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排序方式: 共有451条查询结果,搜索用时 15 毫秒
121.
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
122.
Hoischen A van Bon BW Rodríguez-Santiago B Gilissen C Vissers LE de Vries P Janssen I van Lier B Hastings R Smithson SF Newbury-Ecob R Kjaergaard S Goodship J McGowan R Bartholdi D Rauch A Peippo M Cobben JM Wieczorek D Gillessen-Kaesbach G Veltman JA Brunner HG de Vries BB 《Nature genetics》2011,43(8):729-731
Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous. 相似文献
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124.
Rosendahl J Witt H Szmola R Bhatia E Ozsvári B Landt O Schulz HU Gress TM Pfützer R Löhr M Kovacs P Blüher M Stumvoll M Choudhuri G Hegyi P te Morsche RH Drenth JP Truninger K Macek M Puhl G Witt U Schmidt H Büning C Ockenga J Kage A Groneberg DA Nickel R Berg T Wiedenmann B Bödeker H Keim V Mössner J Teich N Sahin-Tóth M 《Nature genetics》2008,40(1):78-82
Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. 相似文献
125.
The conjugation of arginine to proteins is a part of the N-end rule pathway of protein degradation. Three amino (N)-terminal residues--aspartate, glutamate and cysteine--are arginylated by ATE1-encoded arginyl-transferases. Here we report that oxidation of N-terminal cysteine is essential for its arginylation. The in vivo oxidation of N-terminal cysteine, before its arginylation, is shown to require nitric oxide. We reconstituted this process in vitro as well. The levels of regulatory proteins bearing N-terminal cysteine, such as RGS4, RGS5 and RGS16, are greatly increased in mouse ATE1-/- embryos, which lack arginylation. Stabilization of these proteins, the first physiological substrates of mammalian N-end rule pathway, may underlie cardiovascular defects in ATE1-/- embryos. Our findings identify the N-end rule pathway as a new nitric oxide sensor that functions through its ability to destroy specific regulatory proteins bearing N-terminal cysteine, at rates controlled by nitric oxide and apparently by oxygen as well. 相似文献
126.
An all-silicon Raman laser 总被引:4,自引:0,他引:4
The possibility of light generation and/or amplification in silicon has attracted a great deal of attention for silicon-based optoelectronic applications owing to the potential for forming inexpensive, monolithic integrated optical components. Because of its indirect bandgap, bulk silicon shows very inefficient band-to-band radiative electron-hole recombination. Light emission in silicon has thus focused on the use of silicon engineered materials such as nanocrystals, Si/SiO2 superlattices, erbium-doped silicon-rich oxides, surface-textured bulk silicon and Si/SiGe quantum cascade structures. Stimulated Raman scattering (SRS) has recently been demonstrated as a mechanism to generate optical gain in planar silicon waveguide structures. In fact, net optical gain in the range 2-11 dB due to SRS has been reported in centimetre-sized silicon waveguides using pulsed pumping. Recently, a lasing experiment involving silicon as the gain medium by way of SRS was reported, where the ring laser cavity was formed by an 8-m-long optical fibre. Here we report the experimental demonstration of Raman lasing in a compact, all-silicon, waveguide cavity on a single silicon chip. This demonstration represents an important step towards producing practical continuous-wave optical amplifiers and lasers that could be integrated with other optoelectronic components onto CMOS-compatible silicon chips. 相似文献
127.
This paper suggests that the metaphors of experimentation and the laboratory are applicable when positioning action research vis-à-vis more conventional business school research. Following on from three different action research projects in a large multinational pharmaceutical company, the paper argues that an action researcher can never construct a sheltered environment wherein certain qualities of nature can be isolated, purified, and enhanced, but must always undertake research activities in vivo, in real life organizational setting. Still, the metaphor of the laboratory is applicable because it enables for an understanding of how what Ian Hacking calls interventions in the hard sciences share certain characteristics with the action research activities. When action researchers intervene within organizations, the activities are always experimental in nature, i.e., they can never be fully predicted or anticipated, but are initial steps in an emergent process of organizational change. 相似文献
128.
Lin Y Böker A He J Sill K Xiang H Abetz C Li X Wang J Emrick T Long S Wang Q Balazs A Russell TP 《Nature》2005,434(7029):55-59
The organization of inorganic nanostructures within self-assembled organic or biological templates is receiving the attention of scientists interested in developing functional hybrid materials. Previous efforts have concentrated on using such scaffolds to spatially arrange nanoscopic elements as a strategy for tailoring the electrical, magnetic or photonic properties of the material. Recent theoretical arguments have suggested that synergistic interactions between self-organizing particles and a self-assembling matrix material can lead to hierarchically ordered structures. Here we show that mixtures of diblock copolymers and either cadmium selenide- or ferritin-based nanoparticles exhibit cooperative, coupled self-assembly on the nanoscale. In thin films, the copolymers assemble into cylindrical domains, which dictate the spatial distribution of the nanoparticles; segregation of the particles to the interfaces mediates interfacial interactions and orients the copolymer domains normal to the surface, even when one of the blocks is strongly attracted to the substrate. Organization of both the polymeric and particulate entities is thus achieved without the use of external fields, opening a simple and general route for fabrication of nanostructured materials with hierarchical order. 相似文献
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