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| | + | [[Team:Rice_University/OUR TEAM|OUR TEAM]] ::: [[Team:Rice_University|SUMMARY]] ::: [[Team:Rice_University/BACKGROUND|BACKGROUND]] ::: |
| | + | [[Team:Rice_University/STRATEGY|STRATEGY]] ::: [[Team:Rice_University/CONSTRUCTS|CONSTRUCTS]] ::: [[Team:Rice_University/RESULTS|RESULTS]] ::: [[Team:Rice_University/CONCLUSIONS|ONGOING WORK]] |
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| - | <!--- The Mission, Experiments --->
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| - | == '''Welcome to Rice University's 2008 iGEM wiki page.''' == | + | |
| - | Our project for this year is BIOBEER, where we are genetically engineering the biosynthetic pathway for resveratrol production into a brewing yeast strain. Resveratrol has been shown to have a plethora of health benefits, including anti-cancer and anti-viral activity, cardio- and neuro-protective effects, modulation of diabetes, and anti-aging effects. Although research has been done previously to produce resveratrol in various organisms, no one to date has developed a yeast strain able to synthesize resveratrol in a ''de novo'' manner. We are going one step further, characterizing resveratrol production during anaerobic fermentation with the intent of creating a beer that contains all the health benefits of wine. Get ready for resveratrol in a fizzy ready-to-consume beverage!
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| - | == '''BioBeer: Producing Resveratrol During Beer Fermentation''' == | + | {|align="justify" style="background-color:#FFFFFF;text-indent: 15pt;text-align:justify" cellpadding="30" width="90%" |
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| | + | Resveratrol, a phytochemical in plants, has been implicated as a natural product that extends lifespan and prevents cancer, coronary disease and neurodegenerative maladies. Unfortunately, resveratrol is only present at appreciable levels in a small number of foods, such as red wine, peanuts, and blueberries. To create an alternative source for resveratrol consumption, we are introducing a biosynthetic pathway for this compound into a brewing strain of yeast and examining whether this strain can be engineered to produce resveratrol during beer fermentation. Given the high worldwide consumption of beer and the low cost of production, unfiltered beer brewed using our genetically modified yeast should provide a cost-effective source of pharmacologically-active resveratrol. This engineering approach should be useful for cheap biosynthesis of other oxygen-sensitive prophylactics. |
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| - | [[Image:trans-resveratrol.jpg|right|frame|none|trans-Resveratrol]]
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| - | === '''Resveratrol''' ===
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| - | :* First identified as the active component in ''C. quinquangulata'' (cinnamon) extract responsible for anti-inflammatory properties. <BR>
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| - | :* Normally used as a defense mechanism in plants in response to fungal pathogens and UV irradiation. <BR>
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| - | :* Main source in human diet is red wine, but significant amounts are also found in grape juice, peanuts, cranberry juice, and other sources.
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| - | :* There is a tremendous interest in the potential of resveratrol for various health benefits. A PubMed search for 'resveratrol' returns '''2,470''' scientific articles.
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| - | ==='''Resveratrol and Yeast''' ===
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| - | [[Image:RSVYeast.jpg|left|thumb|200px|Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.]]
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| - | :* Resveratrol has been extensively investigated in the Saccharomyces cerevesiae model system. In August 2003, Sinclair and Scherer reported 70% increase in yeast lifespan after induction with 10uM resveratrol.
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| - | :*"In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2, a member of the conserved sirtuin family of NAD+-dependent protein deacetylases2, 3, 4, 5, 6. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan7, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53."
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| - | [[Image:RSV-health.jpg|left|thumb|300px|Resveratrol has been shown to provide a wealth of health benefits.]]
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| - | === '''Health Benefits of Resveratrol''' ===
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| - | :* '''Improved cardiovascular function''': resveratrol has been shown to have cardioprotective effects such as the suppression of atherosclerosis, inhibition of platelet aggregation, vasorelaxation promotion, and modulation of triglyceride blood levels, in a wide variety of ''in vitro'' and ''in vivo'' models [1-4].
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| - | :* '''Inhibition of carcinogenesis''': one well-documented effect of resveratrol is the ability to induce cell death specifically in cancerous cells. This property of resveratrol has been shown for a wide variety of cancers, including colon cancer [5-7], pancreatic cancer [8], prostate cancer [9,10], breast cancer [11,12], and skin cancer [13,14]. In fact, several phase I human clinical trials are investigating the administration of resveratrol as a cancer therapy [15,16]
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| - | :* '''Upregulates the antioxidant systems of cells''', such as SuperOxide Dismutase and glutathione, and these cells are protected against oxidative damage [16,17].
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| - | :* '''Resveratrol decreases several modes of inflammation''' [18-21].
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| - | :* '''Maintenance of neural pathways''': mouse models of Alzheimers and Parkinsons demonstrate the potential of resveratrol as a neuroprotective agent in degenerative neural diseases [22,23]. Experiments with rats, mice, and gerbils show that resveratrol administration protects against brain damage following ischemic stroke [24-26].
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| - | :* '''Improves insulin sensitivity''': resveratrol has been shown as a potent therapeutic for type 2 diabetes [27]. Pharmaceuticals based on resveratrol-like compounds for the treatment of diabetes are currently in Phase I clinical trials [28].
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| - | :* '''Mimics caloric restriction''' in mammals and is '''proven to extend lifespans''' in invertebrates [29,30], a fish model [31] and is shown to reduce the genetic changes associated with aging in a mammalian mouse model [4,32].
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| - | [[Image:brewing.jpg|left]]
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| - | Why resveratrol in beer? <BR>
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| - | -Beer made up 85.8% of all alcoholic beverage consumption (in total volume) in 2005. <BR>
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| - | -->Annual per capita consumption of Beer (2005) = ~20 gallons <BR>
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| - | -->Annual per capita consumption of Wine (2005) = ~2.5 gallons <BR>
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| - | -If resveratrol can be produced during fermentation, it provides an additional health benefit at no additional cost. <BR>
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| - | -->The resveratrol is produced in a ready-to-consume format! <BR>
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| - | -->Dark and anaerobic conditions required for fermentation improve resveratrol stability.
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| - | ==='''References''' ===
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| - | 1: Samuel SM, et al. Akt/FOXO3a/SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity. J Agric Food Chem. 2008 Oct 22;56(20):9692-8. Epub 2008 Oct 1. PMID: 18826227 [PubMed - in process].
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| - | 2: Hwang JT, et al. Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac
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| - | muscle cells.
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| - | Genes Nutr. 2008 Feb;2(4):323-6.
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| - | PMID: 18850225 [PubMed - in process]
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| - | 3: Gresele P, et al. Resveratrol, at concentrations attainable with moderate wine consumption,
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| - | stimulates human platelet nitric oxide production.
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| - | J Nutr. 2008 Sep;138(9):1602-8.
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| - | PMID: 18716157 [PubMed - indexed for MEDLINE]
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| - | 4: Barger JL, et al. A low dose of dietary resveratrol partially mimics caloric restriction and
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| - | retards aging parameters in mice.
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| - | PLoS ONE. 2008 Jun 4;3(6):e2264.
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| - | PMID: 18523577 [PubMed - indexed for MEDLINE]
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| - | 5: Juan ME, et al. Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells.
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| - | J Agric Food Chem. 2008 Jun 25;56(12):4813-8. Epub 2008 Jun 4.
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| - | PMID: 18522405 [PubMed - indexed for MEDLINE]
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| - | 6: Saiko P, et al. Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29
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| - | human colon cancer cells: inhibition of ribonucleotide reductase activity.
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| - | Oncol Rep. 2008 Jun;19(6):1621-6.
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| - | PMID: 18497974 [PubMed - indexed for MEDLINE]
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| - | 7: Marel AK, et al. Inhibitory effects of trans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells.
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| - | Mol Nutr Food Res. 2008 May;52(5):538-48.
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| - | PMID: 18384089 [PubMed - indexed for MEDLINE]
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| - | 8: Bernhaus A, et al. Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells. Invest New Drugs. 2008 Oct 8. [Epub ahead of print]
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| - | PMID: 18841326 [PubMed - as supplied by publisher]
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| - | 9: Seeni A, et al. Suppression of Prostate Cancer Growth by Resveratrol in The Transgenic Rat for Adenocarcinoma of Prostate (TRAP) Model.
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| - | Asian Pac J Cancer Prev. 2008 Jan-Mar;9(1):7-14.
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| - | PMID: 18439064 [PubMed - in process]
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| - | 10: Horvath Z, et al. Novel resveratrol derivatives induce apoptosis and cause cell cycle arrest in prostate cancer cell lines.
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| - | Anticancer Res. 2007 Sep-Oct;27(5A):3459-64.
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| - | PMID: 17970095 [PubMed - indexed for MEDLINE]
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| - | 11: Filomeni G, et al. trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways.
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| - | Genes Nutr. 2007 Dec;2(3):295-305. Epub 2007 Oct 18.
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| - | PMID: 18850184 [PubMed - in process]
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| - | 12: Schlachterman A, et al. Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model.
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| - | Transl Oncol. 2008 Mar;1(1):19-27.
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| - | PMID: 18607509 [PubMed - in process]
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| - | 13: Jang M, Cai L, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.
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| - | Science. 1997 Jan 10;275(5297):218-20.
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| - | PMID: 8985016 [PubMed - indexed for MEDLINE]
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| - | 14: van Ginkel PR, et al. Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.
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| - | Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1299-306.
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| - | PMID: 18385041 [PubMed - indexed for MEDLINE]
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| - | 15: http://www.clinicaltrials.gov/ct/show/NCT00256334
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| - | 16: http://www.cancer.gov/clinicaltrials/CCUM-2004-0535
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| - | 17: Ellen L. Robb, et al. Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD, Biocehm and Biophys Res Comm, 2008
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| - | 18: Kode A, et al. (2007). "Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells". Am J Physiol Lung Cell Mol Physiol.. doi:10.1152 (inactive 2008-06-20). PMID 18162601.
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| - | 19: Venkatachalam K, et al. Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.
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| - | Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2078-87. Epub 2008 Feb 29.
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| - | PMID: 18310510 [PubMed - indexed for MEDLINE]
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| - | 20: Zhu J, et al. Anti-inflammatory effect of resveratrol on TNF-alpha-induced MCP-1 expression in adipocytes.
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| - | Biochem Biophys Res Commun. 2008 May 2;369(2):471-7. Epub 2008 Feb 20.
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| - | PMID: 18291098 [PubMed - indexed for MEDLINE]
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| - | 21: Kennedy A, et al. Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol.
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| - | J Lipid Res. 2008 Sep 5. [Epub ahead of print]
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| - | PMID: 18776171 [PubMed - as supplied by publisher]
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| - | 22: Kim D, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.
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| - | EMBO J. 2007 Jul 11;26(13):3169-79. Epub 2007 Jun 21.
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| - | PMID: 17581637 [PubMed - indexed for MEDLINE]
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| - | 23: Jin F, et al. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats.
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| - | Eur J Pharmacol. 2008 Oct 10. [Epub ahead of print]
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| - | PMID: 18940189 [PubMed - as supplied by publisher]
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| - | 24: Sinha K, et al. Protective effect of resveratrol against oxidative stress in middle cerebral
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| - | artery occlusion model of stroke in rats.
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| - | Life Sci. 2002 Jun 28;71(6):655-65.
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| - | PMID: 12072154 [PubMed - indexed for MEDLINE]
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| - | 25: Inoue H, et al. Brain protection by resveratrol and fenofibrate against stroke requires
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| - | peroxisome proliferator-activated receptor alpha in mice.
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| - | Neurosci Lett. 2003 Dec 11;352(3):203-6.
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| - | PMID: 14625020 [PubMed - indexed for MEDLINE]
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| - | 26: Wang Q, et al. Resveratrol protects against global cerebral ischemic injury in gerbils.
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| - | Brain Res. 2002 Dec 27;958(2):439-47.
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| - | PMID: 12470882 [PubMed - indexed for MEDLINE]
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| - | 27: Milne JC, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
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| - | Nature. 2007 Nov 29;450(7170):712-6.
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| - | PMID: 18046409 [PubMed - indexed for MEDLINE]
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| - | 28: http://www.sirtrispharma.com/pipeline-SRT501.html
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| - | 29: Howitz KT, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
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| - | Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24.
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| - | PMID: 12939617 [PubMed - indexed for MEDLINE]
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| - | 30: Wood JG, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
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| - | Nature. 2004 Aug 5;430(7000):686-9.
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| - | PMID: 15254550 [PubMed - indexed for MEDLINE]
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| - | 31: Valenzano DR, et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.
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| - | Curr Biol. 2006 Feb 7;16(3):296-300.
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| - | PMID: 16461283 [PubMed - indexed for MEDLINE]
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| - | 32: Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1.
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| - | PMID: 17086191 [PubMed - indexed for MEDLINE]
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| - | <BR><BR><BR>
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| - | == '''The Rice 2008 Synthetic BiOWLogists''' ==
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| - | [[Image:iGEM-2008-Splash.jpg|400px|right]]
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| - | === Special Acknowledgements ===
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| - | === Media ===
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| - | [[TEST PAGE]]
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| - | [[Team:Rice_University/TEST PAGE|TEST-PAGE]]
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| - | {| style="color:#1b2c8a;background-color:#0c6;" cellpadding="3" cellspacing="1" border="1" bordercolor="#fff" width="62%" align="center"
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| - | !align="center"|[[Team:Rice_University|Home]]
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| - | !align="center"|[[Team:Rice_University/Team|The Team]]
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| - | !align="center"|[[Team:Rice_University/Project|The Project]]
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| - | !align="center"|[[Team:Rice_University/Parts|Parts Submitted to the Registry]]
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| - | !align="center"|[[Team:Rice_University/Notebook|Notebook]]
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