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排序方式: 共有10000条查询结果,搜索用时 11 毫秒
171.
Rogaeva E Meng Y Lee JH Gu Y Kawarai T Zou F Katayama T Baldwin CT Cheng R Hasegawa H Chen F Shibata N Lunetta KL Pardossi-Piquard R Bohm C Wakutani Y Cupples LA Cuenco KT Green RC Pinessi L Rainero I Sorbi S Bruni A Duara R Friedland RP Inzelberg R Hampe W Bujo H Song YQ Andersen OM Willnow TE Graff-Radford N Petersen RC Dickson D Der SD Fraser PE Schmitt-Ulms G Younkin S Mayeux R Farrer LA St George-Hyslop P 《Nature genetics》2007,39(2):168-177
The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease. 相似文献
172.
Saenz HL Engel P Stoeckli MC Lanz C Raddatz G Vayssier-Taussat M Birtles R Schuster SC Dehio C 《Nature genetics》2007,39(12):1469-1476
The bacterial genus Bartonella comprises 21 pathogens causing characteristic intraerythrocytic infections. Bartonella bacilliformis is a severe pathogen representing an ancestral lineage, whereas the other species are benign pathogens that evolved by radial speciation. Here, we have used comparative and functional genomics to infer pathogenicity genes specific to the radiating lineage, and we suggest that these genes may have facilitated adaptation to the host environment. We determined the complete genome sequence of Bartonella tribocorum by shotgun sequencing and functionally identified 97 pathogenicity genes by signature-tagged mutagenesis. Eighty-one pathogenicity genes belong to the core genome (1,097 genes) of the radiating lineage inferred from genome comparison of B. tribocorum, Bartonella henselae and Bartonella quintana. Sixty-six pathogenicity genes are present in B. bacilliformis, and one has been lost by deletion. The 14 pathogenicity genes specific for the radiating lineage encode two laterally acquired type IV secretion systems, suggesting that these systems have a role in host adaptability. 相似文献
173.
Maller JB Fagerness JA Reynolds RC Neale BM Daly MJ Seddon JM 《Nature genetics》2007,39(10):1200-1201
The association of variants in complement factors H and B with age-related macular degeneration has led to more intense genetic and functional analysis of the complement pathway. We identify a nonsynonymous coding change in complement factor 3 that is strongly associated with risk of age-related macular degeneration in a large case-control sample. 相似文献
174.
MacArthur DG Seto JT Raftery JM Quinlan KG Huttley GA Hook JW Lemckert FA Kee AJ Edwards MR Berman Y Hardeman EC Gunning PW Easteal S Yang N North KN 《Nature genetics》2007,39(10):1261-1265
More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein alpha-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that alpha-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of alpha-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism. 相似文献
175.
Gout AM;ADPKD Gene Variant Consortium Ravine D Harris PC Rossetti S Peters D Breuning M Henske EP Koizumi A Inoue S Shimizu Y Thongnoppakhun W Yenchitsomanus PT Deltas C Sandford R Torra R Turco AE Jeffery S Fontes M Somlo S Furu LM Smulders YM Mercier B Ferec C Burtey S Pei Y Kalaydjieva L Bogdanova N McCluskey M Geon LJ Wouters CH Reiterova J Stekrová J San Millan JL Aguiari G Del Senno L 《Nature genetics》2007,39(4):427-428
176.
Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral
blue/black freckling [1–9]. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency
of PJS [4]. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal
cancers. In 1997, linkage studies mapped PJS to chromosome 19p [10, 11], and subsequently a serine/threonine kinase gene defect
(LKB1) was noted in a majority of PJS cases [12, 13]. A phenotypically similar syndrome has been produced in an LKB1 mouse
knockout model [14–18]. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci [19–22].
The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis.
Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage
the magnitude of cancer risk for affected individuals.
Received 20 February 2006; received after revision 5 May 2006; accepted 15 June 2006 相似文献
177.
Site- and state-specific lysine methylation of histones is catalyzed by a family of proteins that contain the evolutionarily
conserved SET domain and plays a fundamental role in epigenetic regulation of gene activation and silencing in all eukaryotes.
The recently determined three-dimensional structures of the SET domains from chromosomal proteins reveal that the core SET
domain structure contains a two-domain architecture, consisting of a conserved anti-parallel β-barrel and a structurally variable
insert that surround a unusual knot-like structure that comprises the enzyme active site. These structures of the SET domains,
either in the free state or when bound to cofactor S-adenosyl-L-homocysteine and/or histone peptide, mimicking an enzyme/cofactor/substrate complex, further yield the structural insights
into the molecular basis of the substrate specificity, methylation multiplicity and the catalytic mechanism of histone lysine
methylation.
Received 10 June 2006; accepted 22 August 2006 相似文献
178.
Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation
and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human
cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute
to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of
an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target,
and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft
models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently
being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight
some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer.
Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006 相似文献
179.
In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that
control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition,
is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of
neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted
therapeutic approach to cancer.
Received 30 November 2005; received after revision 7 February 2005; accepted 8 February 2006 相似文献
180.
On the basis of evidence collected from the literature, we propose a general model by which protein kinase (PK) A and the
different PKC isoforms can inversely affect cell growth. Molecular switches, which are able to direct the signal towards antiproliferative
or mitogenic pathways, are the different isoforms of Raf and PKC. Conflicting data are also reported and discussed in an attempt
to reconcile them.
Received 10 November 2005; received after revision 28 December 2005; accepted 3 January 2006 相似文献