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131.
Day-Williams AG Southam L Panoutsopoulou K Rayner NW Esko T Estrada K Helgadottir HT Hofman A Ingvarsson T Jonsson H Keis A Kerkhof HJ Thorleifsson G Arden NK Carr A Chapman K Deloukas P Loughlin J McCaskie A Ollier WE Ralston SH Spector TD Wallis GA Wilkinson JM Aslam N Birell F Carluke I Joseph J Rai A Reed M Walker K;arcOGEN Consortium Doherty SA Jonsdottir I Maciewicz RA Muir KR Metspalu A Rivadeneira F Stefansson K Styrkarsdottir U Uitterlinden AG van Meurs JB Zhang W Valdes AM Doherty M 《American journal of human genetics》2011,(3):446-450
Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11–1.23], p = 2.1 × 10−8) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients. 相似文献
132.
Stathopoulou MG Dedoussis GV Trovas G Theodoraki EV Katsalira A Dontas IA Hammond N Deloukas P Lyritis GP 《The Journal of nutritional biochemistry》2011,22(8):752-757
The aim of this study was to investigate the effect of common vitamin D receptor (VDR) gene polymorphisms on the bone mineral density (BMD) of Greek postmenopausal women. Healthy postmenopausal women (n=578) were recruited for the study. The BMD of the lumbar spine and hip was measured using dual-energy X-ray absorptiometry with the Lunar DPX-MD device. Assessment of dietary calcium intake was performed with multiple 24-h recalls. Genotyping was performed for the BsmI, TaqI and Cdx-2 polymorphisms of the VDR gene. The selected polymorphisms were not associated with BMD, osteoporosis or osteoporotic fractures. Stratification by calcium intake revealed that in the low calcium intake group (<680 mg/day), all polymorphisms were associated with the BMD of the lumbar spine (P<.05). After adjustment for potential covariates, BsmI and TaqI polymorphisms were associated with the presence of osteoporosis (P<.05), while the presence of the minor A allele of Cdx-2 polymorphism was associated with a lower spine BMD (P=.025). In the higher calcium intake group (>680 mg/day), no significant differences were observed within the genotypes for all polymorphisms. The VDR gene is shown to affect BMD in women with low calcium intake, while its effect is masked in women with higher calcium intake. This result underlines the significance of adequate calcium intake in postmenopausal women, given that it exerts a positive effect on BMD even in the presence of negative genetic predisposition. 相似文献
133.
P. G. Milonas M. Savopoulou-Soultani & D. G. Stavridis 《Journal of Applied Entomology》2001,125(9-10):515-518
The generation time of Lobesia botrana (Den. & Schiff.) was estimated as the number of day-degrees required between the start of a flight and the start of the following flight in two regions in northern Greece. The day-degrees required for the first generation ( x =339.3, Naoussa; x =275.6, Thessaloniki) were significantly shorter than for the second ( x =751.5, Naoussa; x =833.8, Thessaloniki) and the third generations ( x =899.5, Naoussa; x =1197.0, Thessaloniki). Nonlinear models were developed using trap catches of male L. botrana during 1987–1989 for predicting its flight activity. A lower threshold temperature of 6.45°C was used in calculating daily day-degrees from 1 March. The models predicted with sufficient accuracy the accumulated male moth catch and they accounted for the 60–78% and 86–91% of year-to-year variation in male flight activity in Thessaloniki and Naoussa, respectively. 相似文献
134.
James M. Noble Nikolaos Scarmeas Romanita S. Celenti Mitchell S. V. Elkind Clinton B. Wright Nicole Schupf Panos N. Papapanou 《PloS one》2014,9(12)
Background
Periodontitis and Alzheimer disease (AD) are associated with systemic inflammation. This research studied serum IgG to periodontal microbiota as possible predictors of incident AD.Methods
Using a case-cohort study design, 219 subjects (110 incident AD cases and 109 controls without incident cognitive impairment at last follow-up), matched on race-ethnicity, were drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a cohort of longitudinally followed northern Manhattan residents aged >65 years. Mean follow-up was five years (SD 2.6). In baseline sera, serum IgG levels were determined for bacteria known to be positively or negatively associated with periodontitis (Porphyromonas gingivalis, Tannerella forsythia, Actinobacillus actinomycetemcomitans Y4, Treponema denticola, Campylobacter rectus, Eubacterium nodatum, and Actinomyces naeslundii genospecies-2). In all analyses, we used antibody threshold levels shown to correlate with presence of moderate-severe periodontitis.Results
Mean age was 72 years (SD 6.9) for controls, and 79 years (SD 4.6) for cases (p<0.001). Non-Hispanic Whites comprised 26%, non-Hispanic Blacks 27%, and Hispanics 48% of the sample. In a model adjusting for baseline age, sex, education, diabetes mellitus, hypertension, smoking, prior history of stroke, and apolipoprotein E genotype, high anti-A. naeslundii titer (>640 ng/ml, present in 10% of subjects) was associated with increased risk of AD (HR = 2.0, 95%CI: 1.1–3.8). This association was stronger after adjusting for other significant titers (HR = 3.1, 95%CI: 1.5–6.4). In this model, high anti-E. nodatum IgG (>1755 ng/ml; 19% of subjects) was associated with lower risk of AD (HR = 0.5, 95%CI: 0.2–0.9).Conclusions
Serum IgG levels to common periodontal microbiota are associated with risk for developing incident AD. 相似文献135.
Rotival M Zeller T Wild PS Maouche S Szymczak S Schillert A Castagné R Deiseroth A Proust C Brocheton J Godefroy T Perret C Germain M Eleftheriadis M Sinning CR Schnabel RB Lubos E Lackner KJ Rossmann H Münzel T Rendon A;Cardiogenics Consortium Erdmann J Deloukas P Hengstenberg C Diemert P Montalescot G Ouwehand WH Samani NJ Schunkert H Tregouet DA Ziegler A Goodall AH Cambien F Tiret L Blankenberg S 《PLoS genetics》2011,7(12):e1002367
136.
Siu P. Ngok Rory Geyer Miaoliang Liu Antonis Kourtidis Sudesh Agrawal Chuanshen Wu Himabindu Reddy Seerapu Laura J. Lewis-Tuffin Karen L. Moodie Deborah Huveldt Ruth Marx Jay M. Baraban Peter Storz Arie Horowitz Panos Z. Anastasiadis 《The Journal of cell biology》2012,199(7):1103-1115
Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous. VEGF caused translocation of Syx from cell junctions, promoting junction disassembly, whereas Ang1 maintained Syx at the junctions, inducing junction stabilization. The VEGF-induced translocation of Syx from EC junctions was caused by PKD1 (protein kinase D1)-mediated phosphorylation of Syx at Ser806, which reduced Syx association to its junctional anchors. In support of the pivotal role of Syx in regulating EC junctions, syx−/− mice had defective junctions, resulting in vascular leakiness, edema, and impaired heart function. 相似文献
137.
138.
Li R Brockschmidt FF Kiefer AK Stefansson H Nyholt DR Song K Vermeulen SH Kanoni S Glass D Medland SE Dimitriou M Waterworth D Tung JY Geller F Heilmann S Hillmer AM Bataille V Eigelshoven S Hanneken S Moebus S Herold C den Heijer M Montgomery GW Deloukas P Eriksson N Heath AC Becker T Sulem P Mangino M Vollenweider P Spector TD Dedoussis G Martin NG Kiemeney LA Mooser V Stefansson K Hinds DA Nöthen MM Richards JB 《PLoS genetics》2012,8(5):e1002746
Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson''s disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson''s disease, and decreased fertility, providing important insights into the pathophysiology of these conditions. 相似文献
139.
Bell JT Tsai PC Yang TP Pidsley R Nisbet J Glass D Mangino M Zhai G Zhang F Valdes A Shin SY Dempster EL Murray RM Grundberg E Hedman AK Nica A Small KS;MuTHER Consortium Dermitzakis ET McCarthy MI Mill J Spector TD Deloukas P 《PLoS genetics》2012,8(4):e1002629
Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes. 相似文献
140.
Nicolas Greliche Tanja Zeller Philipp S. Wild Maxime Rotival Arne Schillert Andreas Ziegler Panos Deloukas Jeanette Erdmann Christian Hengstenberg Willem H. Ouwehand Nilesh J. Samani Heribert Schunkert Thomas Munzel Karl J. Lackner Fran?ois Cambien Alison H. Goodall Laurence Tiret Stefan Blankenberg David-Alexandre Trégou?t Cardiogenics Consortium 《PloS one》2012,7(9)
We aimed to assess whether pri-miRNA SNPs (miSNPs) could influence monocyte gene expression, either through marginal association or by interacting with polymorphisms located in 3''UTR regions (3utrSNPs). We then conducted a genome-wide search for marginal miSNPs effects and pairwise miSNPs × 3utrSNPs interactions in a sample of 1,467 individuals for which genome-wide monocyte expression and genotype data were available. Statistical associations that survived multiple testing correction were tested for replication in an independent sample of 758 individuals with both monocyte gene expression and genotype data. In both studies, the hsa-mir-1279 rs1463335 was found to modulate in cis the expression of LYZ and in trans the expression of CNTN6, CTRC, COPZ2, KRT9, LRRFIP1, NOD1, PCDHA6, ST5 and TRAF3IP2 genes, supporting the role of hsa-mir-1279 as a regulator of several genes in monocytes. In addition, we identified two robust miSNPs × 3utrSNPs interactions, one involving HLA-DPB1 rs1042448 and hsa-mir-219-1 rs107822, the second the H1F0 rs1894644 and hsa-mir-659 rs5750504, modulating the expression of the associated genes.As some of the aforementioned genes have previously been reported to reside at disease-associated loci, our findings provide novel arguments supporting the hypothesis that the genetic variability of miRNAs could also contribute to the susceptibility to human diseases. 相似文献