DIETARY SUPPLEMENT AND RELATED METHOD

Abstract

A composition including a unique combination of fruits, vegetables, herbs, and optionally vitamins, minerals and specialty ingredients. The composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient, is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can be administered to subjects to correct a dietary deficiency of phytochemicals and other nutrients, improve plasma concentrations of antioxidant nutrients, and increase the activity of genetic mechanisms for DNA repair and stability.

Description

BACKGROUND OF THE INVENTION

The present invention relates to a composition and method for correcting a dietary deficiency, including an inadequacy of phytochemicals, vitamins and minerals.

Many people fail to practice healthy eating habits, such as consuming an adequate quantity and variety of food to meet U.S. Recommended Dietary Allowances. Only 22% of the subjects of a National Cancer Institute Study consumed the recommended daily number of dietary servings of fruits and vegetables—despite the fact that the recommended dietary intake of fruits and vegetables is well-known. For example. The California Daily Food Guide; Dietary Guidelines for California, California Department of Health Services (1990) recommends that each person consume at least five to nine servings of fruit and vegetables per day, including one serving of a vitamin A-rich deep green or dark orange fruit or vegetable, and at least one serving of a vitamin C-rich fruit or vegetable. Additionally, it is well reported that each person should consume at least 3 servings per week of vegetable protein in the form of legumes, nuts, or seeds. Some researchers suggest that a target of 400 grams (13 ounces) of fruits and vegetables is a sensible goal for the optimal quantity to be consumed daily. In terms of variety, it is recommended that persons should eat at least three different colors of fruits and vegetables daily.

The benefits of consuming a sufficient amount and variety of fruits and vegetables are many. For example, consuming fruits and vegetables has been shown to reduce the risk of a variety of degenerative diseases. In a prospective cohort study of 41,837 postmenopausal women, the association of fruit and vegetable consumption with lung cancer risk was investigated. The researchers found that the risk of lung cancer was approximately halved when the consumption of fruits and vegetables increased from 24 or less servings to an excess of 48 servings per week. Similarly, the risk of lung cancer was approximately halved when the consumption of green leafy vegetables, including spinach and parsley sources, increased from one or fewer servings to six or more servings per week. Steinmetz, K. et al., “Vegetables, Fruit, and Lung Cancer in the Iowa Women's Health Study,” Cancer Res. 53:536-43 (1993). Another study found that an increased intake of fresh tomatoes (a major source of lycopene) was associated with a pattern of protection for all sites of digestive tract cancer. Stahl, W. et al., “Lycopene: A Biologically Important Carotenoid for Humans?” Arc. Biochem. Biophys. 336:1-9 (1996).

In addition to fruits and vegetables, herbs also provide health benefits. For example, the herb, rosemary, contains antioxidants such as carnosol, which may play a preventive role in cholesterol oxidation. Likewise, the herb, basil is known for its antioxidant activity. Like fruits and vegetables, however, the dietary intake of beneficial herbs is unsatisfactory.

Further research has shown that the typical U.S. diet is lacking in phytochemicals. Phytochemicals generally refer to plant-derived compounds which, when taken daily in combination with vitamins and minerals, provide improved cardiovascular and bone health, an improved antioxidant profile, decreased free radical damage, and overall enhancement of the body's natural defense system.

The typical diet, especially the U.S. diet, includes an inadequate amount and variety of fruits, vegetables and herbs, as well as the phytochemicals and associated antioxidants present in these materials. A typical diet is similarly deficient in necessary vitamins and minerals associated with fruits and vegetables. Although conventional multivitamins can supplement western diets with needed vitamins and minerals, many of these multivitamins fail to provide phytochemicals that target free radicals in the body and thereby improve the antioxidant profile of the supplement.

SUMMARY OF THE INVENTION

The present invention provides a composition including a unique combination of fruit vegetable, and herb dehydrates, concentrates, or extracts; and optionally vitamins, minerals and specialty ingredients to correct a dietary deficiency of those materials.

The composition of the present invention provides substantial health benefits. For example, in one embodiment, it can support the health of people who consume a nutritionally deficient diet; improve antioxidant and nutrient status; replenish serum nutrient and phytochemical levels as a result of inadequate diets to levels associated with decreased risk of certain degenerative disease states; minimize free radical damage that occurs as a result of normal aging processes and exposure to environmental stresses; and/or improve the status of specific biomarkers indicative of optimal health, namely homocysteine, lipid byproducts, mineral status and glutathione peroxidase.

In a more specific embodiment, the composition of the present invention can provide p-carotene, a-lipoic acid, selenium, and vitamins C and E, which improve the antioxidant profile of a person. Increased levels of folic acid and vitamins E target and improve cardiovascular health. Calcium, magnesium, and vitamin D targets and improves bone health. B vitamins improve energy metabolism. The compositions according to the invention can provide 100% of the U.S. Recommended Daily Intake of all vitamins and most minerals. The composition also can provide a variety of phytochemicals to produce a diverse antioxidant profile.

In an even more specific embodiment, the composition can include a combination of fruit, vegetable and herbal ingredients, wherein the fruit ingredients are selected from acerola, apple, blueberry, citrus bioflavonoids, cranberry, grape skin, plum, and pomegranate; wherein the vegetable ingredients are selected from asparagus, alfalfa, brassica, kale, lutein, lycopene, and watercress; and wherein the herbal ingredients are selected from basil, oregano, parsley, sage and rosemary. These ingredients can be concentrated, for example they may be extracted from raw ingredients. Optionally, the fruit ingredients, vegetable ingredients and herbal ingredients can be present in the composition in a ratio of about 3.5:1:1 by weight. Specialty ingredients, such as alpha lipoic acid and inositol can be added to the composition.

In yet another embodiment, the composition can include at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, plum and raspberry; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.

In another embodiment, a method is provided for enhancing the immune system, as well as treating and/or reducing die risk of DMA damage of the human body comprising administering an effective amount of a composition including at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, and plum; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.

These and other objects, advantages and features of the invention will be more readily understood and appreciated by reference to the detailed description of the invention and the drawings. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the effect the composition has on Vitamin C levels.

FIG. 2 is a graph depicting the effect the composition has on beta carotene levels.

FIG. 3 is a graph depicting the effect the composition has on Vitamin B₆ levels.

FIG. 4 is a graph depicting the effect the composition has on Vitamin B₁₂ levels.

FIG. 5 is a graph depicting the effect the composition has on Folate levels.

FIG. 6 is a graph depicting the effect the composition has on homocysteine levels.

FIG. 7 is a graph depicting the numbers of genes related to DNA or chromatin maintenance or repair that were modulated by consumption of the composition.

FIGS. 8A and 8B which are a diagram (FIG. 8A) and a graph (FIG. 8B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 2-hydroxybutarate.

FIGS. 9A and 9B are a diagram (FIG. 9A) and a graph (FIG. 9B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 5-oxoproline.

FIG. 10 is a graph depicting the change in plasma beta-carotene concentration after treatment.

FIG. 11 is a graph depicting the change in plasma folate concentration after treatment.

FIG. 12 is a graph depicting the change in plasma vitamin B6 concentration after treatment.

FIG. 13 is a graph depicting the change in plasma vitamin B12 concentration after treatment.

FIG. 14 is a graph depicting the change in plasma homocysteine concentration after treatment.

FIG. 15 is a graph depicting the change in DNA damage after treatment.

FIG. 16 is a graph depicting the change in baseline expression activity of genes associated with DNA maintenance genes after treatment.

DETAILED DESCRIPTION OF THE INVENTION

I. Overview

In general, the invention relates to a composition comprising fruits, vegetables and herbs. In one embodiment, the composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can also be combined with a known therapy that can impact chromatin stability thereby limiting the detrimental effects of such therapy.

The following fruit ingredients also can be present in the composition: acerola, apple, blueberry, cranberry, grape skin, and plum. Further, the following vegetable ingredients also can be present in the composition: alfalfa, brassica, and kale. Finally, the following herbal ingredients also can be present in the composition: sage and parsley.

The composition has a synergistic effect in the treatments discussed herein. Thus, the components of the composition together are more effective that individually. Additionally, the composition modulates, and more specifically as discussed herein up-regulates, genes associated with chromatin stability, examples of which are discussed in the figures and examples.

Example of genes involved in telomere maintenance include, but are not limited to, Ku, Cdc 13 protein, the catalytic subunit EST2, and three other genes, EST1, EST3, EST4/CDC13, MRE11, RAD50, XRS2 (yeast)/NBS1, p53, hTERT, ATM, TRF2, the TERF family of genes.

The composition of the present invention can either treat or reduce the occurrences/risks of chromatin damage, and thus support genome stability, by increasing the expression of genes involved in identifying and correcting damage to DNA as well as associated protein structures (i.e., chromatin). The reduction in the occurrence/risk of chromatin damage includes any statistically significant reduction that correlates to a biological response or outcome. These genes control activities including, but not limited to, repair of base pair mismatches, repair of double strand breaks, or other maintenance, repair or supervisory roles. Most damage is caused by oxidation, nutrient deficiency, radiation or toxins. There are four main types of damage to DNA due to endogenous cellular processes or exogenous insult such as ultraviolet radiation: oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species, alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine hydrolysis of bases, such as deamination, depurination and depyrimidination, mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted. There are four major DNA-repair pathways in human cells: mismatch repair, nucleotide-excision repair (NER), base-excision repair (BER), and double-strand-break (DSB) repair. The NER pathway mainly removes bulky DNA adducts. The BER pathway is responsible for removal of oxidized DNA bases that may arise endogenously or from exogenous agents. The DSB pathway is responsible for repairing double-strand breaks caused by a variety of exposures, including ionizing radiation, free radicals, and telomere dysfunction. Examples of such genes include, but are not limited to ERCC, RAD2, RAD6, RAD7, RAD18, RAD23, RAD51, RAD54, CDC7, CDC8, CDC9, MAG1, PHR1, DIN1, DDR48, RNR1, RNR2, RNR3, UB14, repB, repD and APE. These genes are impacted by the composition of the present invention can modulate any of the types of damage disclosed above.

The composition can thus be used to treat diseases associated with DNA repair problems including, but not limited to, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, Werner's syndrome, Bloom's syndrome and ataxia telangiectasia. All of which are associated with improper repair of DNA.

The composition can also be used to affect/modulate the function of mitochondria function-specific genes, examples of such genes are provided in Table 8 below. These genes generally fall into four categories. First, genes for mitochondrial transcription/translation, examples of which include, but are not limited to, MTRF1L, which is involved in mitochondrial translational machinery, GFM2, which is a protein involved in protein elongation, MRPL3, which is a mitochondrial ribosomal protein, TOMM20, which is a central component of the receptor complex responsible for the recognition and translocation of cytosolically synthesized mitochondrial preproteins and together with TOM22 functions as the transit peptide receptor at the surface of the mitochondrion outer membrane and facilitates the movement of preproteins into the TOM40 translocation pore. COX15, which is predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos) involved in heme biosynthesis, POLG2, mtDNA that is replicated accurately by DNA polymerase gamma, and MRPS10, which is part of mitochondrial 28S Ribosomal protein. Second, genes for mitochondrial structure examples of such genes include, but are not limited to, DNMIL, which is critical for maintenance of mitochondrial morphology, OPA1, which is a major organizer of the mitochondria); inner membrane and is required for the maintenance of cristae integrity, MFN1, which is an essential transmembrane GTPase, which mediates mitochondrial fusion (MFN1 acts independently of the cytoskeleton.), BNIP3, which provides regulation of mitochondrial permeability, COX18, which is required for the insertion of integral membrane proteins into the mitochondrial inner membrane and is essential for the activity and assembly of cytochrome c oxidase and plays a central role in the translocation and export of the C-terminal part of the COX2 protein into the mitochondrial intermembrane space, and DNM1L, which functions in mitochondrial and peroxisomal division probably by regulating membrane fission and enzyme hydrolyzing GTP that oligomerizes to form ring-like structures and is able to remodel membranes. Third, miscellaneous mitochondrial proteins examples of such genes include, but are not limited to, WWOX, a tumor suppressor gene, PPIF, for protein folding, CoQ9, 10GB, which is involved in the final steps in the synthesis of CoQ, SLC25A37, which is a mitochondrial iron transporter that specifically mediates iron uptake in developing erythroid cells, thereby playing an essential role in heme biosynthesis, ABCB7, which is involved in the transport of heme from the mitochondria to the cytosol, and SLC25A36, which is a transporter for mitochondria. Fourth, genes for mitochondrial enzymes examples of such genes include, but are not limited to, SDHD, which is part of the respiratory chain, ATPAF1 enzymes which are critical for generation of ATP, NARS2, IARS2, EARS2, LARS2, HARS2, which are enzymes involved in the production of amino acid, ASN, ILE and GLN, LEU and HIS respectively, HIBADH, which is an enzyme providing succinyl coA for TCA cycle, ACADSB, which is an enzyme catalyzing one of the steps in fatty acid beta oxidation, MIB1, which is a E3 ligase necessary for protein ubiquitnation (deletion lethal), BCKDHB and ACAD8, for the generation of succiny Co A for TCA, AFG3L2, which is a AAA protease protecting against oxiative stress, PEO1, which is a DNA helicase, critical for lifetime maintenance of mtDNA integrity and to maintain mtDNA copy number, HK2 (Hexokinase 2), and HADHB, which is involved in fatty acid beta-oxidation.

The composition can also be combined with a known therapy to create a combinatorial therapy. This can primarily be used in instances where the known therapy has known detrimental side effects that impact DNA stability, such as chemotherapeutics and radiotherapeutics. Other compounds can also be used that negatively impact DNA repair and stability.

The invention also relates to a method for correcting a diet-induced deficiency of fruits, vegetables and herbs, and the nutrients present in such materials. The composition of the present invention additionally can contain phytochemicals, vitamins, and minerals known to improve the body's natural defenses against oxidants, free radicals, and diseases.

II. Composition and Method of Manufacture

The composition can include a combination of fruit, vegetable, herbal and other ingredients that provide significant health benefits. The following tables illustrate representative daily amounts of suitable fruits, vegetables, herbs, vitamins, and minerals which can be included in the composition. The dosages and methods of administration can be varied as desired from application to application. For example, Dosage A represents a range of dosages of the respective ingredients that is suitable for purposes of the present, invention. Dosage B represents a dosage of a particular embodiment. The unit “mg” in Tables 1-5 means that that the amount recited is given in the number of, e.g., milligrams, provided in a two-tablets per day dosage, unless otherwise noted, e.g., “JU” is recited. Thus, to determine the amount of a specific ingredient per single tablet, the amount recited in the respective tables must be halved.

	TABLE 1
	Fruit Ingredient	Dosage A, mg/day	Dosage B, mg/day
	Acerola Powder	50-500	300
	Apple extract	25-1000	50
	Citrus Bioflavanoids	25-1000	100
	Grape skin extract	25-1000	50
	Plum extract	25-1000	50
	Cranberry extract	25-1000	50
	Pomagranate	5-500	25
	Blueberry extract	25-1000	50

The citrus bioflavonoids are commercially available from Access Business Group International LLC of Ada, Mich. This ingredient can be in a concentrate form, and can include, but are not limited to, naringen, hesperidin, narirutin, diosmin, rutin, tangeretin, diosmetin, neohesperidin, nobiletin, and quercetin.

TABLE 2
Vegetable Ingredient	Dosage A, mg/day	Dosage B, mg/day
Asparagus	25-1000	50
Alfalfa	25-1000	70
Brassica	25-1000	50
Kale	20-1000	75
Lycopene	0.1-100	2
Lutein esters	0.1-100	2
NUTRILITE Watercress	5-500	28

NUTRILITE watercress is available from Access Business Group International LLC. The Brassica and/or kale can be in dehydrated, powdered form. As used herein the Brassica ingredient may include any material derived from plants in the Brassicae family, for example, broccoli. The lutein esters used in the composition can be of the type sold under the name Xangold 10% beadlets, which is available from Cognis Nutrition & Health of Cincinnati, Ohio. The lycopene used in the composition can be of the type sold under the name Lycobeads 5%, which is available from H. Reisman Corp. of Orange, N.J.

TABLE 3
Vegetable Ingredient	Dosage A, mg/day	Dosage B, mg/day
Basil extract	25-1000	50
Rosemary extract	25-1000	50
Sage	5-500	25
Oregano extract	25-1000	50
NUTRILITE Parsley	5-500	25

NUTRILITE parsley is available from Access Business Group International LLC. The composition can also include ingredients in addition to the fruit, vegetable and herbal ingredients noted above. For example, suitable vitamins for use in the compositions and methods of the present invention can include, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin/niacinamide, pantothenic acid, folic acid, biotin, choline, vitamin C, vitamin D, and vitamin E. Table 4 below includes a suitable vitamin profile.

TABLE 4
Vitamin Profile
		Dosage B,
Ingredient	Dosage A, mg/day	mg/day
Vitamin C from Acerola	20-100	60
Powder
Ascorbic Acid (C)	100-700	440
Vitamin A from Beta Carotene	1000-10,000 IU	7500 IU
Biotin	0.01-4	0.300
Pantothenic Acid from Cal	5-300	50
Pan Gran
Choline	10-400	50
Folic Acid	0.01-10	0.8
Inositol	5-100	25
Vitamin E	10-5000 IU	150 IU
Mixed Tocopherols	5-300	50
Niacin/Niacinamide	5-300	40
Pyridoxine (B6)	10-100	15
Riboflavin (B2)	1-100	12.75
Thiamine (B1)	1-100	11.25
Vitamin A from Acetate	100-10,000 IU	2500 IU
Vitamin B12	0.01-50	0.045
Vitamin D3	10-2000 IU	400 IU
Yeast, Standardized@	5-350	60
(source of 100% RDA Bs)

In addition to the vitamins listed above, minerals for use in the compositions and methods of the present invention include, for example, boron, calcium, chromium, copper, iodine, magnesium, manganese, molybdenum, potassium, selenium, vanadium, and zinc. Other vitamins and minerals may also be used. Table 5 below includes a mineral profile suitable for the composition of the present invention.

TABLE 5
Mineral Profile
	Ingredient	Dosage A, mg/day	Dosage B, mg/day
	Calcium	100-2000	750
	Chromium	0.01-5	0.120
	Copper	0.01-5	2
	Iodine	0.001-5	0.15
	Magnesium	10-1000	300
	Manganese	1-20	5
	Molybdenum	0.001-75	0.075
	Potassium	5-300	80
	Selenium	0.001-5	0.100
	Zinc	1-50	15

With the ingredients of Tables 1-3, and optionally the ingredients of Tables 4-5, the composition of the present invention can provide a significant portion of, and in many cases exceed, the recommended daily requirement for a variety of vitamins and minerals. Tables 6 and 7 below illustrate the potency of the composition, when taken in the above daily amounts, in terms of percentages of the daily requirements for the listed vitamins and minerals.

	TABLE 6
	Vitamin	Amount/Day	% Daily Value
	Vitamin A (75% as β-	10,000	200%
	Carotene), IU
	Vitamin C, mg	500	833%
	Vitamin D, IU	400	100%
	Vitamin E, IU	150	500%
	Niacin/Niacinamide, mg	40	200%
	Vitamin B6, mg	15	750%
	Vitamin B12, mcg	45	750%
	Folic Acid, mcg	800	200%
	Biotin, mcg	300	100%
	Pantothenic Acid, mg	50	500%

	TABLE 7
	Minerals	Amount/Day	% Daily Value
	Calcium, mg	750	75%
	Magnesium, mg	300	75%
	Iodine, mcg	150	100%
	Potassium, mg	80	2%
	Copper, mg	2	100%
	Zinc, mg	15	100%
	Manganese, mg	5	100%
	Chromium, mcg	120	100%
	Selenium, mcg	100	143%
	Molybdenum, mcg	75	100%

Additional specialty ingredients which can be used in the composition include, for example, methyl sulfonyl methane (MSM), α-lipoic acid (10 mg/day), catechins, polyphenols, flavanoids, lycopene, lutein, yeast, inositol, and para-aminobenzoic acid (PABA).

The composition of the present invention can be formulated using any pharmaceutically acceptable form of respective fruit concentrates, vegetable concentrates, herb concentrates, phytochemicals, vitamins, minerals, and other nutrients, including their salts. The compositions can be formulated into tablets, powders, gels, or liquids (a tablet, for the purposes of the present invention and as used throughout the application disclosure, refers to any form of a solid oral dosage, including but not limited to tablets, caplets, capsules, powders, etc.). The compositions can be formulated as powders, for example, for mixing with consumable liquids such as milk, juice, water, or consumable gels or syrups for mixing into other liquids or foods. The compositions can also be formulated with other foods or liquids to provide pre-measured compositional foods, for example, single-serving bars. Flavorings, binders, protein, complex carbohydrates, and the like can be added as needed.

According to one aspect of the invention, the composition is administered as three separate tablets, all three of which are administered twice a day; however, the composition may be administered in other forms and unit dosages as desired.

The composition of the present invention will be illustrated by, but is not intended to be limited to, the following examples.

EXAMPLE 1

Three tablets may be prepared to provide a) fruit, vegetable and herbal ingredients, b) vitamins and c) minerals. The first tablet includes the fruit, vegetable and herbal ingredients of Tables 1-3. The amount of each ingredient in this first tablet is half of the amount listed in the Dosage B of the Tables, as the table-listed amount is the amount present in two such tablets. The first tablet may also include carriers and other tableting aids such as silicon dioxide, magnesium oxide, calcium carbonate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate in amounts that may be varied for purposes well known to those of skill in the art.

The second tablet includes vitamins of Table 4. The amount of each ingredient in this second tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The second tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide.

The third tablet includes minerals of Table 5. The amount of each ingredient in this third tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The third tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide.

The three tablets, when administered twice a day, complete the gap in phytochemicals that is present in the typical diet.

EXAMPLE 2

The following examples relate to methods of preparing the above three tablets. The ingredients are the same as those referred to above in Tables 1-5. For purposes of the following examples, however, tablets including the fruit, vegetable and herbal ingredients from Tables 1-3 are referred to as “Tablet 1”; tablets including the vitamin ingredients from Table 4 are referred to as “Tablet 2”; and tablets including the mineral ingredients from Table 5 are referred to as “Tablet 3.” It is noted that other methods for preparing the tablets and other suitable delivery vehicles can be used as desired.

Tablet 1

Mixed tocopherols, D-alpha-tocopherol (succinate), and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes Magnesium oxide (D.C. heavy), Acerola concentrate, citrus bioflavonoids complex, plum extract, apple extract, rosemary extract, basil extract, grape skin extract, cranberry extract, kale powder, asparagus extract, blueberry extract, parsley dehydrate, oregano extract, sage extract, pomegranate extract, and inositol are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.

Lycopene (5%), lutein ester (beadlets), mixed tocopherols, calcium carbonate (granular), croscarmellose sodium and microcrystalline cellulose (silicified) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The mixture is blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

Tablet 2

Acerola concentrate, microcrystalline cellulose (silicified) and alpha lipoic acid are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot P.K. blender. The ingredients are blended for ten minutes. Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender: thiamine mononitrate (97%), riboflavin, niacinamide, biotin trituration (1%), vitamin B12 (1.1%), calcium pantothenate granular, folic acid, pyridoxine HCl (95%), and choline bitartrate. The ingredients are blended for ten minutes. Next, the following items are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender; beta carotene (beadlets), vitamin D3 (beadlets), yeast (standardized) and vitamin A (acetate). The mixture is blended for an additional ten minutes.

Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 1.00 cubic foot PK blender: ascorbic acid (97%), calcium carbonate (granular), croscarmellose sodium, d-alpha-tocopherol succinate, silicon dioxide (NF fine powder). The mixture is blended for an additional ten minutes.

Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

Tablet 3

Zinc amino acid chelate, mixed tocopherols and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Co-processed alfalfa concentrate/microcrystalline cellulose/calcium carbonate, selenium yeast, microcrystalline cellulose, copper amino acid chelate, manganese amino acid chelate, potassium iodide trituration, chromium amino acid chelate, molybdenum amino acid chelate, brassica dehydrate, watercress dehydrate and croscarmellose sodium are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.

Potassium chloride, magnesium oxide (D.C. heavy) and calcium carbonate (granulation) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional live minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

EXAMPLE 3

The clinical study was an independent Review Board-approved, double-blind, placebo-controlled, parallel-groups study.

Subjects

Subjects were 1.20 healthy adult Japanese-Americans in California and Hawaii Subjects were ethnically Japanese (both parents and four grandparents ethnically Japanese) and ate a mostly Japanese diet

Treatment

Subjects took either composition or placebo as directed (12 tablets a day) for 8 weeks. The composition is the same formula as is currently marketed in Japan under the Alticor name of Triple X™. All products were coated and provided in coded foil packs to preserve double-blindedness.

There were four main categories of outcome measures; (1) plasma concentrations of a representative water-soluble antioxidant nutrient [vitamin c], and a representative fat-soluble antioxidant nutrient [beta carotene], (2) plasma concentrations of the “anti-homocysteine triad” vitamin B6, vitamin B12, and folate, as well as plasma concentrations of homocysteine, (3) nutrigenomic mechanisms of genomic stability, and (4) plasma metabolomic profile changes.

Analyses for plasma nutrient and homocysteine concentrations were based on blood samples obtained from 120 subjects (60 treated with Triple X, and 60 treated with Placebo), at baseline, Week 4, and Week 8.

Nutrigenomic analyses were based on blood samples obtained from 14 subjects (7 treated with Triple X, and 7 treated with Placebo) at baseline and Week 2.

Statistics

Plasma nutrient and homocysteine change score results were assessed with independent-groups t-test for between-groups comparisons. A P value smaller than 0.05 was considered significant.

Nutrigenomic data were first analyzed with paired t-tests within the composition-treated group only to identify which from among 44,000 genes measured showed a significant change in expression level following treatment. A P value smaller than 0.05 was considered significant. A Q value (false discovery rate) of 0.4 was used to control for false positive findings. This analysis identified about 2,000 genes, which were then examined for biologically relevant patterns of change.

Results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking composition showed increased levels of folate, vitamin B6, vitamin B12, and vitamin C, as well as decreased levels of homocysteine, all within 4 weeks of treatment, with results maintained at 8 weeks. Metabolomic analyses indicate decreased oxidative stress. Nutrigenomic analyses indicate increased genomic integrity and tumor suppressor mechanisms, homocysteine metabolism, resistance to oxidative stress and lipid peroxidation.

Clinical interpretation of nutrigenomic data revealed the unexpected finding that about 150 genes [Do you have a listing of the genes?], each known to function to support genomic stability (via chromatin maintenance, damage detection, and repair), were significantly increased in the Triple X group compared to the placebo group. Subsequent analysis of these genes in the Placebo-treated group showed no change following Placebo treatment. Compared to baseline, consumption of the composition of the present invention led to statistically significant increases in the expression of genes related to DNA maintenance, replication, or repair (FIG. 7).

Clinical interpretation of metabolomic data revealed the unexpected findings that consumption of Triple X led to significant decrease increases in 2-hydroxy bury rate, a metabolite related to oxidative stress (FIG. 9), as well as a trend towards a decrease in 5-oxoproline, also a metabolite related to oxidative stress (FIG. 10). This shows that the consumption of the composition can lead to increased plasma concentration of antioxidant nutrients, increased expression of chromatin maintenance and repair genes, decreased homocysteine, and decreased metabolomic indicators of oxidative stress.

EXAMPLE 4

Clinical testing was conducted to confirm the efficacy of the composition of the present invention. It was expected that consumption of the composition would: correct dietary deficiencies of phytochemicals; improve the amount of antioxidants in the body; decrease free radical damage; increase plasma vitamin, mineral and phytochemical concentrations; and improve plasma and systemic antioxidant capacity, among other things.

Inclusion criteria for this study were healthy men and women, from 18 to 80 years of age, who consume fewer than 12 items found on the Recommended Foods Checklist per week. These subjects are selected after administration of a food frequency questionnaire and application of the Recommended Foods Score (RFS). The RFS consists of 23 foods, 14 of which are fruits and vegetables, that when consumed on a weekly basis have been associated with reduced mortality. This was demonstrated in a cohort study of 42,254 women. Those with a mean RFS of 16.0 (highest quartile) had an all-cause mortality relative risk of 0.69 compared to those with a mean RFS of 6.4 (lowest quartile) who have an all-cause mortality relative risk. It was noted that those in the highest quartile consumed significantly more calories (131%), fiber (200%), Vitamin C (230%), folate (181%), and pro-Vitamin A carotenoids (253%) compared to those in the lowest quartile.

The clinical study encompassed a double-blind (i.e. to subjects and investigators) study of 120 subjects over a six-week period. During the six-week trial, subjects were told to consume three tablets, either the composition, or a placebo, twice a day, such as morning and evening. The subjects were tested by taking blood and urine samples and performing the following assays: total polyphenols, plasma ORAC (Oxygen Radical Absorption Capacity), CP450 enzyme induction, cytokinesis block micronucleus assay, comet assay, bioenergetics assay, urinary bile acids, B6, B12, folate, Vitamin C, homocysteine, alpha and gama tocopherols, beta-carotene, C-reactive protein and urinary 8-epi prostaglandins F2α, which were tested at baseline, two weeks, four weeks and six weeks into the study. Improvement, and thus, efficacy of the composition, was measured based on: plasma concentrations of vitamins, minerals and phytochemicals; plasma and systemic antioxidant capacity; detoxification capacity; cellular energy dynamics; genomic stability; other risk factors and subjective effects.

It was expected that the results of the study would show that following six weeks of composition consumption, subjects would have significantly increased plasma levels of alpha tocopherols, B12, B6, folate, Vitamin C, and other antioxidants, which indicates an improvement in the amount of antioxidants in the body and which is associated with a correction of dietary deficiencies in vitamins, nutrients and phytochemicals, and/or a decrease in free radical damage, as well as increased genomic stability (i.e., decreased DNA damage) among other things.

Results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking the composition showed increased plasma concentrations of Beta Carotene, Alpha-Tocopherol, Folate, and Vitamins B6 and B12. Subjects taking composition also showed significantly reduced homocysteine, as well as decreased DNA damage as indicated by the cytokinesis micronucleus block assay. This shows that the consumption of the composition can increase plasma concentrations of antioxidant nutrients, decrease homocysteine, and decrease DNA damage.

The above descriptions are those of the preferred embodiments of the invention. Various alterations and changes can be made without departing from the spirit and broader aspects of the invention as defined in the appended claims, which are to be interpreted in accordance with the principles of patent law including the doctrine of equivalents. Any references to claim elements in the singular, for example, using the articles “a,” “an,” “the,” or “said,” is not to be construed as limiting the element to the singular.

TABLE 8
ADH5	\alcohol	Removal of S-nitrosoglutathione and	Anti-
	dehydrogenase	thus controls its levels as well as levels	Nitrosative
	5 (class III),	of nitrosylated proteins. Protects against	stress activity
	chi	nitrosative stress. Low amounts of this	gene
	polypeptide\“”	enzyme or absence can increase whole
		cell nitrosylation and tissue damage and
		susceptibility to bacteria.
TXNL1	thioredoxin-	TXNL1 acts as an effector of oxidants or	Anti-oxidant
	like 1	a redox sensor	activity gene
TXNRD3	thioredoxin	Thioredoxin reductases (EC 1.6.4.5),	Anti-oxidant
	reductase 3	such as TXNRD3, are selenocysteine	activity gene
		(sec)-containing flavoenzymes that
		maintain thioredoxins, small proteins
		that catalyze redox reactions, in the
		reduced state using the reducing power
		of NADPH, sec residue of TXNRD1
		serves as a sensor of reactive oxygen
		species.
UHRF2	\ubiquitin-like,	Absence of this gene makes cells more	Anti-oxidant
	containing	sensitive to X rays, UV light and	activity gene
	PHD and	hydroxyurea
	RING finger
	domains, 2\“”
VPS8	vacuolar	VPS3, VPS8 and PEP7 genes to rescue	Anti-oxidant
	protein sorting	lethal effects of oxidative damage	activity gene
	8 homolog (S. cerevisiae)	resulted from the overexpression of
		these genes.
PAFAH2	\platelet-	Membrane phospholipids are	Anti-oxidant	Detoxification
	activating	susceptible to oxidation, which is	activity gene	activity
	factor	involved in various pathological		gene
	acetylhydrolase	processes such as inflammation,
	2, 40 kDa\“”	atherogenesis, neurodegeneration, and
		aging. One enzyme that may help to
		remove oxidized phospholipids from
		cells is intracellular type II platelet-
		activating factor acetylhydrolase (PAF-
		AH (II)), which hydrolyzes oxidatively
		fragmented fatty acyl chains attached to
		phospholipids. Overexpression of PAF-
		AH (II) in cells or tissues was previously
		shown to suppress oxidative stress-
		induced cell death.
ME2	\malic enzyme	The primary role of malic enzyme,	Anti-oxidant
	2, NAD(+)-	however, may be to generate reduced	activity gene
	dependent,	NADP+ for biosynthesis rather than to
	mitochondrial\	form an intermediate of carbohydrate
	“”	catabolism. NADPH provides the
		reducing equivalents for biosynthetic
		reactions and for oxidation-reduction
		involved in protection against the toxicity
		of ROS
PON2	paraoxonase 2	The encoded protein is ubiquitously	Anti-oxidant
		expressed in human tissues, membrane-	activity gene
		bound, and may act as a cellular
		antioxidant, protecting cells from
		oxidative stress. Hydrolytic activity
		against acylhomoserine lactones,
		important bacterial quorum-sensing
		mediators, suggests the encoded protein
		may also play a role in defense
		responses to pathogenic bacteria.
IVNS1ABP	influenza virus	Protects cells from cell death induced by	Anti-viral
	NS1A binding	actin destabilization; Protects neurons
	protein	from dendritic spines and actin filaments
		damage induced by the actin-
		destabilizing cytochalasin B when
		overexpressed. May be a component of
		the cellular splicing machinery with a
		role in pre-mRNA splicing; may mediate
		the inhibition of splicing by NS/influenza
		virus NS1A protein. Highly present in
		neutrophil
ILF3	\interleukin	Nuclear factor of activated T-cells	Anti-viral
	enhancer	(NFAT) is a transcription factor required	activity gene
	binding factor	for T-cell expression of interleukin 2.
	3, 90 kDa\“”	NFAT binds to a sequence in the IL2
		enhancer known as the antigen receptor
		response element 2. In addition, NFAT
		can bind RNA and is an essential
		component for encapsidation and
		protein priming of hepatitis B viral
		polymerase. NFAT is a heterodimer of
		45 kDa and 90 kDa proteins, the larger
		of which is the product of this gene. The
		encoded protein, which is primarily
		localized to ribosomes, probably
		regulates transcription at the level of
		mRNA elongation, required for IL2
		mRNA stabilization. Anti-viral activity
SRPK2	SFRS protein	SRPK1 and SRPK2 in HBV replication	Anti-viral
	kinase 2	and found that both of them could	activity gene
		suppress HBV replication by reducing
		the packaging efficiency of the pgRNA
		without affecting the formation of the
		viral core particles.
PTX3	\pentraxin-	anti-viral activity	Anti-viral
	related gene,		activity gene
	rapidly
	induced by IL-
	1 beta\“”
RIPK2	receptor-	Anti-viral response	Anti-viral
	interacting		activity gene
	serine-
	threonine
	kinase 2
SMARCE1	\SWI/SNF	Suppression of hepatitis B virus (HBV)	Anti-viral
	related, matrix	replication, a causative agent for chronic	activity gene
	associated,	hepatitis, is an effective approach to
	actin	controlling disease progression. Host
	dependent	factors have a significant effect on viral
	regulator of	replication efficiency and need to be
	chromatin,	better characterized.. Cellular
	subfamily e,	transcription modulator SMARCE1 binds
	member 1\“”	to HBV core promoter containing
		naturally occurring deletions and
		represses viral replication.
		Transcriptional coactivator cooperating
		with nuclear hormone receptors to
		potentiate transcriptional activation, he
		SWI/SNF chromatin remodeling
		complexes are evolutionarily conserved
		multimeric enzymatic machines that alter
		the nucleosomal structure using energy
		derived from ATP hydrolysis (34). Ample
		experimental evidence suggests that the
		SWI/SNF complexes play important
		roles in fundamental cellular processes
		such as transcription, replication, and
		the repair of chromatin
TLR7	toll-like	TLR7-specific agonists activate	Anti-viral
	receptor 7	plasmacytoid DCs (pDCs) and B cells	activity gene
		and induce mainly IFN-a and IFN-
		regulated cytokines, the natural ligands
		of TLR7 and TLR8 were identified as
		single-stranded RNA (ssRNA), single
		stranded (ss)RNA viruses [either
		vesicular stomatitis virus (VSV; a
		rhabdovirus) or influenza virus (an
		orthomyxovirus)] stimulate type I IFN
		responses through TLR7.
ZNF175	zinc finger	OTK18 was copiously expressed in	Anti-viral
	protein 175	macrophages following HIV type I	activity gene
		infection and diminished progeny virion
		production. A mechanism for this
		antiretroviral activity was by suppression
		of HIV type 1 Tat-induced viral long
		terminal repeat promoter activity.
BNIP2	BCL2/adenovirus	Adenovirus E1B 19-kD protein protects	Anti-viral
	E1B	against cell death induced by viral	activity gene
	19 kDa	infection and certain external stimuli.
	interacting
	protein 2
CDKN1A	\cyclin-	is an endogenous cellular component in	Anti-viral
	dependent	stem cells that provides a molecular	activity gene
	kinase	barrier to HIV-1 infection., anti-viral
	inhibitor 1A
	(p21, Cip1)\“”
CREBZF	CREB/ATF	The neuronal host cell factor-binding	Anti-viral
	bZIP	protein Zhangfei inhibits herpes simplex	activity gene
	transcription	virus replication.
	factor
ELF1	E74-like factor	ELF-1 belongs to a subset of Ets factors	Blood vessel
	1 (ets domain	that regulate vascular-specific gene	development
	transcription	expression during blood vessel	gene
	factor)	development.
NUS1	nuclear	Acts as a specific receptor for the N-	Blood vessel
	undecaprenyl	terminus of Nogo-B, a neural and	development
	pyrophosphate	cardiovascular regulator. Able to	gene
	synthase 1	regulate vascular remodeling and
	homolog (S. cerevisiae)	angiogenesis. Its similarity with UPP
		synthetase proteins suggests that it may
		act as a scaffold for the binding of
		isoprenyl lipids and/or prenylated
		proteins. Nogo-B receptor localizes with
		the ligand Nogo-B during VEGF and
		wound healing angiogenesis in vivo,
		mediates chemotaxis in a heterologous
		expression system and chemotaxis, and
		3D tube formation in native endothelial
		cells. Thus, identification of this receptor
		may lead to the discovery of agonists or
		antagonists of this pathway to regulate
		vascular remodeling and angiogenesis.
CLIC4	chloride	CLIC4 is involved in formation of the	Blood vessel
	intracellular	blood vessel lumen. Blood vessel	development
	channel 4	formation. Chloride channel or a	gene
		regulator or accessory subunit of other
		proteins that could provide the pore-
		forming function.
SGPP1	sphingosine-	Sphingosine-1-phosphate (S1P) is a highly	Blood vessel
	1-phosphate	bioactive lipid that exerts numerous biological	development
	phosphatase 1	effects both intracellularly as a second messenger	gene
		and extracellularly by binding to its G-protein-
		coupled receptors of the endothelial differentiation
		gene family (S1P receptors-(1-5)). Intracellularly,
		at least two enzymes, sphingosine kinase and S1P
		phosphatase, regulate the activity of S1P by
		governing the phosphorylation status of S1P. It is
		now well established that S1P is the natural ligand
		for specific G protein-coupled receptors (GPCRs),
		hereafter referred to as S1PRs. To date, five
		members, EDG-1/S1P1, vascular smooth muscle
		cells and pericytes to migrate around arteries and
		capillaries and properly reinforce
		them angiogenesis.
DMTF1	cyclin D	DMP1 is a pivotal tumor suppressor for	Bone health
	binding myb-	both human and murine lung cancers.
	like	DMP1 is essential for normal postnatal
	transcription	chondrogenesis and subsequent
	factor 1	osteogenesis-bone
LEMD3	LEM domain	LEMD3 is involved in both BMP (see	Bone Health
	containing 3	112264) and TGF-beta (190180)	Activity Gene
		signaling, an integral protein of the inner
		nuclear membrane, binds Smad2 and
		Smad3 and antagonizes transforming
		growth factor-beta signaling. Involved in
		multiple bone disorders.
MBTPS1	\membrane-	Site-1 protease (S1P) has an essential	Bone Health
	bound	function in the conversion of latent,	Activity Gene
	transcription	membrane-bound transcription factors to
	factor	their free, active form. In mammals,
	peptidase,	abundant expression of S1P in
	site 1\“”	chondrocytes suggests an involvement
		in chondrocyte function. Catalyzes the
		first step in the proteolytic activation of
		the sterol regulatory element-binding
		proteins (SREBPs). Other known
		substrates are BDNF and ATF6.
RPS6KA3	\ribosomal	Rsk2 plays an important role in neuronal	Bone Health
	protein S6	plasticity. RSK2 is required for	Activity Gene
	kinase,	osteoblast differentiation and function.
	90 kDa,	Rsk2-null mice develop progressive
	polypeptide	osteopenia due to impaired osteoblast
	3\“”	function and normal osteoclast
		differentiation.
BCAT1	\branched	This gene encodes the cytosolic form of	Cell health
	chain	the enzyme branched-chain amino acid	Maintenance
	aminotransferase	transaminase. This enzyme catalyzes	Gene
	1,	the reversible transamination of
	cytosolic\“”	branched-chain alpha-keto acids to
		branched-chain L-amino acids essential
		for cell growth.
CEPT1	choline/ethanolamine	Cholinephosphotransferase catalyses	Cell health
	phosphotransferase 1	the final step in the synthesis of	Maintenance
		phosphatidylcholine by the transfer of	Gene
		phosphocholine from CDP-choline to
		diacylglycerol. The synthesis of
		phosphatidylethanolamine by
		ethanolaminephosphotransferase occurs
		using an analogous reaction. This gene
		codes for a
		choline/ethanolaminephosphotransferase.
		The protein can synthesize either
		choline- or ethanolamine-containing
		phospholipids. Phosphatidylcholine is a
		class of phospholipids called “essential
		phospholipids
DSCR1	Down	The DSCR1 (Adapt78) gene is	Cell health
	syndrome	transiently induced by stresses to	Maintenance
	critical region	temporarily protect cells against further	Gene
	gene 1	potentially lethal challenges.
PAPOLA	poly(A)	Polymerase that creates the 3′ poly(A)	Cell health
	polymerase	tail of mRNA's. Also required for the	Maintenance
	alpha	endoribonucleolytic cleavage reaction at	Gene
		some polyadenylation sites.
HSBP1	heat shock	exert cytoprotection and anti-apoptotic	Cell health
	factor binding	effects	Maintenance
	protein 1		Gene
METAP1	methionyl	Protein synthesis is initiated with a	Cell health
	aminopeptidase 1	methionine residue in eukaryotic cells or	Maintenance
		a formylated methionine in prokaryotes,	Gene
		mitochondria, and chloroplasts. For a
		large subset of proteins, the initiator
		methionine is cotranslationally removed
		before further posttranslational
		modification. The proteolytic removal of
		N-terminal methionine is catalyzed by a
		family of enzymes known as methionine
		aminopeptidases (MetAPs).
SGMS1	sphingomyelin	Suppresses BAX-mediated apoptosis	Cell health
	synthase 1	and also prevents cell death in response	Maintenance
		to stimuli such as hydrogen peroxide,	Gene
		osmotic stress, elevated temperature
		and exogenously supplied sphingolipids.
		May protect against cell death by
		reversing the stress-inducible increase in
		levels of proapoptotic ceramide.
		Required for cell growth
STK39	\serine	STE20 kinases involved in the regulation	Cell health
	threonine	of ion homoeostasis and volume control	Maintenance
	kinase 39	in mammalian cells	Gene
	(STE20/SPS1
	homolog,
	yeast)\“”
VCL	vinculin	Involved in cell adhesion. May be	Cell health
		involved in the attachment of the actin-	Maintenance
		based microfilaments to the plasma	Gene
		membrane. May also play important
		roles in cell morphology and locomotion.
XPNPEP1	\X-prolyl	prolyl aminopeptidase (EC 3.4.11.9) is a	Cell health
	aminopeptidase	proline-specific metalloaminopeptidase	Maintenance
	(aminopeptidase	that specifically catalyzes the removal of	Gene
	P) 1,	any unsubstituted N-terminal amino acid
	soluble\“”	that is adjacent to a penultimate proline
		residue. Because of its specificity toward
		proline, it has been suggested that X-
		prolyl aminopeptidase is important in the
		maturation and degradation of peptide
		hormones, neuropeptides, and
		tachykinins, as well as in the digestion of
		otherwise resistant dietary protein
		fragments, thereby complementing the
		pancreatic peptidases. Deficiency of X-
		prolyl aminopeptidase results in
		excretion of large amounts of imino-
		oligopeptides in urine
NCAPD3	\non-SMC	Regulatory subunit of the condensin II	Chomatin
	condensin II	complex, a complex which establishes	stability
	complex,	mitotic chromosome architecture and is
	subunit D3\“”	involved in physical rigidity of the
		chromatid axis.
AOF2	amine	a family of multiprotein corepressor	Chromatin
	oxidase (flavin	complexes that function through	modification
	containing)	modifying chromatin structure to keep
	domain 2	genes silent. The polypeptide
		composition of these complexes
		includes a common core of 2 subunits,
		HDAC1 (601241)/HDAC2 (605164) and
		the FAD-binding protein AOF2.
		functions as a histone demethylase and
		transcriptional corepressor, histone
		lysine-specific demethylase LSD1
		interacts with p53 (191170) to repress
		p53-mediated transcriptional activation,
		and to inhibit the role of p53 in
		promoting apoptosis.
HMGN1	high-mobility	HMGN1 enhances the rate of heat	Chromatin
	group	shock-induced chromatin remodeling in	modification
	nucleosome	the HSP70 promoter, thereby leading to
	binding	an increase in the levels of HSP70
	domain 1	transcripts during the early stages of
		heat shock induction.
INOC1	INO80	INOC1 defines a subfamily of	Chromatin
	complex	SWI2/SNF2 chromatin remodeling	modification
	homolog 1 (S. cerevisiae)	proteins. INOC1 displayed ATPase
		activity specific to double-stranded DNA
		and exhibited activity on isolated human
		mononucleosomes. ATP hydrolysis of
		double-stranded DNA occurred in a
		linear time course with a calculated Km
		of 167 microM, similar to that of other
		ATPases of the SNF2/SWI2 family.
PCAF	p300/CBP-	Histone acetyltransferase; Functions as	Chromatin
	associated	a histone acetyltransferase (HAT) to	modification
	factor	promote transcriptional activation. Has
		significant histone acetyltransferase
		activity with core histones (H3 and H4),
		and also with nucleosome core particles.
RBBP4	retinoblastoma	Core histone-binding subunit that may	Chromatin
	binding	target chromatin remodeling factors,	modification
	protein 4	histone acetyltransferases and histone
		deacetylases to their histone substrates
		in a manner that is regulated by
		nucleosomal DNA. Component of
		several complexes which regulate
		chromatin metabolism.
RCBTB1	regulator of	May be involved in cell cycle regulation	Chromatin
	chromosome	by chromatin remodeling.	modification
	condensation
	(RCC1) and
	BTB (POZ)
	domain
	containing
	protein 1
TOP2B	topoisomerase	essential for mammalian neural	Chromatin
	(DNA) II	development; catalyses topological	modification
	beta 180 kDa	genomic changes essential for
		chromosome segregation, chromatin
		reorganization,
TSN	translin	Translin and TRAX have been proposed	Chromatin
		to be involved in DNA recombination,	modification
		chromosomal translocation and mRNA
		transport and translation.
TSNAX	translin-	Translin and TRAX have been proposed	Chromatin
	associated	to be involved in DNA recombination,	modification
	factor X	chromosomal translocation and mRNA
		transport and translation.
TSPYL1	TSPY-like 1	chromatin remodeling factor	Chromatin
			modification
UTX	\ubiquitously	Histone H3 methylation at Lys27 (H3K27	Chromatin
	transcribed	methylation) is a hallmark of silent	modification
	tetratricopeptide	chromatin, dUTX, specifically
	repeat, X	demethylates di- and trimethylated but
	chromosome\“”	not monomethylated H3K27, dUTX is
		intimately associated with actively
		transcribed genes
WAPAL	wings apart-	regulates heterochromatin organization;	Chromatin
	like homolog	Wapl is a new regulator of sister	modification
	(Drosophila)	chromatid resolution
PHC3	polyhomeotic	Component of the Polycomb group	Chromatin
	homolog 3	(PcG) multiprotein PRC1 complex, a	modification
	(Drosophila)	complex required to maintain the
		transcriptionally repressive state of many
		genes, including Hox genes, throughout
		development. PcG PRC1 complex acts
		via chromatin remodeling and
		modification of histones;
CDYL	\chromodomain	Proteins encoded by this gene	Chromatin
	protein, Y-	superfamily possess a chromodomain, a	modification
	like\“”	motif implicated in chromatin binding
		and gene suppression, and a catalytic
		domain believed to be involved in
		histone acetylation.
CENPJ	centromere	structural role for CPAP to maintain	Chromatin
	protein J	centrosome integrity and normal spindle	modification
		morphology during cell division.
TPK1	thiamin		Cofactor
	pyrophosphokinase 1		biosynthesis
			gene
RFK	riboflavin		Cofactor
	kinase		biosynthesis
			gene
VNN1	vanin 1	VNN1 gene product is involved in the	Cofactor
		thymus homing of bone marrow cells	biosynthesis
		and in late adhesion steps of thymus	gene
		homing under physiologic,
		noninflammatory conditions.
		Recently VNN1 gene upregulation has
		been linked to increased HDL level
		The product of CD1c gene is expressed
		on cortical thymocytes, immature
		myeloid dendritic cells, subset of normal
		peripheral B cells and activated T cells
P4HA1	\procollagen-	When expressed intracellularly or	Collagen	Tumor
	proline, 2-	exogenously delivered, P4HA1	formation	suppressor
	oxoglutarate	significantly inhibited tumor growth in	activity gene	activity
	4-	mice. Prolyl 4-hydroxylase (EC		gene
	dioxygenase	1.14.11.2) plays a central role in
	(proline 4-	collagen synthesis. It catalyzes the
	hydroxylase),	formation of 4-hydroxyproline in
	alpha	collagens by hydroxylation of proline
	polypeptide	residues in peptide linkages. The 4-
	I\“”	hydroxyproline residues are essential for
		the folding of the newly synthesized
		procollagen polypeptide chain into triple
		helical molecules.
CHST2	carbohydrate	CHST1 and CHST2 contribute to the	Control of
	(N-	generation of optimal L-selectin ligands	inflammation
	acetylglucosamine-	in vascular endothelial cells at sites of	activity gene
	6-O)	inflammation and thus control
	sulfotransferase 2	inflammation.
PAPSS1	3′-	3′-phosphoadenosine 5′-phosphosulfate	Detoxification
	phosphoadenosine	(PAPS) synthase (PAPSS) catalyzes the	Activity Gene
	5′-	biosynthesis of PAPS which serves as
	phosphosulfate	the universal sulfonate donor compound
	synthase 1	for all sulfotransferase reactions. PAPSS
		forms PAPS in two sequential steps.
		First inorganic sulfate combines with
		ATP to form adenosine 5′-
		phosphosulfate (APS) and
		pyrophosphate catalyzed by ATP
		sulfurylase domain and in the second
		step, APS combines with another
		molecule of ATP to form PAPS and ADP
		catalyzed by APS kinase domain. The
		bifunctional PAPSS1 is comprised of
		NH2-terminal APS kinase domain
		(approximately 1-260 aa), and a COOH-
		terminal ATP sulfurylase domain
		(approximately 220-623 aa).. Many
		different endogenous and xenobiotic
		molecules are substrates for the
		sulfotransferases; sulfation affects many
		different physiological processes,
		including: 1) deactivation and
		bioactivation of xenobiotics, 2)
		inactivation of hormones and
		catecholamines, 3) structure and
		function of macromolecules, and 4)
		elimination of end products of
		catabolism. PAPS is the obligate
		cosubstrate that is synthesized in
		tissues to make available an “activated
		form” of sulfate for the sulfation reaction.
PPA2	pyrophosphatase	Inorganic pyrophosphates are generated	Detoxification
	(inorganic) 2	as byproducts of many biosynthetic	Activity Gene
		reactions, including DNA and RNA
		synthesis, fatty acid and amino acid
		activation, and cyclic nucleotide
		synthesis. Inorganic pyrophosphatases
		(EC 3.6.1.1), such as PPA2, maintain
		the thermodynamic favorability of these
		reactions by catalyzing the hydrolysis of
		pyrophosphates into organic
		phosphates, which are then exported
		across the cell membrane (Curbo et al.,
		2006)
RTN1	reticulon 1	In the presence of high RTN-1C levels,	Detoxification
		genotoxic drugs become ineffective as a	Activity Gene
		consequence of the cytoplasm
		translocation of p53 protein, while the
		silencing of endogenous RTN-1C results
		in the potentiation of the genotoxic drugs
		action. Highly present in CNS. CNS
		stem cells?
ATRN	attractin	in its natural serum form, it mediates the	Detoxification	mitochondrial
		spreading of monocytes that becomes	Activity Gene,	function
		the focus for the clustering of		maintenance
		nonproliferating T lymphocytes.		activity
		Necessary for proper mitochondrial		gene
		function and suppress oxidative stress.
		Atrn may play a protective role against
		environmental toxins
PGK1	phosphoglycerate	Glycolysis enzyme generating 1	Energy
	kinase 1	molecule of ATP	Generation
GLS	glutaminase	human platelets. It is the major enzyme	Energy
		yielding glutamate from glutamine.	generation
		Significance of the enzyme derives from
		its possible implication in behavior
		disturbances in which glutamate acts as
		a neurotransmitter, platelet
		glutaminase activity is entirely
		represented by the phosphate
		dependent glutaminase or glutaminase I,
		most probably localized in the
		mitochondrial platelet fraction and
		classified by kinetic analysis as a kidney-
		type form. The following step of the
		glutamine metabolizing pathway,
		allowing the entrance of the amino acid
		skeleton carbons in the Krebs cycle,
		might be catalyzed by both glutamate
		dehydrogenase and aspartate
		transaminase
GLUD2	glutamate	The following step of the glutamine	Energy
	dehydrogenase 2	metabolizing pathway, allowing the	generation
		entrance of the amino acid skeleton
		carbons in the Krebs cycle, might be
		catalyzed by both glutamate
		dehydrogenase and aspartate
		transaminase
MUT	methylmalonyl	In mammalian cells only two enzymes	Energy
	Coenzyme A	are known to require cobalamin (vitamin	generation
	mutase	B12) as a cofactor: methionine
		synthase, which uses methylcobalamin,
		and methylmalonyl-coenzyme A (CoA)
		mutase, which uses 5′-deoxyadenosyl-
		cobalamin (AdoCbl) Methylmalonyl-CoA
		mutase (MUT) (EC 5.4.99.2) is a
		mitochondrial enzyme that catalyzes the
		isomerization of methylmalonyl-CoA to
		succinyl-CoA. Methylmalonyl-CoA
		mutase occupies a key position in the
		pathway converting propionyl-CoA to
		succinyl-CoA, with the catabolism of
		isoleucine, methionine, threonine, and
		valine, as well as of cholesterol, odd
		chain fatty acids, thymine, and uracil
		leading to propionyl-CoA production.
		The enzyme is, therefore, part of a
		gluconeogenic pathway for converting
		amino acids, lipids, and pyrimidines to
		carbohydrates
PPAT	phosphoribosyl	Phosphopantetheine	Energy
	pyrophosphate	adenylyltransferase (PPAT) is an	generation
	amidotransferase	essential enzyme in Coenzyme A
		biosynthesis. Biosynthesis of coenzyme
		A (CoA) from pantothenic acid (vitamin
		B5) is an essential universal pathway in
		prokaryotes and eukaryotes. COASY is
		a bifunctional enzyme that catalyzes the
		2 last steps in CoA synthesis.
MTHFR	\5,10-	Methylenetetrahydrofolate reductase	Homocysteine
	methylenetetrahydrofolate	(EC 1.5.1.20) catalyzes the conversion	metabolism
	reductase	of 5,10-methylenetetrahydrofolate to 5-
	(NADPH)\“”	methyltetrahydrofolate, a cosubstrate for
		homocysteine remethylation to
		methionine.
MTR	5-	The remethylation of homocysteine to	Homocysteine
	methyltetrahydrofolate-	form methionine is catalyzed by the	metabolism
	homocysteine	cytoplasmic enzyme 5-
	methyltransferase	methyltetrahydrofolate-homocysteine S-
		methyltransferase (EC 2.1.1.13), which
		is also called methionine synthase. This
		enzyme requires methylcobalamin
		(MeCbl), a derivative of cobalamin, or
		vitamin B12, for activity.
MTRR	5-	Methionine is an essential amino acid	Homocysteine
	methyltetrahydrofolate-	required for protein synthesis and one	metabolism
	homocysteine	carbon metabolism. Its synthesis is
	methyltransferase	catalyzed by the enzyme methionine
	reductase	synthase. Methionine synthase
		eventually becomes inactive due to the
		oxidation of its cob(l)alamin cofactor.
		The protein encoded by this gene
		regenerates a functional methionine
		synthase via reductive methylation. It is
		a member of the ferredoxin-NADP(+)
		reductase (FNR) family of electron
		transferases.
ADCY7	adenylate	Necessary for proper Eucaryotic signal	Immune health
	cyclase 7	transduction in platelets and other blood
		associated cells including natural killer
		cells, monocytes, and neutrophils
NCKAP1L	NCK-	Expressed only in cells of hematopoietic	Immune
	associated	origin.	Health
	protein 1-like
ABCB7	\ATP-binding	essential for hematopoiesis	Immune
	cassette, sub-		Health
	family B
	(MDR/TAP),
	member 7\“”
AHI1	Abelson	expression of mouse and human AHI1	Immune
	helper	was highest in the most primitive types	Health
	integration	of normal hematopoietic cells and was
	site 1	downregulated during early
		differentiation. This indicates that early
		precursors of blood cells are likely
		present in the peripheral blood.
CD164	\CD164	myeloid cells, T cells, epithelial cells,	Immune
	molecule,	bone marrow stroma cells; adhesion	Health
	sialomucin\“”	molecule haem progenitor cells to
		stroma
CD200	CD200	Normal brain and B-cell lines	Immune
	molecule		Health
CD74	\CD74	B cells, macrophages, monocytes, MHC	Immune health
	molecule,	class II positive cells
	major
	histocompatibility
	complex,
	class II
	invariant
	chain\“”
CD83	CD83	Activated B cells, activated T cells,	Immune health
	molecule	circulating dendritic cells;
CD8A	CD8a	The CD8 antigen is a cell surface	Immune health
	molecule	glycoprotein found on most cytotoxic T
		lymphocytes that mediates efficient cell-
		cell interactions within the immune
		system. The CD8 antigen, acting as a
		coreceptor, and the T-cell receptor on
		the T lymphocyte recognize antigen
		displayed by an antigen presenting cell
		(APC) in the context of class I MHC
		molecules. Cytotoxic T cells (TC cells, or
		CTLs) destroy virally infected cells and
		tumor cells, and are also implicated in
		transplant rejection. These cells are also
		known as CD8+ T cells, since they
		express the CD8 glycoprotein at their
		surface. Through interaction with helper
		T cells, these cells can be transformed
		into regulatory T cells, which prevent
		autoimmune diseases such as
		experimental autoimmune
		encephalomyelitis
CERK	ceramide	Catalyzes specifically the	Immune
	kinase	phosphorylation of ceramide to form	Health
		ceramide 1-phosphate. Ceramide 1-
		Phosphate, a Mediator of Phagocytosis,
		might function as components of a
		‘rheostat’ that regulates immune cell
		functions, including mast cell
		responsiveness, neutrophil and
		macrophage priming, chemotaxis, and
		survival of many types of immune cells.
CIAPIN1	cytokine	CIAPIN1, a necessary molecule for	Immune
	induced	hematopoiesis that mediates	Health
	apoptosis	antiapoptotic effects of various
	inhibitor 1	cytokines.
CIITA	\calss II,	Highly present in B-lymphocytes. This	Immune health
	major	gene encodes a protein with an acidic
	histocompatibility	transcriptional activation domain, 4
	complex,	LRRs (leucine-rich repeats) and a GTP
	transactivator\	binding domain. The protein is located in
	“”	the nucleus and acts as a positive
		regulator of class II major
		histocompatibility complex gene
		transcription, and is referred to as the
		“master control factor” for the expression
		of these genes. Mutations (lack of
		fuction) in this gene have been
		associated with bare lymphocyte
		syndrome type II (also known as
		hereditary MHC class II deficiency or
		HLA class II-deficient combined
		immunodeficiency), increased
		susceptibility to rheumatoid arthritis,
		multiple sclerosis, and possibly
		myocardial infarction.
CLEC10A	\C-type lectin	Probable role in regulating adaptive and	Immune
	domain family	innate immune responses. Binds in a	Health
	10, member	calcium-dependent manner to terminal
	A\“”	galactose and N-acetylgalactosamine
		units, linked to serine or threonine.
CPNE3	copine III	copine III were expressed in the more	Immune
		immature neutrophil precursors	Health
CPVL	\carboxypeptidase,	CPVL protein expression was induced	Immune
	vitellogenic-	during maturation of monocytes into	Health
	like\“”	macrophages.
CTNNB1	\catenin	Hematopoietic stem cells (HSCs) have	Immune
	(cadherin-	the ability to renew themselves and to	Health
	associated	give rise to all lineages of the blood.
	protein), beta	Reya et al. (2003) showed that the WNT
	1, 88 kDa\“”	signaling pathway has an important role
		in this process. Overexpression of
		activated beta-catenin expands the pool
		of HSCs in long-term cultures by both
		phenotype and function, beta-catenin is
		essential for fate decisions of skin stem
		cells: in the absence of beta-catenin,
		stem cells failed to differentiate into
		follicular keratinocytes and instead
		adopted an epidermal fate
CTSC	cathepasin C	Needed for activity and stability of	Immune
		neutrophil-derived serine proteases.	Health
CYFIP2	cytoplasmic	Necessary for T-cell adhesion function	Immune
	FMR1		Health
	interacting
	protein 2
DPP8	dipeptidyl-	involve in immune functions	Immune
	peptidase 8		Health
DPP9	dipeptidyl-	involve in immune functions	Immune
	peptidase 9		Health
DPYSL2	dihydropyrimidinase-	involved in T-cell polarization and	Immune
	like 2	migration.	Health
DUSP5	dual	Mkp5-deficient cells produced greatly	Immune
	specificity	enhanced levels of proinflammatory	Health
	phosphatase 5	cytokines during innate immune
		responses and exhibited greater T-cell
		activation than their wildtype
		counterparts. However, Mkp5-deficient T
		cells proliferated poorly upon activation,
		which resulted in increased resistance to
		experimental autoimmune
		encephalomyelitis. By contrast, Mkp5-
		deficient CD4+ (186940) and CD8+
		(186910) effector T cells produced
		significantly increased levels of
		cytokines compared with wildtype cells,
		which led to much more robust and
		rapidly fatal immune responses to
		secondary infection with lymphocytic
		choriomeningitis virus. Zhang et al.
		(2004) concluded that MKP5 has a
		principal function in both innate and
		adaptive immune responses.
EDG1	\endothelial	Adaptive immunity depends on T-cell	Immune
	differentiation,	exit from the thymus and T and B cells	Health
	sphingolipid	travelling between secondary lymphoid
	G-protein-	organs to survey for antigens. After
	coupled	activation in lymphoid organs, T cells
	receptor, 1\“”	must again return to circulation to reach
		sites of infection; however, the
		mechanisms regulating lymphoid organ
		exit are unknown. S1P1-dependent
		chemotactic responsiveness is strongly
		upregulated in T-cell development
		before exit from the thymus, whereas
		S1P1 is downregulated during peripheral
		lymphocyte activation, and this is
		associated with retention in lymphoid
		organs.
FCRL5	Fc receptor-	May be involved in B-cell development	Immune
	like 5	and differentiation in peripheral lymphoid	Health
		organs and may be useful markers of B-
		cell stages. May have an
		immunoregulatory role in marginal zone
		B-cells.
FER	fer (fps/fes	Fps/Fes modulates the innate immune	Immune
	related)	response of macrophages to LPS, in	Health
	tyrosine	part, by regulating internalization and
	kinase	down-regulation of the TLR4 receptor
	(phosphoprotein	complex. Fps/Fes and Fer are members
	NCP94)	of a distinct subfamily of cytoplasmic
		protein tyrosine kinases that have
		recently been implicated in the
		regulation of innate immunity, evidence
		for functional redundancy between Fps
		and Fer kinases in regulating
		hematopoiesis.
FLT3	fms-related	CD135 is a cytokine receptor expressed	Immune
	tyrosine	on the surface of hematopoietic	Health
	kinase 3	progenitor cells. Signaling through
		CD135 plays a role in cell survival,
		proliferation, and differentiation. CD135
		is important for lymphocyte (B cell and T
		cell) development, but not for the
		development of other blood cells
		(myeloid development).
NKTR	natural killer-	The natural killer triggering receptor	Immune
	tumor	(NKTR) is involved in the recognition of	Health
	recognition	tumor cells by large granular
	sequence	lymphocytes (LGLs) (Frey et al., 1991;
		Anderson et al., 1993). LGLs are a
		subpopulation of white blood cells that
		have the ability to kill target tumor cells
		by an MHC-independent mechanism.
		The protein product of the NKTR gene is
		present on the surface of LGLs and
		facilitates their binding to tumor targets.
		The gene codes for a protein of 150,000
		Da, with a unique amino acid structure
		consisting of a 58-amino acid
		hydrophobic amino terminus followed by
		a cyclophilin-related domain.
PABPC4	\poly(A)	might be necessary for regulation of	Immune
	binding	stability of labile mRNA species in	Health
	protein,	activated T cells.
	cytoplasmic 4
	(inducible
	form)\“”
PAG1	phosphoprotein	Absence of external stimuli, the PAG-	Immune health
	associated	Csk complex transmits negative
	with	regulatory signals and thus may help to
	glycosphingolipid	keep resting T cells in a quiescent state.
	microdomains 1	PAG-CSK complex increases the
		signaling threshold required for initiating
		an immune response, thus helping to
		keep lymphocytes in a resting state.
ADRBK2	\adrenergic,	Specifically phosphorylates the agonist-	Immune health
	beta, receptor	occupied form of the beta-adrenergic
	kinase 2\“”	and closely related receptors, in
		leukocytes from patients with active
		relapsing-remitting multiple sclerosis
		(MS) or with secondary progressive MS,
		GRK2 levels are significantly reduced,
		probable role in immune Maintenance
		and health
GFI1	growth factor	Gfi1 maintained hematopoietic stem cell	Immune health
	independent 1	self-renewal, multilineage differentiation,
		and efficient reconstitution of
		hematopoiesis in transplanted hosts by
		restricting stem cell proliferation
GPR34	G protein-	GPR34 is the functional mast cell lysoPS	Immune health
	coupled	receptor. Lysophosphatidyl-L-serine
	receptor 34	(lysoPS) is thought to be an
		immunological regulator
GPR44	G protein-	This receptor also called, CRTH2 is a	Immune health
	coupled	receptor for PGD2, PGD2 functions as a
	receptor 44	neuromodulator as well as a trophic
		factor in the central nervous system.
		PGD2 is also involved in smooth muscle
		contraction/relaxation and is a potent
		inhibitor of platelet aggregation,
		receptor for prostaglandin (PG) D(2),
		which is a major mast cell product
		released during the allergic response.
		CRTH2 mediates the chemotaxis of
		eosinophils, basophils, and Th2
		lymphocytes
HHEX	hematopoietically	Transcriptional repressor. May play a	Immune health
	expressed	role in hematopoietic differentiation.
	homeobox
ID2	\inhibitor of	Id2 has an essential role in the	Immune health
	DNA binding	generation of peripheral lymphoid
	2, dominant	organs and NK cells. D (inhibitor of DNA
	negative	binding) HLH proteins lack a basic DNA-
	helix-loop-	binding domain but are able to form
	helix protein\“”	heterodimers with other HLH proteins,
		thereby inhibiting DNA binding,
		importance of Id2 in regulating gene
		expression by CD8(+) T cells and the
		magnitude of effector responses,
		suggesting a mechanism involving Id
		protein- and E protein-mediated survival
		and differentiation of mature T cells,
		helix-loop-helix (HLH) transcription factor
		Id2 (inhibitor of DNA
		binding/differentiation 2) acts as a
		molecular switch in development of
		Langerhans cells (LCs), the cutaneous
		contingent of dendritic cells (DCs), and
		of specific DC subsets and B cells.
IL10RA	\interleukin 10	The protein encoded by this gene is a	Immune health
	receptor,	receptor for interleukin 10. This protein is
	alpha\“”	structurally related to interferon
		receptors. It has been shown to mediate
		the immunosuppressive signal of
		interleukin 10, and thus inhibits the
		synthesis of proinflammatory cytokines.
		This receptor is reported to promote
		survival of progenitor myeloid cells
		through the insulin receptor substrate-
		2/PI 3-kinase/AKT pathway. Activation of
		this receptor leads to tyrosine
		phosphorylation of JAK1 and TYK2
		kinases.
IL7R	interleukin 7	This protein has been shown to play a	Immune health
	receptor	critical role in the V(D)J recombination
		during lymphocyte development. This
		protein is also found to control the
		accessibility of the TCR gamma locus by
		STAT5 and histone acetylation.
		Knockout studies in mice suggested that
		blocking apoptosis is an essential
		function of this protein during
		differentiation and activation of T
		lymphocytes. The functional defects in
		this protein may be associated with the
		pathogenesis of the severe combined
		immunodeficiency (SCID). Receptor for
		interleukin-7. Also acts as a receptor for
		thymic stromal lymphopoietin
IRF8	interferon	ICSBP in regulating the proliferation	Immune health
	regulatory	and differentiation of hematopoietic
	factor 8	progenitor cells, antiviral responses
		associated with impaired production of
		IFN-gamma
ITK	IL2-inducible	Tec kinases Itk and Rlk provide	Immune health
	T-cell kinase	important signals for terminal maturation,
		efficient cytokine production, and
		peripheral survival of NKT cells. This
		gene encodes an intracellular tyrosine
		kinase expressed in T-cells. The protein
		contains both SH2 and SH3 domains
		which are often found in intracellular
		kinases. It is thought to play a role in T-
		cell proliferation and differentiation.
JAK1	Janus kinase	Tyrosine kinase of the non-receptor	Immune health
	1 (a protein	type, involved in the IFN-
	tyrosine	alpha/beta/gamma signal pathway.
	kinase)	Kinase partner for the interleukin (IL)-2
		receptor. The Janus kinase-signal
		transducer and activator of transcription
		(Jak-Stat) pathway stands as a
		paradigm of how diverse extracellular
		signals can elicit rapid changes in gene
		expression in specific target cells. This
		pathway is widely used by members of
		the cytokine receptor superfamily,
		including those for the clinically
		important cytokines granulocyte colony-
		stimulating factor (G-CSF),
		erythropoietin, thrombopoietin, the
		interferons, and numerous interleukins,
		which makes it central to hematopoietic
		cell biology and hematologic therapy
		alike. Impaired lymphoid development
		in the absensce of JAK1
JMJD1A	jumonji	Jmjd1a and Jmjd2c histone H3 Lys 9	Immune health
	domain	demethylases regulate self-renewal in
	containing 1A	embryonic stem cells.
JMJD2C	jumonji	Jmjd1a and Jmjd2c histone H3 Lys 9	Immune health
	domain	demethylases regulate self-renewal in
	containing 2C	embryonic stem cells.
KIR2DS2	\killer cell	Killer-cell immunoglobulin-like receptors	Immune health
	immunoglobulin-	(KIRs), are a family of cell surface
	like	proteins found on important cells of the
	receptor, two	immune system called natural killer (NK)
	domains,	cells. They regulate the killing function of
	short	these cells by interacting with MHC class
	cytoplasmic	I molecules, which are expressed on all
	tail, 2\“”	cell types. This interaction allows them
		to detect virally infected cells or tumor
		cells that have a characteristic low level
		of Class I MHC on their surface. Most
		KIRs are inhibitory, meaning that their
		recognition of MHC suppresses the
		cytotoxic activity of their NK cell. Only a
		limited number of KIRs have the ability
		to activate cells. This gene is an
		activating receptor.
KLRC1	\killer cell	Natural killer (NK) cells are lymphocytes	Immune health
	lectin-like	that can mediate lysis of certain tumor
	receptor	cells and virus-infected cells without
	subfamily C,	previous activation. They can also
	member 1\“”	regulate specific humoral and cell-
		mediated immunity. NK cells
		preferentially express several calcium-
		dependent (C-type) lectins, which have
		been implicated in the regulation of NK
		cell function.
L3MBTL3	l(3)mbt-like 3	H-L(3)MBT protein, whose deletion is	Immune health
	(Drosophila)	predicted to be responsible for myeloid
		hematopoietic malignancies, tumor
		suppressor gene.
MEMO1	mediator of	Highly present in NK cells and other	Immune health
	cell motility 1	hematopoeitic cells
NAGA	\N-	Highly present in monocytes (Ascenta)	Immune health
	acetylgalactos	what are the implications? lysosomal
	aminidase,	glycohydrolase that cleaves alpha-N-
	alpha-\“”	acetylgalactosaminyl moieties from
		glycoconjugates.
NDFIP1	Nedd4 family	Ndfip1 protein promotes the function of	Immune health
	interacting	itch ubiquitin ligase to prevent T cell
	protein 1	activation and T helper 2 cell-mediated
		inflammation.
NR1D2	\nuclear	Heme as the ligand	Immune health
	receptor
	subfamily 1,
	group D,
	member 2\“”
PRNP	\prion protein	PrPc is expressed on hematopoietic	Immune health	Red blood
	(p27-30)	cells, including erythroid precursors.		cell health
	(Creutzfeldt-	Prion protein is expressed on long-term
	Jakob	repopulating hematopoietic stem cells
	disease,	and is important for their self-renewal.
	Gerstmann-	PrP is a marker for long-term
	Strausler-	hematopoietic stem cells. Prion protein
	Scheinker	expression may be involved in both the
	syndrome,	metabolism of copper and resistance to
	fatal familial	oxidative stress, neuroprotective role of
	insomnia)\“”	cellular prion protein (PrPC) rion protein
		interferes with divalent metal Mn uptake
		and protects against Mn-induced
		oxidative stress
PSCD1	\pleckstrin	Members of this family appear to	Immune health
	homology,	mediate the regulation of protein sorting
	Sec7 and	and membrane trafficking. The PSCD1
	coiled-coil	is highly expressed in natural killer and
	domains	peripheral T cells, and regulates the
	1(cytohesin	adhesiveness of integrins at the plasma
	1)\“”	membrane of lymphocytes.
PTGER4	prostaglandin	This receptor can activate T-cell factor	Immune health
	E receptor 4	signaling. It has been shown to mediate
	(subtype EP4)	PGE2 induced expression of early
		growth response 1 (EGR1), regulate the
		level and stability of cyclooxygenase-2
		mRNA, and lead to the phosphorylation
		of glycogen synthase kinase-3.
		Knockout studies in mice suggest that
		this receptor may be involved in the
		neonatal adaptation of circulatory
		system, osteoporosis, as well as
		initiation of skin immune responses.
		Receptor for prostaglandin E2 (PGE2).
		The activity of this receptor is mediated
		by G(s) proteins that stimulate adenylate
		cyclase. Has a relaxing effect on smooth
		muscle. May play an important role in
		regulating renal hemodynamics,
		intestinal epithelial transport, adrenal
		aldosterone secretion, and uterine
		function.
PTPN11	\protein	Shp-2 is a widely expressed nonreceptor	Immune health
	tyrosine	protein tyrosine phosphatase that
	phosphatase,	participates early in hematopoietic
	non-receptor	development.
	type 11
	(Noonan
	syndrome
	1)\“”
PTPN22	\protein	This gene encodes a protein tyrosine	Immune health
	tyrosine	phosphatase which is expressed
	phosphatase,	primarily in lymphoid tissues. This
	non-receptor	enzyme associates with the molecular
	type 22	adapter protein CBL and may be
	(lymphoid)\“”	involved in regulating CBL function in
		the T-cell receptor signaling pathway.
PTPRC	\protein	This gene is specifically expressed in	Immune health
	tyrosine	hematopoietic cells. This PTP has been
	phosphatase,	shown to be an essential regulator of T-
	receptor type,	and B-cell antigen receptor signaling. It
	C\“”	functions through either direct interaction
		with components of the antigen receptor
		complexes, or by activating various Src
		family kinases required for the antigen
		receptor signaling. This PTP also
		suppresses JAK kinases, and thus
		functions as a regulator of cytokine
		receptor signaling.
RASSF5	Ras	Potential tumor suppressor. Seems to	Immune health
	association	be involved in lymphocyte adhesion by
	(RalGDS/AF-	linking RAP1A activation upon T cell
	6) domain	receptor or chemokine stimulation to
	family 5	integrin activation. Isoform 2 stimulates
		lymphocyte polarization and the patch-
		like distribution of ITGAL/LFA-1,
		resulting in an enhanced adhesion to
		ICAM1. Together with RAP1A may
		participate in regulation of microtubule
		growth. The association of isoform 2 with
		activated RAP1A is required for
		directional movement of endothelial cells
		during wound healing
RFX5	\regulatory	MHC class II molecules play a key role	Immune health
	factor X, 5	in the immune system. They present
	(influences	exogenous antigenic peptides to the
	HLA class II	receptor of CD4+ T-helper lymphocytes,
	expression)\“”	thereby triggering the antigen-specific T-
		cell activation events required for the
		initiation and sustenance of immune
		responses.. Activates transcription from
		class II MHC promoters. Differentiation
		of hematopoietic stem and progenitors
		cells is an intricate process controlled in
		large part at the level of transcription.
		new transcriptional regulators of
		megakaryopoiesis.
SENP6	SUMO1/sentrin	important in adult hematopoietic self-	Immune health
	specific	renewal
	peptidase 6
SERPINB9	\serpin	The intracellular granzyme B inhibitor,	Immune health
	peptidase	proteinase inhibitor 9, is up-regulated
	inhibitor,	during accessory cell maturation and
	clade B	effector cell degranulation, and its
	(ovalbumin),	overexpression enhances CTL (cytotoxic
	member 9\“”	lymphocyte) potency, the presence and
		subcellular localization of PI-9 in
		leukocytes and DCs are consistent with
		a protective role against ectopic or
		misdirected grB during an immune
		response.
SOX4	SRY (sex	Sox4 contribute to the survival and	Immune health
	determining	proliferation of pro-B cells in response to
	region Y)-box 4	extracellular signals.
SPEN	\spen	The ability of Ott1 to affect	Immune health
	homolog,	hematopoietic cell fate and expansion in
	transcriptional	multiple lineages is a novel attribute for
	regulator	a spen family member and delineates
	(Drosophila)\“”	Ott1 from other known effectors of
		hematopoietic development.
SYBL1	synaptobrevin-	VAMP-7 is a crucial component of	Immune health
	like 1	granzyme B release and target cell
		killing in the NK cell
TMPO	thymopoietin	It is possible that TCERG1 interacts with	Immune health
		the nascent transcript (or RNP) and
		directly alters splicing decisions. This
		could be consistent with independent
		effects on transcription elongation and
		alternative processing. Alternatively,
		TCERG1 could work at
VNN1	vanin 1	VNN1 gene product is involved in the	Immune health
		thymus homing of bone marrow cells
		and in late adhesion steps of thymus
		homing under physiologic,
		noninflammatory conditions.
		Recently VNN1 gene upregulation has
		been linked to increased HDL level
		The product of CD1c gene is expressed
		on cortical thymocytes, immature
		myeloid dendritic cells, subset of normal
		peripheral B cells and activated T cells
ZFX	\zinc finger	Zfx controls the self-renewal of	Immune health
	protein, X-	embryonic and hematopoietic stem cells.
	linked\“”	Zfx as a shared transcriptional regulator
		of ESC and HSC, suggesting a common
		genetic basis of self-renewal in
		embryonic and adult SC.
ZNF317	zinc finger	ZNF317 may play an important role in	Immune health	Red blood
	protein 317	erythroid maturation and lymphoid		cell health
		proliferation
ZNF589	zinc finger	Characterization of SZF1 implicates its	Immune health
	protein 589	role in hematopoiesis.
OGT	O-linked N-	The regulation of topoisomerase I (topo	Immune
	acetylglucosamine	I) activity is of prime importance for gene	Health
	(GlcNAc)	expression. It participates in DNA
	transferase	replication, transcription, recombination,
	(UDP-N-	and DNA repair, and serves as a target
	acetylglucosamine:	for anticancer drugs. Many proteins and
	polypeptide-	enzymes are modified by O-linked beta-
	N-	N-acetylglucosamine (O-GlcNAc), which
	acetylglucosaminyl	exerts profound effects on their function.
	transferase)	OGT is a central factor for T- and B-
		lymphocytes activation.. OGT
		participation in intracellular glycosylation
		is essential for embryonic stem cell
		viability
PIK3R1	\phosphoinositide-	Important in adult hematopoietic self-	Immune
	3-kinase,	renewal	Health
	regulatory
	subunit 1 (p85
	alpha)\“”
NKRF	NF-kappaB	Interacts with a specific negative	Inflammation
	repressing	regulatory element (NRE) 5′-	control
	factor	AATTCCTCTGA-3′ to mediate
		transcriptional repression of certain NK-
		kappa-B responsive genes. NF-κB-
		repressing factor (NRF) is a
		constitutively expressed nuclear
		transcription factor that binds to beta
		interferon (IFN-β), interleukin-8 (IL-8),
		and inducible nitric oxide synthase
		(iNOS) promoters and represses the
		basal transcription of these genes
NR3C1	\nuclear	The glucocorticoid receptor (GR) is a	Inflammation
	receptor	ligand-dependent transcription factor	control
	subfamily 3,	belonging to the nuclear hormone
	group C,	receptor superfamily. Due to its almost
	member 1	ubiquitous expression, GR plays an
	(glucocorticoid	important role in many physiological and
	receptor)\“”	pathological processes. These include
		regulation of homeostasis, adaptation to
		stress, and modulation of central
		nervous system. In addition, GR is a
		major modulator of the immune system
		due to its proficient anti-inflammatory
		and immunosuppressive activity; and its
		function is important for proper
		regulation of many physiological
		processes.
ZCCHC11	\zinc finger,	ZCCHC11 is a unique TLR signal	Inflammation
	CCHC	regulator, which interacts with TIFA after	control
	domain	LPS treatment and suppresses the
	containing	TRAF6-dependent activation of NF-
	11\“”	kappaB.
SIRT1	sirtuin (silent	Longevity gene	Longevity
	mating type		gene
	information
	regulation 2
	homolog) 1
	(S. cerevisiae)
YTHDF2	\YTH domain	A polymorphism of the YTHDF2 gene	Longevity
	family,	(1p35) located in an Alu-rich genomic	gene
	member 2\“”	domain is associated with human
		longevity.
AP15	apoptosis	Survival gene or anti-apoptotic gene	Longevity
	inhibitor 5		gene
ARNT	aryl	Bmal1-null mice lose circadian	Longevity
	hydrocarbon	rhythmicity but also display tendon	gene
	receptor	calcification and decreased activity,
	nuclear	body weight, and longevity
	translocator
FRAP1	FK506	a gene expression signature associated	Longevity
	binding	with mammalian target of rapamycin	gene
	protein 12-	(mTOR) activity that was down-regulated
	rapamycin	with age but preserved by CR in both
	associated	WAT and heart, mammalian cells the
	protein 1	mammalian TOR (mTOR) pathway plays
		a significant role in determining both
		resting oxygen consumption and
		oxidative capacity, mTOR activity may
		play an important role in determining the
		relative balance between mitochondrial
		and non-mitochondrial sources of ATP
		generation.
HSPA9	heat shock	this member of the hsp70 family governs	Longevity
	70 kDa protein	the longevity of worms and thus there	gene
	9 (mortalin)	are common pathways that determine
		mammalian and worm longevity
POLG2	\polymerase	Mitochondrial polymerase processivity	Mitochondrial
	(DNA	subunit. Stimulates the polymerase and	DNA Health
	directed),	exonuclease activities, and increases
	gamma 2,	the processivity of the enzyme. Binds to
	accessory	sc-DNA.
	subunit\“”
OPA1	optic atrophy	Mitochondrial health is defined by	Mitochondrial
	1 (autosomal	various parameters including fusion and	Health
	dominant)	fission events. In older cells, giant
		mitochondria accumulates. This is
		because of insufficient autophagy.
		These giants don't fuse with each other
		or with normal mitochondria and it was
		noticed that OPA1 is reduced in these
		giant mitochondria, mitochondria fuse
		and divide to change their morphology in
		response to a multitude of signals.
		During the past decade, work using
		yeast and mammalian cells has
		identified much of the machinery
		required for fusion and division,
		including the dynamin-related GTPases--
		mitofusins (Fzo1p in yeast) and OPA1
		(Mgm1p in yeast) for fusion and Drp1
		(Dnm1p) for division. Mitochondrial fusion
		requires coordinated fusion of the outer
		and inner membranes. This process
		leads to exchange of contents, controls
		the shape of mitochondria, and is
		important for mitochondrial function.
		OPA1 is a major organizer of the
		mitochondrial inner membrane and is
		required for the maintenance of cristae
		integrity. As the loss of OPA1 committed
		cells to apoptosis without any other
		stimulus. Olichon et al. (2003) proposed
		that OPA1 is involved in the
		sequestration of cytochrome c, and that
		OPA1 may be a target for mitochondrial
		apoptotic effectors.
PDSS2	\prenyl	PDSS2 gene, which encodes a subunit	Mitochondrial
	(decaprenyl)	of decaprenyl diphosphate synthase, the	Health
	diphosphate	first enzyme of the CoQ(10) biosynthetic
	synthase,	pathway.
	subunit 2\“”
MFN1	mitofusin 1	The regulated equilibrium between	Mitochondrial
		mitochondrial fusion and fission is	Health
		essential to maintain integrity of the
		organelle. Mechanisms of mitochondrial
		fusion are largely uncharacterized in
		mammalian cells. It is unclear whether
		OPA1, a dynamin-related protein of the
		inner membrane mutated in autosomal
		dominant optic atrophy, participates in
		fusion or fission. OPA1 promoted the
		formation of a branched network of
		elongated mitochondria, requiring the
		integrity of both its GTPase and C-
		terminal coiled-coil domain. Stable
		reduction of OPA1 levels by RNA
		interference resulted in small,
		fragmented, and scattered mitochondria.
		Levels of OPA1 did not affect
		mitochondrial docking, but they
		correlated with the extent of fusion as
		measured by polyethylene glycol
		mitochondrial fusion assays. A genetic
		analysis proved that OPA1 was unable
		to tubulate and fuse mitochondria
		lacking the outer membrane mitofusin 1
		but not mitofusin 2. Our data show that
		OPA1 functionally requires mitofusin 1 to
		regulate mitochondrial fusion and reveal
		a specific functional difference between
		mitofusin 1 and 2.
MTRF1L	mitochondrial		Mitochondrial
	translational		Health
	release factor
	1-like
NDUFC2	\NADH	Accessory subunit of the mitochondrial	Mitochondrial
	dehydrogenase	membrane respiratory chain NADH	Health
	(ubiquinone)	dehydrogenase (Complex I), that is
	1,	believed to be not involved in catalysis.
	subcomplex	Complex I functions in the transfer of
	unknown, 2,	electrons from NADH to the respiratory
	14.5 kDa\“”	chain. The immediate electron acceptor
		for the enzyme is believed to be
		ubiquinone.
NDUFS1	\NADH	Core subunit of the mitochondrial	Mitochondrial
	dehydrogenase	membrane respiratory chain NADH	Health
	(ubiquinone)	dehydrogenase (Complex I) that is
	Fe—S protein	believed to belong to the minimal
	1.75 kDa	assembly required for catalysis.
	(NADH-	Complex I functions in the transfer of
	coenzyme Q	electrons from NADH to the respiratory
	reductase)\“”	chain. The immediate electron acceptor
		for the enzyme is believed to be
		ubiquinone (By similarity). This is the
		largest subunit of complex I and it is a
		component of the iron-sulfur (IP)
		fragment of the enzyme. It may form part
		of the active site crevice where NADH is
		oxidized.
SDHD	\succinate	Complex II of the respiratory chain,	Mitochondrial
	dehydrogenase	which is specifically involved in the	Health
	complex,	oxidation of succinate, carries electrons
	subunit D,	from FADH to CoQ. The complex is
	integral	composed of four nuclear-encoded
	membrane	subunits and is localized in the
	protein\“”	mitochondrial inner membrane.
ENC1	ectodermal-	Highly present in neuronal cells (and	Nervous
	neural cortex	brain tissues from Ascenta-almost	System Health
	(with BTB-like	absent in other tissues) and involved in
	domain)	neuronal differentiation. Likely a Redox
		controlling protein
ADNP	activity-	Involved in proper lipid metabolism,	Nervous
	dependent	coagulation as well as in neurogenesis.	System Health
	neuroprotector	Multiple Roles in Neuronal
		Differentiation and Maintenance,
		neuroprotective protein
AGTPBP1	ATP/GTP	zinc carboxypeptidase that contains	Nervous
	binding	nuclear localization signals and an	System Health
	protein 1	ATP/GTP-binding motif that was initially
		cloned from regenerating spinal cord
		neurons of the mouse. Role in
		preventing neurodegeneration.
OAT	ornithine	OAT encodes the mitochondrial enzyme	Nervous
	aminotransferase	ornithine aminotransferase, which is a	system health
	(gyrate	key enzyme is the pathway that converts
	atrophy)	arginine and ornithine into the major
		excitatory and inhibitory
		neurotransmitters glutamate and GABA.
		Vitamin B6 dependent enzyme.
PTDSS1	Phosphatidylserine	Phosphatidylserine (PS or PtdSer) is a	Nervous
	synthase 1	phospholipid nutrient found in fish, green	system health
		leafy vegetables, soybeans, and rice,
		and is essential for the normal
		functioning of neuronal cell membranes,
		activating protein kinase C (PKC), which
		has been shown to be involved in
		memory function. PS has been
		investigated in a small number of
		double-blind placebo trials and has been
		shown to increase memory performance
		in the elderly. Because of the potential
		cognitive benefits of phosphatidylserine,
		the substance is sold as a dietary
		supplement to people that believe they
		can benefit from an increased intake.
SPOCK2	\sparc/osteonectin,	May participate in diverse steps of	Nervous
	cwcv	neurogenesis	system health
	and kazal-like
	domains
	proteoglycan
	(testican) 2\“”
ADSS	adenylosuccinate	carries out the first of a 2-step sequence	Nucleotide
	synthase	in the biosynthesis of AMP from IMP.	Biosynthesis
		Plays an important role in the de novo
		pathway of purine nucleotide
		biosynthesis. AMP, is a nucleotide that
		is found in RNA.
DCTD	dCMP	Supplies the nucleotide substrate for	Nucleotide
	deaminase	thymidylate synthetase which is the	Biosynthesis
		enzyme used to generate thymidine
		monophosphate (dTMP), which is
		subsequently phosphorylated to
		thymidine triphosphate for use in DNA
		synthesis and repair.
HPRT1	hypoxanthine	HPRT1 has a central role in the	Nucleotide
	phosphoribosyltransferase	generation of purine nucleotides through	biosynthesis
	1 (Lesch-	the purine salvage pathway. HPRT1
	Nyhan	catalyzes conversion of hypoxanthine to
	syndrome)	inosine monophosphate and guanine to
		guanosine monophosphate via transfer
		of the 5-phosphoribosyl group from 5-
		phosphoribosyl 1-pyrophosphate
PRPS1	phosphoribosyl	Phosphoribosylpyrophosphate	Nucleotide
	pyrophosphate	synthetase (PRPS; EC 2.7.6.1)	biosynthesis
	synthetase 1	catalyzes the phosphoribosylation of
		ribose 5-phosphate to 5-phosphoribosyl-
		1-pyrophosphate, which is necessary for
		the de novo and salvage pathways of
		purine and pyrimidine biosynthesis
CMPK	cytidylate	Uridine monophosphate (UMP)/cytidine	Nucleotide	Mitochondrial
	kinase	monophosphate (CMP) kinase (EC	Biosynthesis	Health
		2.7.4.4) catalyzes the phosphoryl
		transfer from ATP to UMP, CMP, and
		deoxy-CMP (dCMP), resulting in the
		formation of ADP and the corresponding
		nucleoside diphosphate. These
		nucleoside diphosphates are required
		for cellular nucleic acid synthesis.
		Enzyme deficiency in the salvage
		pathway of deoxyribonucleotide
		synthesis in mitochondria can cause
		mtDNA depletion syndromes.
		Maintenance of mitochondrial health.
ABCD3	\ATP-binding	Peroxisome biogenesis	Peroxisome
	cassette, sub-		Health
	family D
	(ALD),
	member 3\“”
ABCD4	\ATP-binding	Peroxisome biogenesis	Peroxisome
	cassette, sub-		Health
	family D
	(ALD),
	member 4\“”
PEX12	peroxisomal		Peroxisome
	biogenesis		Health
	factor 12
PEX3	peroxisomal		Peroxisome
	biogenesis		Health
	factor 3
RABGAP1L	RAB GTPase	Lower levles in platelet dysfunction	Platelet health
	activating
	protein 1-like
CANX	calnexin	Calcium-binding protein that interacts	Protein quality
		with newly synthesized glycoproteins in	control
		the endoplasmic reticulum. It may act in
		assisting protein assembly and/or in the
		retention within the ER of unassembled
		protein subunits. It seems to play a
		major role in the quality control
		apparatus of the ER by the retention of
		incorrectly folded proteins.
CLPX	ClpX	Clp ATPases are protein machines	Protein quality
	caseinolytic	involved in protein degradation. The	control
	peptidase X	ClpXP ATPase-protease complex is a
	homolog (E. coli)	major component of the protein quality
		control machinery in the cell.
DERL1	\Der1-like	Derlin-1 is an important factor for the	Protein quality
	domain	extraction of certain aberrantly folded	control
	family,	proteins from the mammalian ER.
	member 1\“”	Functional component of endoplasmic
		reticulum-associated degradation
		(ERAD) for misfolded lumenal proteins.
		May act by forming a chann
DNAJA1	\DnaJ	Human DnaJ 2 (Hdj-2) is a co-	Protein quality
	(Hsp40)	chaperone of heat shock cognate 70	control
	homolog,	(Hsc70) which is localized to the
	subfamily A,	cytosolic face of the ER. Necessary for
	member 1\“”	proper folding of proteins and therefore
		proper functions of various proteins.
EDEM3	\ER	enhances glycoprotein endoplasmic	Protein quality
	degradation	reticulum-associated degradation and	control
	enhancer,	mannose trimming, accelerates ERAD of
	mannosidase	misfolded glycoproteins.
	alpha-like 3\“”
OMA1	\OMA1	The integrity of the inner membrane of	Protein quality
	homolog, zinc	mitochondria is maintained by a	control
	metallopeptidase	membrane-embedded quality control
	S. cerevisiae)\	system that ensures the removal of
	“”	misfolded membrane proteins. Two
		ATP-dependent AAA proteases with
		catalytic sites at opposite membrane
		surfaces are key components of this
		proteolytic system, identify Oma1 as a
		novel component of the quality control
		system in the inner membrane of
		mitochondria. Mitochondrial protease
CTSO	cathepsin O	normal cellular protein degradation and	Protein quality
		tumover	control
HSP90AB1	\heat shock	HSP90's function in the regulation and	Protein quality
	protein 90 kDa	correct folding of at least 100	control
	alpha	proteins[26] allows it to refold and/or
	(cytosolic),	degrade these products before they
	class B	trigger cell death. They participate in the
	member 1\“”	regulation of the stress response [2, 3]
		and, when associated with other co-
		chaperones, function in correctly folding
		newly synthesized proteins, stabilizing
		and refolding denatured proteins after
		stress, preventing misfolding and
		aggregation of unfolded or partially
		folded proteins, and assisting in protein
		transport across the endoplasmic
		reticulum (ER) and organellar
		membranes [4-8]. HSP90 members
		have key roles in the maturation of
		signal transduction proteins, like
		hormone receptors, various kinases,
		nitric oxide synthase and calcineurin
HSPBAP1	HSPB (heat		Protein quality
	shock 27 kDa)		control
	associated
	protein 1
NGLY1	N-glycanase 1	N-glycanase is a highly conserved	Protein quality
		enzyme that catalyzes deglycosylation	control
		of misfolded N-linked glycoproteins by
		cleaving the glycan chain before the
		proteins are degraded by the
		proteasome
SACS	spastic ataxia	The presence of heat-shock domains	Protein quality
	of Charlevoix-	suggested a function for sacsin in	control
	Saguenay	chaperone-mediated protein folding.
	(sacsin)
SELS	selenoprotein S	SEPS1 gene helps in ridding the cell of	Protein quality
		misfolded proteins, preventing it from	control
		accumulating and subsequently resulting
		to inflammation. SEPS1 as a type of
		“garbage truck” that helps clear faulty
		proteins that accumulate in cells when
		they are placed under stress, causing
		inflammation to develop.
ST13	suppression	Hip facilitates may facilitate the	Protein quality
	of	chaperone function of Hsc/Hsp70 in	control
	tumorigenicity	protein folding and repair, and in
	13 (colon	controlling the activity of regulatory
	carcinoma)	proteins such as steroid receptors and
	(Hsp70	regulators of proliferation or apoptosis.
	interacting
	protein)
PDIA6	\protein	Formation and rearrangement of	Protein quality
	disulfide	disulfide bonds during the correct folding	control
	isomerase	of nascent proteins is modulated by a
	family A,	family of enzymes known as thiol
	member 6\“”	isomerases, which include protein
		disulfide isomerase (PDI),
PDCL	phosducin-like	most members of the phosducin family	Protein quality
		act as co-chaperones with the cytosolic	control
		chaperonin complex (CCT) to assist in
		the folding of a variety of proteins from
		their nascent polypeptides
PDCL3	phosducin-like 3	most members of the phosducin family	Protein quality
		act as co-chaperones with the cytosolic	control
		chaperonin complex (CCT) to assist in
		the folding of a variety of proteins from
		their nascent polypeptides
AGA	aspartylglucos	key enzyme in the catabolism of N-	Protein quality;
	aminidase	linked oligosaccharides of glycoproteins.	Nervous
		It cleaves the asparagine from the	system health
		residual N-acetylglucosamines as one of
		the final steps in the lysosomal
		breakdown of glycoproteins. Needed for
		proper folding of proteins, particularly in
		the nervous system
ABCB10	\ATP-binding	a mitochondrial inner membrane	Red blood cell
	cassette, sub-	erythroid transporter involved in heme	health
	family B	biosynthesis
	(MDR/TAP),
	member 10\“”
CAPRIN2	caprin family	Involved in regulation of growth as	Red blood cell
	member 2	erythroblasts shift from a highly	health
		proliferative state towards their terminal
		phase of differentiation.
CYBRD1	cytochrome b	Cybrd1 (duodenal cytochrome b) is not	Red blood cell
	reductase 1	necessary for dietary iron absorption in	health
		mice. Likely participates in enhanced
		iron demand due to erythropoesis, ay
		be involved in extracellular ascorbate
		recycling in erythrocyte membranes.
EDRF1	Erythroid	Transcription factor involved in erythroid	Red blood cell
	differentiation-	differentiation. Involved in transcriptional	health
	related	activation of the globin gene.
	factor 1
ERMAP	erythroblast	Human Ermap is highly expressed in	Red blood cell
	membrane-	erythroid tissues and the protein	health
	associated	localizes to the plasma membrane,
	protein	particularly in sites of cell contact, and
	(Scianna	“cytoplasmic bodies.” Ermap expression
	blood group)	was restricted to fetal and adult erythroid
		tissues
ETS1	v-ets	ETS is responsible for erythroblast and	Red blood cell	Immune
	erythroblastos	fibroblast transformation. Critical for	health	Health
	is virus E26	maturation of the T Cells. Tumor
	oncogene	suppressor.
	homolog 1
	(avian)
FLVCR1	feline	Exports cytoplasmic heme. May be	Red blood cell
	leukemia virus	required to protect developing erythroid	health
	subgroup C	cells from heme toxicity.
	cellular
	receptor 1
ADD3	adducin 3	ADD3 may have a role in erythroblasts	Red blood cell
	(gamma)	and play an earlier role in erythropoiesis,	health
		hypertension.
IKZF1	IKAROS	structure of a chromatin remodeling	Red blood cell
	family zinc	complex (PYR complex) with Ikaros as	health
	finger 1	its DNA binding subunit that is
	(Ikaros)	specifically present in adult murine and
		human hematopoietic cells. Ikaros is
		involved in human adult or fetal erythroid
		differentiation as well as in the
		commitment between erythroid and
		myeloid cells.
MAEA	macrophage	The association of erythroblasts with	Red blood cell
	erythroblast	macrophages plays a central role in the	health
	attacher	terminal maturation and enucleation of
		erythroblasts. MAEA mediates
		attachment of erythroblasts to
		macrophages.
MYB	v-myb	c-Myb is strictly required for expression	Red blood cell
	myeloblastosis	of the c-Kit receptor in erythroid cells.	health
	viral	The transcription factor c-Myb is
	oncogene	expressed at high levels in immature
	homolog	progenitors of all hematopoietic lineages
	(avian)	and is involved in the regulation of
		proliferation, differentiation, and survival,
		role for c-Myb as a factor promoting
		commitment to erythropoiesis and
		progression from early to late stages of
		differentiation (FIG. 6). We have
		shown that this function of c-Myb is
		probably not related to the cell cycle but
		rather to the control of a network of
		hematopoietic regulators. The
		expression of c-Kit in erythroid
		progenitors was tightly dependent on c-
		Myb levels. Finally, we demonstrated
		that c-Myb acts as a coordinator at the
		CFU-E stage by promoting further
		progression while supporting terminal
		cell divisions.
NFE2L3	nuclear factor	Activates erythroid-specific, globin gene	Red blood cell
	(erythroid-	expression	health
	derived 2)-like 3
SMAP1	stromal	SMAP-1 may have a stimulatory effect	Red blood cell
	membrane-	on stroma-supported erythropoiesis.	health
	associated
	protein 1
ZNF266	zinc finger	HZF1 play important roles in erythroid	Red blood cell
	protein 266	and megakaryocytic differentiation.	health
		Increased HZF1 mRNA expression was
		observed following erythroid
		differentiation of K562 cells induced by
		hemin or megakaryocytic differentiation
		of K562 cells induced by phorbol
		myristate acetate (PMA). Both of the
		antisense method and RNA interference
		assay revealed that
RNPS1	\RNA binding	Formation of transcription-induced R-	RNA Quality
	protein S1,	loops poses a critical threat to genomic	Control
	serine-rich	integrity throughout evolution., RNA
	domain\“”	binding protein RNPS1 alleviates
		ASF/SF2 depletion-induced genomic
		instability. RNPS1, that when
		overexpressed strongly suppresses the
		high molecular weight (HMW) DNA
		fragmentation, hypermutation, and G2
		cell cycle arrest phenotypes of ASF/SF2-
		depleted cells. Involved in RENT2-
		dependent nonsense-mediated decay
		(NMD) of mRNAs containing premature
		stop codons. Also mediates increase of
		mRNA abundance and translational
		efficiency. Binds spliced mRNA 20-25 nt
		upstream of exon-exon junctions, low
		NMD efficiency is shown to be
		functionally related to the reduced
		abundance of the exon junction
		component RNPS1
PAPOLG	poly(A)	This gene encodes a member of the	RNA Quality
	polymerase	poly(A) polymerase family which	Control
	gamma	catalyzes template-independent
		extension of the 3′ end of a DNA/RNA
		strand. This enzyme is exclusively
		localized in the nucleus and exhibits
		both nonspecific and CPSF (cleavage
		and polyadenylation specificity
		factor)/AAUAAA-dependent
		polyadenylation activity.
DCP2	DCP2	Necessary for the degradation of	RNA Quality
	decapping	mRNAs, both in normal mRNA tumover	Control
	enzyme	and in nonsense-mediated mRNA
	homolog (S. cerevisiae)	decay.
DDX5	DEAD (Asp-	Nonsense mediated RNA degradation	RNA Quality
	Glu-Ala-Asp)		Control
	box
	polypeptide 5
ERLIN2	ER lipid raft	key ERAD pathway component that may	RNA Quality
	associated 2	act as a substrate recognition factor.	Control
PARN	pol(A)-	3′-exoribonuclease that has a preference	RNA quality
	specific	for poly(A) tails of mRNAs, thereby	control
	ribonuclease	efficiently degrading poly(A) tails.
	(deadenylation	Exonucleolytic degradation of the
	nuclease)	poly(A) tail is often the first step in the
		decay of eukaryotic mRNAs and is also
		used to silence certain maternal mRNAs
		translationally during oocyte maturation
		and early embryonic development.
		Interacts with both the 3′-end poly(A) tail
		and the 5′-end cap structure during
		degradation, the interaction with the cap
		structure being required for an efficient
		degradation of poly(A) tails. Involved in
		nonsense-mediated mRNA decay, a
		critical process of selective degradation
		of mRNAs that contain premature stop
		codons.
UPF2	UPF2	Nonsense-mediated mRNA decay	RNA quality
	regulator of	(NMD) represents a key mechanism to	control
	nonsense	control the expression of wild-type and
	transcripts	aberrant mRNAs. Phosphorylation of the
	homolog	protein UPF1 in the context of
	(yeast)	translation termination contributes to
		committing mRNAs to NMD.
UPF3A	UPF3	They promote nonsense-mediated	RNA quality
	regulator of	mRNA decay (NMD), and they also	control
	nonsense	regulate translation efficiency.
	transcripts
	homolog A
	(yeast)
TRNT1	\tRNA	Adds and repairs the conserved 3′-CCA	RNA quality
	nucleotidyl	sequence necessary for the attachment	control
	transferase,	of amino acids to the 3′ terminus of
	CCA-adding,	tRNA molecules, using CTP and ATP as
	1\“”	substrates.
MAT2B	\methionine	Methionine adenosyltransferase (MAT;	SAM
	adenosyltransferase	S-adenosyl-L-methionine synthetase,	Biosynthetic
	II,	EC 2.5.1.6)1 is an essential enzyme that	machinary
	beta\“”	catalyzes the synthesis of S-
		adenosylmethionine (AdoMet) from L-
		methionine (L-Met) and ATP (1, 2).
		AdoMet is the major methyl group donor,
		participating in the methylation of
		proteins, DNA, RNA, phospholipids, and
		other small molecules (reviewed in Refs.
		3-5). In addition, AdoMet is the ultimate
		source of the propylamine moiety used
		in polyamine biosynthesis, and it serves
		as co-factor for other key enzymes in the
		one-carbon metabolism pathway.
		Methionine adenosyltransferase (MAT;
		EC 2.5.1.6) catalyzes the biosynthesis of
		S-adenosylmethionine (AdoMet) from
		methionine and ATP. MAT II is a broadly
		expressed MAT consisting of catalytic
		alpha and noncatalytic beta subunits
		encoded by MAT2A (601468) and
		MAT2B, respectively. Methionine
		adenosyltransferase (MAT) catalyzes
		the biosynthesis of S-
		adenosylmethionine (AdoMet), a key
		molecule in transmethylation reactions
		and polyamine biosynthesis. The MAT II
		isozyme consists of a catalytic alpha2
		and a regulatory beta subunit. Down-
		regulation of the MAT II beta subunit
		expression causes a 6-10-fold increase
		in intracellular AdoMet levels.
SKIV2L2	superkiller	mutation in skiv2l2 causes defects in cell	Skin Health
	viralicidic	proliferation, suggesting that skiv2l2
	activity 2-like	plays a role in regulating melanoblast
	2 (S. cerevisiae)	proliferation during early stages of
		melanocyte regeneration. Skin
ALDH18A1	\aldehyde	Defects in this enzyme plays a role in	Skin health,	Nervous
	dehydrogenase	neurodegeneration, joint laxity, skin		system
	18 family,	hyperelasticity. Role in L-Proline		health
	member A1\“”	biosynthesis
KIT	Mast/stem cell	mobilization of hematopoetic stem cells	Stem cell
	growth factor	into peripheral blood; marker for HSCs	health
	receptor	and MSCs
	precursor
FLT3	FMS-like	restricted to CD34+ (high proportion of	Stem cell
	tyrosine	stem/progenitor cells)	health
	kinase 3)
ITK	IL2-inducible	play a role in T cell proliferation and	Stem cell
	T-cell kinase	differentiation	health
CD74	Cluster of	Hematopoietic Stem Cell survival	Stem cell
	Differentiation	pathway	health
	74
HOXB2	Homeobox	Expressed in erythromegakaryocytic	Stem cell
	B2,	cells and Hematopoietic Stem Cells	health
CIAPIN1	Cytokine	Necessary for hematopoiesis	Stem cell
	induced		health
	apoptosis
	inhibitor 1
NOTCH4		hematopoietic stem/progenitor cells	Stem cell
			health
NCOR1	nuclear	NCOR, a repressor or transcription, is a	Stem cell
	receptor co-	principal regulator in neural stem cells	health
	repressor 1
PUM2	pumilio	Sequence-specific RNA-binding protein	Stem cell
	homolog 2	that regulates translation and mRNA	health
	(Drosophila)	stability by binding the 3′-UTR of mRNA
		targets. Its interactions and tissue
		specificity suggest that it may be
		required to support proliferation and self-
		renewal of stem cells by regulating the
		translation of key transcripts.
SLAIN2	\SLAIN motif	Slain1 was expressed at the stem cell	Stem cell
	family,	and epiblast stages of ESC	health
	member 2\“”	differentiation
ACVR1	\activin A	Necessary for proper skeletal/bone	Stem cell
	receptor, type	formation; regulate the fate of	health
	I\“”	hematopoietic progenitor and stem cells
		during development
PDCD4	programmed	The translation inhibitor programmed cell	Tumor
	cell death 4	death 4 (Pdcd4) suppresses	suppresor
	(neoplastic	tumorigenesis and invasion.
	transformation
	inhibitor)
AXIN2	\axin 2	The Axin-related protein, Axin2,	Tumor
	(conductin,	presumably plays an important role in	suppressor
	axil)\“”	the regulation of the stability of beta-	function
		catenin in the Wnt signaling pathway,
		like its rodent homologs, mouse
		conductin/rat axil. In mouse, conductin
		organizes a multiprotein complex of APC
		(adenomatous polyposis of the colon),
		beta-catenin, glycogen synthase kinase
		3-beta, and conductin, which leads to
		the degradation of beta-catenin.
		Apparently, the deregulation of beta-
		catenin is an important event in the
		genesis of a number of malignancies.
		The AXIN2 gene has been mapped to
		17q23-q24, a region that shows frequent
		loss of heterozygosity in breast cancer,
		neuroblastoma, and other tumors.
		Mutations in this gene have been
		associated with colorectal cancer with
		defective mismatch repair.
AZIN1	antizyme	It has been shown to regulate DNA	Tumor
	inhibitor 1	methylation and has tumor suppressor	suppressor
		activity, enhances the nonhomologous	function
		end-joining repair of DNA double-strand
		breaks in human oral cancer cells.
BECN1	\beclin 1	UVRAG interacts with Beclin 1, leading	Tumor
	(coiled-coil,	to activation of autophagy and thereof	suppressor
	myosin-like	inhibition of tumorigenesis.	function
	BCL2
	interacting
	protein)\“”
CREBBP	CREB binding	CBP has tumor suppressing activity. CBP	Tumor
	protein	may function as a ‘master-switch’	suppressor
	(Rubinstein-	between energy storage and	function
	Taybi	expenditure, long term memory.
	syndrome)
CREBL2	cAMP	potential tumor suppressor	Tumor
	responsive		suppressor
	element		function
	binding
	protein-like 2
DIDO1	death inducer-	Putative transcription factor, weakly pro-	Tumor
	obliterator 1	apoptotic when overexpressed (By	suppressor
		similarity). Tumor suppressor.	function
ING2	\inhibitor of	Tumor suppressor	Tumor
	growth family,		suppressor
	member 2\“”		function
KRAS	v-Ki-ras2	Pfeifer (2001) noted an interesting	Tumor
	Kirsten rat	parallel to the p53 (191170) tumor	suppressor
	sarcoma viral	suppressor, which was initially described	function
	oncogene	as an oncogene, carrying point
	homolog	mutations in tumors. Later it was
		discovered that it is, in fact, the wildtype
		copy of the gene that functions as a
		tumor suppressor gene and is capable
		of reducing cell proliferation
MTSS1	metastasis	putative metastasis suppressor gene	Tumor
	suppressor 1		suppressor
			function
RB1	retinoblastoma	Key regulator of entry into cell division	Tumor
	1 (including	that acts as a tumor suppressor. Directly	suppressor
	osteosarcoma)	involved in heterochromatin formation by	function
		maintaining overall chromatin structure
		and, in particular, that of constitutive
		heterochromatin by stabilizing histone
		methylation.
SDCCAG1	serologically	can function as a tumor suppressor in	Tumor
	defined colon	human lung cancer cells.	suppressor
	cancer		function
	antigen 1
SMAD4	SMAD family	Common mediator of signal transduction	Tumor
	member 4	by TGF-beta (transforming growth	suppressor
		factor) superfamily; SMAD4 is the	function
		common SMAD (co-SMAD). Promotes
		binding of the SMAD2/SMAD4/FAST-1
		complex to DNA and provides an
		activation function required for SMAD1
		or SMAD2 to stimulate transcription.
		May act as a tumor suppressor.
STK3	\serine/threonine	Novel tumor suppressor function.	Tumor
	kinase 3	Stress-activated, pro-apoptotic kinase	suppressor
	(STE20	which, following caspase-cleavage,	function
	homolog,	enters the nucleus and induces
	yeast)\“”	chromatin condensation followed by
		internucleosomal DNA fragmentation.
UVRAG	UV radiation	UVRAG interacts with Beclin 1, leading	Tumor
	resistance	to activation of autophagy and thereof	suppressor
	associated	inhibition of tumorigenesis.	function
	gene
WWOX	WW domain	critical tumor suppressor gene	Tumor
	containing		suppressor
	oxidoreductase		function
FOXO1	forkhead box	Tumor suppressor and essential role in	Tumor	Immune
	O1	the Maintenance of hematopoetic stem	suppressor	Health
		cells	function
TFRC	\transferrin
	receptor (p90,
	CD71)\“”

Claims

1. A method for modulating the expression of genes related to chromatin stability by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes related to chromatin stability

2. The method of claim 1, wherein said administering step includes administering the composition to a subject in the form of three tablets, each tablet administered twice a day.

3. The method of claim 1, wherein said administering step includes administering a composition that up-regulates the expression of chromatin stability-related genes.

4. A method of modulating the expression of DNA repair-related genes by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes related to DNA repair.

5. The method of claim 4, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.

6. The method of claim 4, wherein said administering step includes administering the composition thereby up-regulating the expression of DNA repair-related genes.

7. A method for reducing the risk of chromatin damage by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes thereby reducing the risk of chromatin damage.

8. The method of claim 7, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.

9. The method of claim 7, wherein said administering step includes administering a composition that up-regulates the expression of chromatin stability-related genes.

10. A combinatorial therapy comprising: an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit, ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes thereby reducing a risk of chromatin damage; anda second composition for treating a disease, wherein said second composition alters chromatin stability.

11. The combinatorial therapy of claim 10 further comprising alfalfa, brassica, and kale.

12. The combinatorial therapy of claim 10 further comprising vitamins and minerals.

13. The combinatorial therapy of claim 12, wherein the vitamins are chosen from vitamin A, vitamin C, vitamin D, vitamin E, niacin, vitamin B6, vitamin B12, folic acid, biotin, and pantothenic acid.

14. The combinatorial therapy of claim 12 wherein the minerals are chosen from calcium, magnesium, iodine, potassium, copper, zinc, phosphorus, manganese, chromium, selenium, and molybdenum.

15. The combinatorial therapy of claim 10 wherein the citrus bioflavonoids are in concentrate form and include naringen, hesperidin and narirutin.

16. The combinatorial therapy of claim 10 wherein the fruit ingredient, the vegetable ingredient and the herbal ingredient are present in a ratio of 3.5:1:1.