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Kyle Lapham Mark N. Kvale Jue Lin Sheryl Connell Lisa A. Croen Brad P. Dispensa Lynn Fang Stephanie Hesselson Thomas J. Hoffmann Carlos Iribarren Eric Jorgenson Lawrence H. Kushi Dana Ludwig Tetsuya Matsuguchi William B. McGuire Sunita Miles Charles P. Quesenberry Jr. Sarah Rowell Marianne Sadler Lori C. Sakoda David Smethurst Carol P. Somkin Stephen K. Van Den Eeden Lawrence Walter Rachel A. Whitmer Pui-Yan Kwok Neil Risch Catherine Schaefer Elizabeth H. Blackburn 《Genetics》2015,200(4):1061-1072
The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis. 相似文献
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Seong Min Lee Erin M. Riley Mark B. Meyer Nancy A. Benkusky Lori A. Plum Hector F. DeLuca J. Wesley Pike 《The Journal of biological chemistry》2015,290(29):18199-18215
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) plays an integral role in calcium homeostasis in higher organisms through its actions in the intestine, kidney, and skeleton. Interestingly, although several intestinal genes are known to play a contributory role in calcium homeostasis, the entire caste of key components remains to be identified. To examine this issue, Cyp27b1 null mice on either a normal or a high calcium/phosphate-containing rescue diet were treated with vehicle or 1,25(OH)2D3 and evaluated 6 h later. RNA samples from the duodena were then subjected to RNA sequence analysis, and the data were analyzed bioinformatically. 1,25(OH)2D3 altered expression of large collections of genes in animals under either dietary condition. 45 genes were found common to both 1,25(OH)2D3-treated groups and were composed of genes previously linked to intestinal calcium uptake, including S100g, Trpv6, Atp2b1, and Cldn2 as well as others. An additional distinct network of 56 genes was regulated exclusively by diet. We then conducted a ChIP sequence analysis of binding sites for the vitamin D receptor (VDR) across the proximal intestine in vitamin D-sufficient normal mice treated with vehicle or 1,25(OH)2D3. The residual VDR cistrome was composed of 4617 sites, which was increased almost 4-fold following hormone treatment. Interestingly, the majority of the genes regulated by 1,25(OH)2D3 in each diet group as well as those found in common in both groups contained frequent VDR sites that likely regulated their expression. This study revealed a global network of genes in the intestine that both represent direct targets of vitamin D action in mice and are involved in calcium absorption. 相似文献
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Wu SC Yoon D Chin J van Kirk K Seethala R Golla R He B Harrity T Kunselman LK Morgan NN Ponticiello RP Taylor JR Zebo R Harper TW Li W Wang M Zhang L Sleczka BG Nayeem A Sheriff S Camac DM Morin PE Everlof JG Li YX Ferraro CA Kieltyka K Shou W Vath MB Zvyaga TA Gordon DA Robl JA 《Bioorganic & medicinal chemistry letters》2011,21(22):6693-6698
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads. 相似文献
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Rodriguez D Ramesh C Henson LH Wilmeth L Bryant BK Kadavakollu S Hirsch R Montoya J Howell PR George JM Alexander D Johnson DL Arterburn JB Shuster CB 《Bioorganic & medicinal chemistry》2011,19(18):5446-5453
Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-Trityl-l-cysteine is an allosteric inhibitor of vertebrate Kinesin Spindle Protein (KSP) that has generated considerable interest due to its anti-cancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as anti-tumor agents. 相似文献
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