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排序方式: 共有272条查询结果,搜索用时 147 毫秒
121.
Siu P. Ngok Rory Geyer Antonis Kourtidis Peter Storz Panos Z. Anastasiadis 《The Journal of biological chemistry》2013,288(9):6640-6650
Syx is a Rho-specific guanine nucleotide exchange factor (GEF) that localizes at cell-cell junctions and promotes junction stability by activating RhoA and the downstream effector Diaphanous homolog 1 (Dia1). Previously, we identified several molecules, including 14-3-3 proteins, as Syx-interacting partners. In the present study, we show that 14-3-3 isoforms interact with Syx at both its N- and C-terminal regions in a phosphorylation-dependent manner. We identify the protein kinase D-mediated phosphorylation of serine 92 on Syx, and additional phosphorylation at serine 938, as critical sites for 14-3-3 association. Our data indicate that the binding of 14-3-3 proteins inhibits the GEF activity of Syx. Furthermore, we show that phosphorylation-deficient, 14-3-3-uncoupled Syx exhibits increased junctional targeting and increased GEF activity, resulting in the strengthening of the circumferential junctional actin ring in Madin-Darby canine kidney cells. These findings reveal a novel means of regulating junctional Syx localization and function by phosphorylation-induced 14-3-3 binding and further support the importance of Syx function in maintaining stable cell-cell contacts. 相似文献
122.
Elin Grundberg Eshwar Meduri Johanna K. Sandling ?sa K. Hedman Sarah Keildson Alfonso Buil Stephan Busche Wei Yuan James Nisbet Magdalena Sekowska Alicja Wilk Amy Barrett Kerrin S. Small Bing Ge Maxime Caron So-Youn Shin the Multiple Tissue Human Expression Resource Consortium Mark Lathrop Emmanouil T. Dermitzakis Mark I. McCarthy Timothy D. Spector Jordana T. Bell Panos Deloukas 《American journal of human genetics》2013,93(6):1158
123.
Justus C. Dachsel Siu P. Ngok Laura J. Lewis-Tuffin Antonis Kourtidis Rory Geyer Lauren Johnston Ryan Feathers Panos Z. Anastasiadis 《Molecular and cellular biology》2013,33(24):4909-4918
The role of RhoA in promoting directed cell migration has been complicated by studies showing that it is activated both in the front and the rear of migrating cells. We report here that the RhoA-specific guanine nucleotide exchange factor Syx is required for the polarity of actively migrating brain and breast tumor cells. This function of Syx is mediated by the selective activation of the RhoA downstream effector Dia1, the subsequent reorganization of microtubules, and the downregulation of focal adhesions and actin stress fibers. The data argue that directed cell migration requires the precise spatiotemporal regulation of Dia1 and ROCK activities in the cell. The recruitment of Syx to the cell membrane and the subsequent selective activation of Dia1 signaling, coupled with the suppression of ROCK and activation of cofilin-mediated actin reorganization, plays a key role in establishing cell polarity during directed cell migration. 相似文献
124.
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
125.
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
126.
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127.
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
128.
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
129.
130.
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