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排序方式: 共有287条查询结果,搜索用时 31 毫秒
121.
Åsa Johansson Fabio Marroni Caroline Hayward Christopher S. Franklin Anatoly V. Kirichenko Inger Jonasson Andrew A. Hicks Veronique Vitart Aaron Isaacs Tatiana Axenovich Susan Campbell Jamie Floyd Nick Hastie Sara Knott Gordan Lauc Irene Pichler Kresimir Rotim Sarah H. Wild Irina V. Zorkoltseva James F. Wilson Igor Rudan Harry Campbell Cristian Pattaro Peter Pramstaller Ben A. Oostra Alan F. Wright Cornelia M. van Duijn Yurii S. Aulchenko Ulf Gyllensten EUROSPAN Consortium 《Obesity (Silver Spring, Md.)》2010,18(4):803-808
As major risk‐factors for diabetes and cardiovascular diseases, the genetic contribution to obesity‐related traits has been of interest for decades. Recently, a limited number of common genetic variants, which have replicated in different populations, have been identified. One approach to increase the statistical power in genetic mapping studies is to focus on populations with increased levels of linkage disequilibrium (LD) and reduced genetic diversity. We have performed joint linkage and genome‐wide association analyses for weight and BMI in 3,448 (linkage) and 3,925 (association) partly overlapping healthy individuals from five European populations. A total of four chromosomal regions (two for weight and two for BMI) showed suggestive linkage (lod >2.69) either in one of the populations or in the joint data. At the genome‐wide level (nominal P < 1.6 × 10?7, Bonferroni‐adjusted P < 0.05) one single‐nucleotide polymorphism (SNP) (rs12517906) (nominal P = 7.3 × 10?8) was associated with weight, whereas none with BMI. The SNP associated with weight is located close to MGAT1. The monoacylglycerol acyltransferase (MGAT) enzyme family is known to be involved in dietary fat absorption. There was no overlap between the linkage regions and the associated SNPs. Our results show that genetic effects influencing weight and BMI are shared across diverse European populations, even though some of these populations have experienced recent population bottlenecks and/or been affected by genetic drift. The analysis enabled us to identify a new candidate gene, MGAT1, associated with weight in women. 相似文献
122.
Valentina C Sladky Katja Knapp Tamas G Szabo Vincent Z Braun Laura Bongiovanni Hilda van den Bos Diana CJ Spierings Bart Westendorp Ana Curinha Tatjana Stojakovic Hubert Scharnagl Gerald Timelthaler Kaoru Tsuchia Matthias Pinter Georg Semmler Floris Foijer Alain de Bruin Thomas Reiberger Nataliya RohrUdilova Andreas Villunger 《EMBO reports》2020,21(12)
Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi‐protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome‐induced p53‐activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro‐tumorigenic effect of PIDDosome‐mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence‐free survival in HCC patients. 相似文献
123.
Leonardo Bottolo Marc Chadeau-Hyam David I. Hastie Tanja Zeller Benoit Liquet Paul Newcombe Loic Yengo Philipp S. Wild Arne Schillert Andreas Ziegler Sune F. Nielsen Adam S. Butterworth Weang Kee Ho Rapha?le Castagné Thomas Munzel David Tregouet Mario Falchi Fran?ois Cambien B?rge G. Nordestgaard Fredéric Fumeron Anne Tybj?rg-Hansen Philippe Froguel John Danesh Enrico Petretto Stefan Blankenberg Laurence Tiret Sylvia Richardson 《PLoS genetics》2013,9(8)
Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n = 3,175), when compared with the largest published meta-GWAS (n>100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This provides a powerful tool for the analysis of diverse genomic features, for instance including gene expression and exome sequencing data, where complex dependencies are present in the predictor space. 相似文献
124.
Sonja Melman Ellen NC Schoorel Carmen Dirksen Anneke Kwee Luc Smits Froukje de Boer Madelaine Jonkers Mallory D Woiski Ben Willem J Mol Johannes PR Doornbos Harry Visser Anjoke JM Huisjes Martina M Porath Friso MC Delemarre Simone MI Kuppens Robert Aardenburg Ivo MA Van Dooren Francis PJM Vrouenraets Frans TH Lim Gunilla Kleiverda Paulien CM van der Salm Karin de Boer Marko J Sikkema Jan G Nijhuis Rosella PMG Hermens Hubertina CJ Scheepers 《Implementation science : IS》2013,8(1):1-8
Background
Caesarean section (CS) rates are rising worldwide. In the Netherlands, the most significant rise is observed in healthy women with a singleton in vertex position between 37 and 42 weeks gestation, whereas it is doubtful whether an improved outcome for the mother or her child was obtained. It can be hypothesized that evidence-based guidelines on CS are not implemented sufficiently. Therefore, the present study has the following objectives: to develop quality indicators on the decision to perform a CS based on key recommendations from national and international guidelines; to use the quality indicators in order to gain insight into actual adherence of Dutch gynaecologists to guideline recommendations on the performance of a CS; to explore barriers and facilitators that have a direct effect on guideline application regarding CS; and to develop, execute, and evaluate a strategy in order to reduce the CS incidence for a similar neonatal outcome (based on the information gathered in the second and third objectives).Methods
An independent expert panel of Dutch gynaecologists and midwives will develop a set of quality indicators on the decision to perform a CS. These indicators will be used to measure current care in 20 hospitals with a population of 1,000 women who delivered by CS, and a random selection of 1,000 women who delivered vaginally in the same period. Furthermore, by interviewing healthcare professionals and patients, the barriers and facilitators that may influence the decision to perform a CS will be measured. Based on the results, a tailor-made implementation strategy will be developed and tested in a controlled before-and-after study in 12 hospitals (six intervention, six control hospitals) with regard to effectiveness, experiences, and costs.Discussion
This study will offer insight into the current CS care and into the hindering and facilitating factors influencing obstetrical policy on CS. Furthermore, it will allow definition of patient categories or situations in which a tailor-made implementation strategy will most likely be meaningful and cost effective, without negatively affecting the outcome for mother and child.Trial registration
http://www.clinicaltrials.gov: NCT01261676 相似文献125.
Jessica L. Hastie Kyle B. Williams Craig D. Ellermeier 《Journal of bacteriology》2013,195(14):3135-3144
During growth in the environment, bacteria encounter stresses which can delay or inhibit their growth. To defend against these stresses, bacteria induce both resistance and repair mechanisms. Many bacteria regulate these resistance mechanisms using a group of alternative σ factors called extracytoplasmic function (ECF) σ factors. ECF σ factors represent the largest and most diverse family of σ factors. Here, we demonstrate that the activation of a member of the ECF30 subfamily of ECF σ factors, σV in Bacillus subtilis, is controlled by the proteolytic destruction of the anti-σ factor RsiV. We will demonstrate that the degradation of RsiV and, thus, the activation of σV requires multiple proteolytic steps. Upon exposure to the inducer lysozyme, the extracellular domain of RsiV is removed by an unknown protease, which cleaves at site 1. This cleavage is independent of PrsW, the B. subtilis site 1 protease, which cleaves the anti-σ factor RsiW. Following cleavage by the unknown protease, the N-terminal portion of RsiV requires further processing, which requires the site 2 intramembrane protease RasP. Our data indicate that the N-terminal portion of RsiV from amino acid 1 to 60, which lacks the extracellular domain, is constitutively degraded unless RasP is absent, indicating that RasP cleavage is constitutive. This suggests that the regulatory step in RsiV degradation and, thus, σV activation are controlled at the level of the site 1 cleavage. Finally, we provide evidence that increased resistance to lysozyme decreases σV activation. Collectively, these data provide evidence that the mechanism for σV activation in B. subtilis is controlled by regulated intramembrane proteolysis (RIP) and requires the site 2 protease RasP. 相似文献
126.
Lonneke Smeding Jan Willem Kuiper Frans B Pl?tz Martin CJ Kneyber AB Johan Groeneveld 《Respiratory research》2013,14(1):92
Background
Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca2+)-dependent mechanism.Materials and methods
N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (Vt) of 6 mL/kg and 5 cmH2O positive end-expiratory pressure (PEEP)) or injurious ventilation (high Vt of 19 mL/kg and 1 cmH2O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca2+ exposure. Key mediators were determined in lung and heart at the mRNA level.Results
Instillation of LPS and high Vt MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high Vt MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dtmax and contractile responses to increasing Ca2+ exposure ex vivo decreased by LPS. High Vt ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca2+ responses.Conclusions
Injurious MV by high Vt aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca2+ handling and sensitivity. 相似文献127.
Array-based comparative genomic hybridization (aCGH) enables the measurement of DNA copy number across thousands of locations in a genome. The main goals of analyzing aCGH data are to identify the regions of copy number variation (CNV) and to quantify the amount of CNV. Although there are many methods for analyzing single-sample aCGH data, the analysis of multi-sample aCGH data is a relatively new area of research. Further, many of the current approaches for analyzing multi-sample aCGH data do not appropriately utilize the additional information present in the multiple samples. We propose a procedure called the Fused Lasso Latent Feature Model (FLLat) that provides a statistical framework for modeling multi-sample aCGH data and identifying regions of CNV. The procedure involves modeling each sample of aCGH data as a weighted sum of a fixed number of features. Regions of CNV are then identified through an application of the fused lasso penalty to each feature. Some simulation analyses show that FLLat outperforms single-sample methods when the simulated samples share common information. We also propose a method for estimating the false discovery rate. An analysis of an aCGH data set obtained from human breast tumors, focusing on chromosomes 8 and 17, shows that FLLat and Significance Testing of Aberrant Copy number (an alternative, existing approach) identify similar regions of CNV that are consistent with previous findings. However, through the estimated features and their corresponding weights, FLLat is further able to discern specific relationships between the samples, for example, identifying 3 distinct groups of samples based on their patterns of CNV for chromosome 17. 相似文献
128.
Maja Pu?i? Ana Kne?evi? Jana Vidi? Barbara Adamczyk Mislav Novokmet Ozren Pola?ek Olga Gornik Sandra ?upraha-Goreta Mark R. Wormald Irma Red?i? Harry Campbell Alan Wright Nicholas D. Hastie James F. Wilson Igor Rudan Manfred Wuhrer Pauline M. Rudd Djuro Josi? Gordan Lauc 《Molecular & cellular proteomics : MCP》2011,10(10)
129.
From both the fundamental and clinical perspectives, there is growing interest in mesenchymal cells and the mechanisms that regulate the two-way switch between mesenchymal and epithelial states. Here, we review recent findings showing that the Wilms' tumor gene (Wt1) is a key regulator of mesenchyme maintenance and the mesenchyme to epithelial balance in the development of certain mesodermal organs. We summarize recent experiments demonstrating, unexpectedly, that Wt1 is also essential for the integrity or function of multiple adult tissues, mainly, we argue, through regulating mesenchymal cells. We also discuss growing evidence that implicates Wt1 in tissue repair and regeneration. Drawing on these findings, we highlight the similarities between Wt1-expressing cells in different tissues. We believe that future studies aimed at elucidating the mechanisms underlying the functions of Wt1 in adult cells will reveal key cell types, pathways, and molecules regulating adult tissue homeostasis and repair. 相似文献
130.