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991.
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Franke A McGovern DP Barrett JC Wang K Radford-Smith GL Ahmad T Lees CW Balschun T Lee J Roberts R Anderson CA Bis JC Bumpstead S Ellinghaus D Festen EM Georges M Green T Haritunians T Jostins L Latiano A Mathew CG Montgomery GW Prescott NJ Raychaudhuri S Rotter JI Schumm P Sharma Y Simms LA Taylor KD Whiteman D Wijmenga C Baldassano RN Barclay M Bayless TM Brand S Büning C Cohen A Colombel JF Cottone M Stronati L Denson T De Vos M D'Inca R Dubinsky M Edwards C Florin T Franchimont D Gearry R 《Nature genetics》2010,42(12):1118-1125
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10??). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease. 相似文献
994.
Stuart PE Nair RP Ellinghaus E Ding J Tejasvi T Gudjonsson JE Li Y Weidinger S Eberlein B Gieger C Wichmann HE Kunz M Ike R Krueger GG Bowcock AM Mrowietz U Lim HW Voorhees JJ Abecasis GR Weichenthal M Franke A Rahman P Gladman DD Elder JT 《Nature genetics》2010,42(11):1000-1004
We carried out a meta-analysis of two recent psoriasis genome-wide association studies with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 × 10?11), one at FBXL19 (rs10782001, combined P = 9 × 10?1?) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 × 10??). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 × 10??; rs10782001, combined P = 4 × 10??; and rs12586317, combined P = 6 × 1??) and purely cutaneous psoriasis (rs4795067, combined P = 1 × 10??; rs10782001, combined P = 2 × 10??; and rs12586317, combined P = 1 × 10??). We also replicated a recently identified association signal near RNF114 (rs495337, combined P = 2 × 10??). 相似文献
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996.
The RNA-binding protein FCA is an abscisic acid receptor 总被引:2,自引:0,他引:2
The phytohormone abscisic acid (ABA) regulates various physiological processes in plants. The molecular mechanisms by which this is achieved are not fully understood. Genetic approaches have characterized several downstream components of ABA signalling, but a receptor for ABA has remained elusive. Although studies indicate that several ABA response genes encode RNA-binding or RNA-processing proteins, none has been found to be functional in binding ABA. Here we show that FCA, an RNA-binding protein involved in flowering, binds ABA with high affinity in an interaction that is stereospecific and follows receptor kinetics. The interaction between FCA and ABA has molecular effects on downstream events in the autonomous floral pathway and, consequently, on the ability of the plant to undergo transition to flowering. We further show that ABA binding exerts a direct control on the FCA-mediated processing of precursor messenger RNA. Our results indicate that FCA is an ABA receptor involved in RNA metabolism and in controlling flowering time. 相似文献
997.
Magnitude and timing of temperature change in the Indo-Pacific warm pool during deglaciation 总被引:27,自引:0,他引:27
Ocean-atmosphere interactions in the tropical Pacific region have a strong influence on global heat and water vapour transport and thus constitute an important component of the climate system. Changes in sea surface temperatures and convection in the tropical Indo-Pacific region are thought to be responsible for the interannual to decadal climate variability observed in extra-tropical regions, but the role of the tropics in climate changes on millennial and orbital timescales is less clear. Here we analyse oxygen isotopes and Mg/Ca ratios of foraminiferal shells from the Makassar strait in the heart of the Indo-Pacific warm pool, to obtain synchronous estimates of sea surface temperatures and ice volume. We find that sea surface temperatures increased by 3.5-4.0 degrees C during the last two glacial-interglacial transitions, synchronous with the global increase in atmospheric CO2 and Antarctic warming, but the temperature increase occurred 2,000-3,000 years before the Northern Hemisphere ice sheets melted. Our observations suggest that the tropical Pacific region plays an important role in driving glacial-interglacial cycles, possibly through a system similar to how El Ni?o/Southern Oscillation regulates the poleward flux of heat and water vapour. 相似文献
998.
A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes 总被引:23,自引:0,他引:23
999.
The 26S proteasome is responsible for most intracellular proteolysis in eukaryotes. Efficient substrate recognition relies on conjugation of substrates with multiple ubiquitin molecules and recognition of the polyubiquitin moiety by the 19S regulatory complex--a multisubunit assembly that is bound to either end of the cylindrical 20S proteasome core. Only unfolded proteins can pass through narrow axial channels into the central proteolytic chamber of the 20S core, so the attached polyubiquitin chain must be released to allow full translocation of the substrate polypeptide. Whereas unfolding is rate-limiting for the degradation of some substrates and appears to involve chaperone-like activities associated with the proteasome, the importance and mechanism of degradation-associated deubiquitination has remained unclear. Here we report that the POH1 (also known as Rpn11 in yeast) subunit of the 19S complex is responsible for substrate deubiquitination during proteasomal degradation. The inability to remove ubiquitin can be rate-limiting for degradation in vitro and is lethal to yeast. Unlike all other known deubiquitinating enzymes (DUBs) that are cysteine proteases, POH1 appears to be a Zn(2+)-dependent protease. 相似文献
1000.
Walker LM Huber M Doores KJ Falkowska E Pejchal R Julien JP Wang SK Ramos A Chan-Hui PY Moyle M Mitcham JL Hammond PW Olsen OA Phung P Fling S Wong CH Phogat S Wrin T Simek MD;Protocol G Principal Investigators Koff WC Wilson IA Burton DR Poignard P 《Nature》2011,477(7365):466-470
Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine. 相似文献