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51.
Identification of ten loci associated with height highlights new biological pathways in human growth 总被引:1,自引:0,他引:1
Lettre G Jackson AU Gieger C Schumacher FR Berndt SI Sanna S Eyheramendy S Voight BF Butler JL Guiducci C Illig T Hackett R Heid IM Jacobs KB Lyssenko V Uda M;Diabetes Genetics Initiative;FUSION;KORA;Prostate Lung Colorectal Ovarian Cancer Screening Trial;Nurses' Health Study;SardiNIA Boehnke M Chanock SJ Groop LC Hu FB Isomaa B Kraft P Peltonen L Salomaa V Schlessinger D Hunter DJ Hayes RB Abecasis GR Wichmann HE Mohlke KL Hirschhorn JN 《Nature genetics》2008,40(5):584-591
Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait. 相似文献
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Space geodetic evidence for rapid strain rates in the New Madrid seismic zone of central USA 总被引:1,自引:0,他引:1
In the winter of 1811-1812, near the town of New Madrid in the central United States and more than 2,000 km from the nearest plate boundary, three earthquakes within three months shook the entire eastern half of the country and liquefied the ground over distances far greater than any historic earthquake in North America. The origin and modern significance of these earthquakes, however, is highly contentious. Geological evidence demonstrates that liquefaction due to strong ground shaking, similar in scale to that generated by the New Madrid earthquakes, has occurred at least three and possibly four times in the past 2,000 years (refs 4-6), consistent with recurrence statistics derived from regional seismicity. Here we show direct evidence for rapid strain rates in the area determined from a continuously operated global positioning system (GPS) network. Rates of strain are of the order of 10(-7) per year, comparable in magnitude to those across active plate boundaries, and are consistent with known active faults within the region. These results have significant implications for the definition of seismic hazard and for processes that drive intraplate seismicity. 相似文献
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Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1 总被引:26,自引:0,他引:26
Li YM Xu M Lai MT Huang Q Castro JL DiMuzio-Mower J Harrison T Lellis C Nadin A Neduvelil JG Register RB Sardana MK Shearman MS Smith AL Shi XP Yin KC Shafer JA Gardell SJ 《Nature》2000,405(6787):689-694
Cleavage of amyloid precursor protein (APP) by the beta- and gamma-secretases generates the amino and carboxy termini, respectively, of the A beta amyloidogenic peptides A beta40 and A beta42--the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of gamma-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease increase the production of A beta42 (refs 4-6), the more amyloidogenic peptide; gamma-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of gamma-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a gamma-secretase cofactor, or helps to colocalize gamma-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent gamma-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen. 相似文献
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Receptor binding, internalization, and retrograde transport of neurotrophic factors 总被引:15,自引:0,他引:15
This review deals with the receptor interactions of neurotrophic factors, focusing on the neurotrophins of the nerve growth
factor (NGF) family, the glial cell derived neurotrophic factor (GDNF) family, and the ciliary neurotrophic factor (CNTF)
family. The finding that two proteins, p75NTR and Trk, act as receptors for NGF in neurons generated the discovery of other neurotrophic factors/receptor families and
has enhanced our understanding of the development, survival, regeneration, and degeneration of the nervous system. The kinetics
of binding, the structure of the ligand-receptor complex, and the mechanism of retrograde transport of the neurotrophins are
discussed in detail and compared to information available on the GDNF and CNTF families. Each neurotrophic factor family,
i.e., NGF, GDNF, and CNTF, has a set of receptors with specificity for individual members of the family and a common receptor
without member specificity that, in some families, generates the cellular signal and retrograde transport. 相似文献
59.
Chapman HN Fromme P Barty A White TA Kirian RA Aquila A Hunter MS Schulz J DePonte DP Weierstall U Doak RB Maia FR Martin AV Schlichting I Lomb L Coppola N Shoeman RL Epp SW Hartmann R Rolles D Rudenko A Foucar L Kimmel N Weidenspointner G Holl P Liang M Barthelmess M Caleman C Boutet S Bogan MJ Krzywinski J Bostedt C Bajt S Gumprecht L Rudek B Erk B Schmidt C Hömke A Reich C Pietschner D Strüder L Hauser G Gorke H Ullrich J Herrmann S Schaller G Schopper F Soltau H Kühnel KU Messerschmidt M 《Nature》2011,470(7332):73-77
X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (~200?nm to 2?μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage. 相似文献
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