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211.
A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis 总被引:1,自引:0,他引:1
Khor CC Chapman SJ Vannberg FO Dunne A Murphy C Ling EY Frodsham AJ Walley AJ Kyrieleis O Khan A Aucan C Segal S Moore CE Knox K Campbell SJ Lienhardt C Scott A Aaby P Sow OY Grignani RT Sillah J Sirugo G Peshu N Williams TN Maitland K Davies RJ Kwiatkowski DP Day NP Yala D Crook DW Marsh K Berkley JA O'Neill LA Hill AV 《Nature genetics》2007,39(4):523-528
Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction. 相似文献
212.
Plenge RM Cotsapas C Davies L Price AL de Bakker PI Maller J Pe'er I Burtt NP Blumenstiel B DeFelice M Parkin M Barry R Winslow W Healy C Graham RR Neale BM Izmailova E Roubenoff R Parker AN Glass R Karlson EW Maher N Hafler DA Lee DM Seldin MF Remmers EF Lee AT Padyukov L Alfredsson L Coblyn J Weinblatt ME Gabriel SB Purcell S Klareskog L Gregersen PK Shadick NA Daly MJ Altshuler D 《Nature genetics》2007,39(12):1477-1482
To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10(-3), GWA scan; P < 10(-6), replication; P = 10(-9), combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 x 10(-6) in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23. 相似文献
213.
CAI HongTao MA ShuYing DUNLOP M W BOGDANOVA Y DAVIES J A & PITOUT F School of Electronic Information Wuhan University Wuhan China Key Lab of Geospace Environment Geodesy CNEM SSTD Rutherford Appleton Laboratory Chilton OX QX UK Department of Physics La Trobe University Melbourne Victoria Australia Max-Planck-Institut für Extraterrestrische Physik Garching D- Germany 《科学通报(英文版)》2010,55(12):1178-1185
Using coordinated observations from the Cluster,DMSP and ESR radar,high-altitude cusp was investigated for a time period characterized by four fast reversals of the IMF BZ.On February 12,2003,Cluster was flying sunward at duskside over the Northern Hemisphere,across the high-altitude northern cusp twice.Both the two crossings are during steady northward IMF interval,whereas ion fluxes detected during the time period are quite different.The cusp in the first crossing is a typical northward-IMF one,with short... 相似文献
214.
Deary IJ Yang J Davies G Harris SE Tenesa A Liewald D Luciano M Lopez LM Gow AJ Corley J Redmond P Fox HC Rowe SJ Haggarty P McNeill G Goddard ME Porteous DJ Whalley LJ Starr JM Visscher PM 《Nature》2012,482(7384):212-215
Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change. 相似文献
215.
Gehrig SM van der Poel C Sayer TA Schertzer JD Henstridge DC Church JE Lamon S Russell AP Davies KE Febbraio MA Lynch GS 《Nature》2012,484(7394):394-398
Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies. 相似文献
216.
Garnett MJ Edelman EJ Heidorn SJ Greenman CD Dastur A Lau KW Greninger P Thompson IR Luo X Soares J Liu Q Iorio F Surdez D Chen L Milano RJ Bignell GR Tam AT Davies H Stevenson JA Barthorpe S Lutz SR Kogera F Lawrence K McLaren-Douglas A Mitropoulos X Mironenko T Thi H Richardson L Zhou W Jewitt F Zhang T O'Brien P Boisvert JL Price S Hur W Yang W Deng X Butler A Choi HG Chang JW Baselga J Stamenkovic I Engelman JA Sharma SV Delattre O Saez-Rodriguez J Gray NS Settleman J Futreal PA Haber DA 《Nature》2012,483(7391):570-575
Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies. 相似文献
217.
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219.
Shankar Sankaran Bob Dick Kelly Shaw Colleen Cartwright Alan Davies Jacqueline Kelly Barb Vindin 《Systemic Practice and Action Research》2014,27(6):551-573
This article illustrates how scenario planning (SP) and scenario analysis as can be conceptualised as practices contributing to an action research (AR) investigation of leadership development. The project described in this article was intended to strengthen leadership capacity in Australia’s rapidly changing aged care and community care sector. A research team comprising academics from three universities and managers from two faith-based not-for-profit organisations providing aged and community care participated in this study. As part of the research, two sets of scenario-based workshops were held: the first, to identify possible futures using SP; and the second, to deal with plausible scenarios these organisations are likely to face with the changes happening in the aged care environment in Australia by using scenario analysis. Although the researchers did not consider a link between practice theory and AR during the SP phase, practice theory became useful during the scenario analysis phase. The article includes a brief literature review followed by a discussion on the relationship between AR and practice theory. The processes used in the two sets of scenario workshops are then described in detail along with the data collected and analysed. The article concludes with some reflections on the use of scenarios in practice as well as an acknowledgment that practice theory would be useful in investigating leadership capability development. 相似文献
220.
An autosomal transcript in skeletal muscle with homology to dystrophin 总被引:46,自引:0,他引:46
D R Love D F Hill G Dickson N K Spurr B C Byth R F Marsden F S Walsh Y H Edwards K E Davies 《Nature》1989,339(6219):55-58