J.

fingerprint regions.
Chem. Inf. Comput. Sci. 37: 417-424.

HMMER
An algorithm for searching a query sequence against
Krogh, A. et al. (1994) J. Mol. Biol.,
PFAM hits:

hidden Markov model (HMM)-based databases of protein
235: 1501-1531; Sonnhammer, E. L. L. et al.
Probability value =

family consensus sequences, such as PFAM.
(1988) Nucleic Acids Res. 26: 320-322;
1.0E−3 or less Signal

Durbin, R et al. (1998) Our World View, in a
peptide hits: Score =

Nutshell, Cambridge Univ. Press, pp. 1-350.
0 or greater

ProfileScan
An algorithm that searches for structural and sequence
Gribskov, M. et al. (1988) CABIOS 4: 61-66;
Normalized quality

motifs in protein sequences that match sequence patterns
Gribskov, M. et al. (1989) Methods Enzymol.
score ≧ GCG-

defined in Prosite.
183: 146-159; Bairoch, A. et al. (1997) Nucleic
specified “HIGH”

Acids Res. 25: 217-221.
value for that

particular Prosite

motif. Generally,

score = 1.4−2.1.

Phred
A base-calling algorithm that examines automated
Ewing, B. et al. (1998) Genome Res.

sequencer traces with high sensitivity and probability.
8: 175-185; Ewing, B. and P. Green

(1998) Genome Res. 8: 186-194.

Phrap
A Phils Revised Assembly Program including SWAT and
Smith, T. F. and M. S. Waterman (1981) Adv. Appl.
Score = 120

CrossMatch, programs based on efficient implementation
Math. 2: 482-489; Smith, T. F. and M. S.
or greater; Match

of the Smith-Waterman algorithm, useful in searching
Waterman (1981) J. Mol. Biol. 147: 195-197; and
length = 56

sequence homology and assembling DNA sequences.
Green, P., University of Washington,
or greater

Seattle, WA.

Consed
A graphical tool for viewing and editing
Gordon, D. et al. (1998) Genome Res. 8: 195-202.

Phrap assemblies.

SPScan
A weight matrix analysis program that scans protein
Nielson, H. et al. (1997) Protein Engineering 10: 1-
Score = 3.5

sequences for the presence of secretory signal peptides.
6; Claverie, J. M. and S. Audic (1997) CABIOS
or greater

12: 431-439.

TMAP
A program that uses weight matrices to delineate
Persson, B. and P. Argos (1994) J. Mol. Biol.

transmembrane segments on protein sequences and
237: 182-192; Persson, B. and P. Argos (1996)

determine orientation.
Protein Sci. 5: 363-371.

TMHMMER
A program that uses a hidden Markov model (HMM) to
Sonnhammer, E. L. et al. (1998) Proc. Sixth Intl.

delineate transmembrane segments on protein sequences
Conf. on Intelligent Systems for Mol. Biol.,

and determine orientation.
Glasgow et al., eds., The Am. Assoc. for Artificial

Intelligence Press, Menlo Park, CA, pp. 175-182.

Motifs
A program that searches amino acid sequences for
Bairoch, A. et al. (1997) Nucleic Acids Res.

patterns that matched those defined in Prosite.
25: 217-221; Wisconsin Package Program Manual,

version 9, page M51-59, Genetics Computer

Group, Madison, WI.

[0306]

Secretory molecules

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

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