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51.
Elizabeth S. Panke R. J. Reiter M. D. Rollag 《Cellular and molecular life sciences : CMLS》1979,35(10):1405-1406
Summary Peak melatonin levels which are normally present in male Syrian hamsters at 8 h after the onset of darkness in animals maintained under a lightdark cycle of 1410, were significantly decreased following the removal of the Harderian glands.Supported by NSF grant PCM 77-05734. 相似文献
52.
Alexander Negoda Elizabeth A. Cowley Yassine El Hiani Paul Linsdell 《Cellular and molecular life sciences : CMLS》2018,75(16):3027-3038
Cystic fibrosis can be treated by potentiators, drugs that interact directly with the cystic fibrosis transmembrane conductance regulator (CFTR) Cl? channel to increase its open probability. These substances likely target key conformational changes occurring during channel opening and closing, however, the molecular bases of these conformational changes, and their susceptibility to manipulation are poorly understood. We have used patch clamp recording to identify changes in the three-dimensional organization of the extracellularly accessible parts of the CFTR protein during channel opening and closing. State-dependent formation of both disulfide bonds and Cd2+ bridges occurred for pairs of cysteine side-chains introduced into the extreme extracellular ends of transmembrane helices (TMs) 1, 6, and 12. Between each of these three TMs, we found that both disulfide bonds and metal bridges formed preferentially or exclusively in the closed state and that these inter-TM cross-links stabilized the closed state. These results indicate that the extracellular ends of these TMs are close together when the channel is closed and that they separate from each other when the channel opens. These findings identify for the first time key conformational changes in the extracellular parts of the CFTR protein that can potentially be manipulated to control channel activity. 相似文献
53.
Speliotes EK Willer CJ Berndt SI Monda KL Thorleifsson G Jackson AU Lango Allen H Lindgren CM Luan J Mägi R Randall JC Vedantam S Winkler TW Qi L Workalemahu T Heid IM Steinthorsdottir V Stringham HM Weedon MN Wheeler E Wood AR Ferreira T Weyant RJ Segrè AV Estrada K Liang L Nemesh J Park JH Gustafsson S Kilpeläinen TO Yang J Bouatia-Naji N Esko T Feitosa MF Kutalik Z Mangino M Raychaudhuri S Scherag A Smith AV Welch R Zhao JH Aben KK Absher DM Amin N Dixon AL Fisher E Glazer NL Goddard ME 《Nature genetics》2010,42(11):937-948
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. 相似文献
54.
Guo DC Pannu H Tran-Fadulu V Papke CL Yu RK Avidan N Bourgeois S Estrera AL Safi HJ Sparks E Amor D Ades L McConnell V Willoughby CE Abuelo D Willing M Lewis RA Kim DH Scherer S Tung PP Ahn C Buja LM Raman CS Shete SS Milewicz DM 《Nature genetics》2007,39(12):1488-1493
The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta. 相似文献
55.
Mells GF Floyd JA Morley KI Cordell HJ Franklin CS Shin SY Heneghan MA Neuberger JM Donaldson PT Day DB Ducker SJ Muriithi AW Wheater EF Hammond CJ Dawwas MF;UK PBC Consortium;Wellcome Trust Case Control Consortium Jones DE Peltonen L Alexander GJ Sandford RN Anderson CA 《Nature genetics》2011,43(4):329-332
In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10??) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC. 相似文献
56.
Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss 总被引:1,自引:0,他引:1
Klein CJ Botuyan MV Wu Y Ward CJ Nicholson GA Hammans S Hojo K Yamanishi H Karpf AR Wallace DC Simon M Lander C Boardman LA Cunningham JM Smith GE Litchy WJ Boes B Atkinson EJ Middha S B Dyck PJ Parisi JE Mer G Smith DI Dyck PJ 《Nature genetics》2011,43(6):595-600
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases. 相似文献
57.
Brown KM Macgregor S Montgomery GW Craig DW Zhao ZZ Iyadurai K Henders AK Homer N Campbell MJ Stark M Thomas S Schmid H Holland EA Gillanders EM Duffy DL Maskiell JA Jetann J Ferguson M Stephan DA Cust AE Whiteman D Green A Olsson H Puig S Ghiorzo P Hansson J Demenais F Goldstein AM Gruis NA Elder DE Bishop JN Kefford RF Giles GG Armstrong BK Aitken JF Hopper JL Martin NG Trent JM Mann GJ Hayward NK 《Nature genetics》2008,40(7):838-840
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases. 相似文献
58.
Creation of visible artificial optical emissions in the aurora by high-power radio waves 总被引:1,自引:0,他引:1
Generation of artificial light in the sky by means of high-power radio waves interacting with the ionospheric plasma has been envisaged since the early days of radio exploration of the upper atmosphere, with proposed applications ranging from regional night-time street lighting to atmospheric measurements. Weak optical emissions have been produced for decades in such ionospheric 'heating' experiments, where they serve as key indicators of electron acceleration, thermal heating, and other effects of incompletely understood wave-particle interactions in the plasma under conditions difficult to replicate in the laboratory. The extremely low intensities produced previously have, however, required sensitive instrumentation for detection, preventing applications beyond scientific research. Here we report observations of radio-induced optical emissions bright enough to be seen by the naked eye, and produced not in the quiet mid-latitude ionosphere, but in the midst of a pulsating natural aurora. This may open the door to visual applications of ionospheric heating technology or provide a way to probe the dynamics of the natural aurora and magnetosphere. 相似文献
59.
Apolipoprotein-mediated pathways of lipid antigen presentation 总被引:1,自引:0,他引:1
van den Elzen P Garg S León L Brigl M Leadbetter EA Gumperz JE Dascher CC Cheng TY Sacks FM Illarionov PA Besra GS Kent SC Moody DB Brenner MB 《Nature》2005,437(7060):906-910
Peptide antigens are presented to T cells by major histocompatibility complex (MHC) molecules, with endogenous peptides presented by MHC class I and exogenous peptides presented by MHC class II. In contrast to the MHC system, CD1 molecules bind lipid antigens that are presented at the antigen-presenting cell (APC) surface to lipid antigen-reactive T cells. Because CD1 molecules survey endocytic compartments, it is self-evident that they encounter antigens from extracellular sources. However, the mechanisms of exogenous lipid antigen delivery to CD1-antigen-loading compartments are not known. Serum apolipoproteins are mediators of extracellular lipid transport for metabolic needs. Here we define the pathways mediating markedly efficient exogenous lipid antigen delivery by apolipoproteins to achieve T-cell activation. Apolipoprotein E binds lipid antigens and delivers them by receptor-mediated uptake into endosomal compartments containing CD1 in APCs. Apolipoprotein E mediates the presentation of serum-borne lipid antigens and can be secreted by APCs as a mechanism to survey the local environment to capture antigens or to transfer microbial lipids from infected cells to bystander APCs. Thus, the immune system has co-opted a component of lipid metabolism to develop immunological responses to lipid antigens. 相似文献
60.
Porco CC Baker E Barbara J Beurle K Brahic A Burns JA Charnoz S Cooper N Dawson DD Del Genio AD Denk T Dones L Dyudina U Evans MW Fussner S Giese B Grazier K Helfenstein P Ingersoll AP Jacobson RA Johnson TV McEwen A Murray CD Neukum G Owen WM Perry J Roatsch T Spitale J Squyres S Thomas P Tiscareno M Turtle EP Vasavada AR Veverka J Wagner R West R 《Nature》2005,434(7030):159-168
Titan, the largest moon of Saturn, is the only satellite in the Solar System with a substantial atmosphere. The atmosphere is poorly understood and obscures the surface, leading to intense speculation about Titan's nature. Here we present observations of Titan from the imaging science experiment onboard the Cassini spacecraft that address some of these issues. The images reveal intricate surface albedo features that suggest aeolian, tectonic and fluvial processes; they also show a few circular features that could be impact structures. These observations imply that substantial surface modification has occurred over Titan's history. We have not directly detected liquids on the surface to date. Convective clouds are found to be common near the south pole, and the motion of mid-latitude clouds consistently indicates eastward winds, from which we infer that the troposphere is rotating faster than the surface. A detached haze at an altitude of 500 km is 150-200 km higher than that observed by Voyager, and more tenuous haze layers are also resolved. 相似文献