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231.
Arron JR Winslow MM Polleri A Chang CP Wu H Gao X Neilson JR Chen L Heit JJ Kim SK Yamasaki N Miyakawa T Francke U Graef IA Crabtree GR 《Nature》2006,441(7093):595-600
232.
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis 总被引:3,自引:0,他引:3
He C Bassik MC Moresi V Sun K Wei Y Zou Z An Z Loh J Fisher J Sun Q Korsmeyer S Packer M May HI Hill JA Virgin HW Gilpin C Xiao G Bassel-Duby R Scherer PE Levine B 《Nature》2012,481(7382):511-515
Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise. 相似文献
233.
Solt LA Wang Y Banerjee S Hughes T Kojetin DJ Lundasen T Shin Y Liu J Cameron MD Noel R Yoo SH Takahashi JS Butler AA Kamenecka TM Burris TP 《Nature》2012,485(7396):62-68
Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases. 相似文献
234.
235.
Ngo VN Young RM Schmitz R Jhavar S Xiao W Lim KH Kohlhammer H Xu W Yang Y Zhao H Shaffer AL Romesser P Wright G Powell J Rosenwald A Muller-Hermelink HK Ott G Gascoyne RD Connors JM Rimsza LM Campo E Jaffe ES Delabie J Smeland EB Fisher RI Braziel RM Tubbs RR Cook JR Weisenburger DD Chan WC Staudt LM 《Nature》2011,470(7332):115-119
The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations. 相似文献
236.
The developmental transcriptome of Drosophila melanogaster 总被引:2,自引:0,他引:2
Graveley BR Brooks AN Carlson JW Duff MO Landolin JM Yang L Artieri CG van Baren MJ Boley N Booth BW Brown JB Cherbas L Davis CA Dobin A Li R Lin W Malone JH Mattiuzzo NR Miller D Sturgill D Tuch BB Zaleski C Zhang D Blanchette M Dudoit S Eads B Green RE Hammonds A Jiang L Kapranov P Langton L Perrimon N Sandler JE Wan KH Willingham A Zhang Y Zou Y Andrews J Bickel PJ Brenner SE Brent MR Cherbas P Gingeras TR Hoskins RA Kaufman TC Oliver B Celniker SE 《Nature》2011,471(7339):473-479
237.
Wang Z Klipfell E Bennett BJ Koeth R Levison BS Dugar B Feldstein AE Britt EB Fu X Chung YM Wu Y Schauer P Smith JD Allayee H Tang WH DiDonato JA Lusis AJ Hazen SL 《Nature》2011,472(7341):57-63
Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease. 相似文献
238.
Villeda SA Luo J Mosher KI Zou B Britschgi M Bieri G Stan TM Fainberg N Ding Z Eggel A Lucin KM Czirr E Park JS Couillard-Després S Aigner L Li G Peskind ER Kaye JA Quinn JF Galasko DR Xie XS Rando TA Wyss-Coray T 《Nature》2011,477(7362):90-94
In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors. 相似文献
239.
Hinch AG Tandon A Patterson N Song Y Rohland N Palmer CD Chen GK Wang K Buxbaum SG Akylbekova EL Aldrich MC Ambrosone CB Amos C Bandera EV Berndt SI Bernstein L Blot WJ Bock CH Boerwinkle E Cai Q Caporaso N Casey G Cupples LA Deming SL Diver WR Divers J Fornage M Gillanders EM Glessner J Harris CC Hu JJ Ingles SA Isaacs W John EM Kao WH Keating B Kittles RA Kolonel LN Larkin E Le Marchand L McNeill LH Millikan RC Murphy A Musani S Neslund-Dudas C Nyante S Papanicolaou GJ Press MF Psaty BM 《Nature》2011,476(7359):170-175
Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P?value 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution. 相似文献
240.