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排序方式: 共有196条查询结果,搜索用时 140 毫秒
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Willer CJ Sanna S Jackson AU Scuteri A Bonnycastle LL Clarke R Heath SC Timpson NJ Najjar SS Stringham HM Strait J Duren WL Maschio A Busonero F Mulas A Albai G Swift AJ Morken MA Narisu N Bennett D Parish S Shen H Galan P Meneton P Hercberg S Zelenika D Chen WM Li Y Scott LJ Scheet PA Sundvall J Watanabe RM Nagaraja R Ebrahim S Lawlor DA Ben-Shlomo Y Davey-Smith G Shuldiner AR Collins R Bergman RN Uda M Tuomilehto J Cao A Collins FS Lakatta E Lathrop GM Boehnke M Schlessinger D Mohlke KL 《Nature genetics》2008,40(2):161-169
To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls. 相似文献
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McCarroll SA Kuruvilla FG Korn JM Cawley S Nemesh J Wysoker A Shapero MH de Bakker PI Maller JB Kirby A Elliott AL Parkin M Hubbell E Webster T Mei R Veitch J Collins PJ Handsaker R Lincoln S Nizzari M Blume J Jones KW Rava R Daly MJ Gabriel SB Altshuler D 《Nature genetics》2008,40(10):1166-1174
Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.8 million genomic locations. By characterizing 270 HapMap samples, we developed a map of human CNV (at 2-kb breakpoint resolution) informed by integer genotypes for 1,320 copy number polymorphisms (CNPs) that segregate at an allele frequency >1%. More than 80% of the sequence in previously reported CNV regions fell outside our estimated CNV boundaries, indicating that large (>100 kb) CNVs affect much less of the genome than initially reported. Approximately 80% of observed copy number differences between pairs of individuals were due to common CNPs with an allele frequency >5%, and more than 99% derived from inheritance rather than new mutation. Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes. 相似文献
54.
In hyperalgesic states, observed commonly as a major symptom of tissue inflammation or after central or peripheral nerve injury, non-noxious stimuli produce pain and noxious stimuli are perceived as more painful than usual. The mechanisms underlying the generation of hyperalgesia are not known. In patients with causalgia (burning pain and severe hyperalgesia after a nerve injury) activation of sympathetic post-ganglionic neurones or application of noradrenaline to painful skin exacerbates pain and hyperalgesia while sympathectomy may afford complete relief. One suggestion is that noradrenaline released from sympathetic post-ganglionic neurons increases the discharge of damaged small-diameter afferents by a direct action on the primary afferents. Here we present a new model for noradrenaline-sensitive hyperalgesia and demonstrate that the site of action of noradrenaline is not on the primary afferents but rather is presynaptic on the sympathetic post-ganglionic terminals. 相似文献
55.
The author claims to have developed interactional expertise in gravitational wave physics without engaging with the mathematical or quantitative aspects of the subject. Is this possible? In other words, is it possible to understand the physical world at a high enough level to argue and make judgments about it without the corresponding mathematics? This question is empirically approached in three ways: (i) anecdotes about non-mathematical physicists are presented; (ii) the author undertakes a reflective reading of a passage of physics, first without going through the maths and then after engaging with it and discusses the difference between the experiences; (iii) the aforementioned exercise gives rise to a table of Levels of Understanding of mathematics, and physicists are asked about the level mathematical understanding they applied when they last read a paper. Each phase of empirical research suggests that mathematics is not as central to gaining an understanding of physics as it is often said to be. This does not mean that mathematics is not central to physics, merely that it is not essential for every physicist to be an accomplished mathematician, and that a division of labour model is adequate. This, in turn, suggests that a stream of undergraduate physics education with fewer mathematical hurdles should be developed, making it easier to train wider groups of people in physical science comprehension. 相似文献
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Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus 总被引:1,自引:0,他引:1
Nierman WC Pain A Anderson MJ Wortman JR Kim HS Arroyo J Berriman M Abe K Archer DB Bermejo C Bennett J Bowyer P Chen D Collins M Coulsen R Davies R Dyer PS Farman M Fedorova N Fedorova N Feldblyum TV Fischer R Fosker N Fraser A García JL García MJ Goble A Goldman GH Gomi K Griffith-Jones S Gwilliam R Haas B Haas H Harris D Horiuchi H Huang J Humphray S Jiménez J Keller N Khouri H Kitamoto K Kobayashi T Konzack S Kulkarni R Kumagai T Lafon A Lafton A Latgé JP Li W Lord A Lu C Majoros WH May GS 《Nature》2005,438(7071):1151-1156
Aspergillus fumigatus is exceptional among microorganisms in being both a primary and opportunistic pathogen as well as a major allergen. Its conidia production is prolific, and so human respiratory tract exposure is almost constant. A. fumigatus is isolated from human habitats and vegetable compost heaps. In immunocompromised individuals, the incidence of invasive infection can be as high as 50% and the mortality rate is often about 50% (ref. 2). The interaction of A. fumigatus and other airborne fungi with the immune system is increasingly linked to severe asthma and sinusitis. Although the burden of invasive disease caused by A. fumigatus is substantial, the basic biology of the organism is mostly obscure. Here we show the complete 29.4-megabase genome sequence of the clinical isolate Af293, which consists of eight chromosomes containing 9,926 predicted genes. Microarray analysis revealed temperature-dependent expression of distinct sets of genes, as well as 700 A. fumigatus genes not present or significantly diverged in the closely related sexual species Neosartorya fischeri, many of which may have roles in the pathogenicity phenotype. The Af293 genome sequence provides an unparalleled resource for the future understanding of this remarkable fungus. 相似文献
58.
Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene 总被引:21,自引:0,他引:21
Albertson DG Ylstra B Segraves R Collins C Dairkee SH Kowbel D Kuo WL Gray JW Pinkel D 《Nature genetics》2000,25(2):144-146
We show here that quantitative measurement of DNA copy number across amplified regions using array comparative genomic hybridization (CGH) may facilitate oncogene identification by providing precise information on the locations of both amplicon boundaries and amplification maxima. Using this analytical capability, we resolved two regions of amplification within an approximately 2-Mb region of recurrent aberration at 20q13.2 in breast cancer. The putative oncogene ZNF217 (ref. 5) mapped to one peak, and CYP24 (encoding vitamin D 24 hydroxylase), whose overexpression is likely to lead to abrogation of growth control mediated by vitamin D, mapped to the other. 相似文献
59.
A one-hit model of cell death in inherited neuronal degenerations 总被引:18,自引:0,他引:18
Clarke G Collins RA Leavitt BR Andrews DF Hayden MR Lumsden CJ McInnes RR 《Nature》2000,406(6792):195-199
In genetic disorders associated with premature neuronal death, symptoms may not appear for years or decades. This delay in clinical onset is often assumed to reflect the occurrence of age-dependent cumulative damage. For example, it has been suggested that oxidative stress disrupts metabolism in neurological degenerative disorders by the cumulative damage of essential macromolecules. A prediction of the cumulative damage hypothesis is that the probability of cell death will increase over time. Here we show in contrast that the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, a mouse model of cerebellar degeneration and Parkinson's and Huntington's diseases are all exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a 'one-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies. 相似文献
60.