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131.
Comprehensive biochemical analysis of rare prostacyclin receptor variants: study of association of signaling with coronary artery obstruction 总被引:1,自引:0,他引:1
Stitham J Arehart E Elderon L Gleim SR Douville K Kasza Z Fetalvero K MacKenzie T Robb J Martin KA Hwa J 《The Journal of biological chemistry》2011,286(9):7060-7069
Currently, pharmacogenetic studies are at an impasse as the low prevalence (<2%) of most variants hinder their pharmacogenetic analysis with population sizes often inadequate for sufficiently powered studies. Grouping rare mutations by functional phenotype rather than mutation site can potentially increase sample size. Using human population-based studies (n = 1,761) to search for dysfunctional human prostacyclin receptor (hIP) variants, we recently discovered 18 non-synonymous mutations, all with frequencies less than 2% in our study cohort. Eight of the 18 had defects in binding, activation, and/or protein stability/folding. Mutations (M113T, L104R, and R279C) in three highly conserved positions demonstrated severe misfolding manifested by impaired binding and activation of cell surface receptors. To assess for association with coronary artery disease, we performed a case-control study comparing coronary angiographic results from patients with reduced cAMP production arising from the non-synonymous mutations (n = 23) with patients with non-synonymous mutations that had no reduction in cAMP (n = 17). Major coronary artery obstruction was significantly increased in the dysfunctional mutation group in comparison with the silent mutations. We then compared the 23 dysfunctional receptor patients with 69 age- and risk factor-matched controls (1:3). This verified the significantly increased coronary disease in the non-synonymous dysfunctional variant cohort. This study demonstrates the potential utility of in vitro functional characterization in predicting clinical phenotypes and represents the most comprehensive characterization of human prostacyclin receptor genetic variants to date. 相似文献
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Capture–recapture techniques have been used for considerable time to predict population size. Estimators usually rely on frequency counts for numbers of trappings; however, it may be the case that these are not available for a particular problem, for example if the original data set has been lost and only a summary table is available. Here, we investigate techniques for specific examples; the motivating example is an epidemiology study by Mosley et al., which focussed on a cholera outbreak in East Pakistan. To demonstrate the wider range of the technique, we also look at a study for predicting the long-term outlook of the AIDS epidemic using information on number of sexual partners. A new estimator is developed here which uses the EM algorithm to impute unobserved values and then uses these values in a similar way to the existing estimators. The results show that a truncated approach – mimicking the Chao lower bound approach – gives an improved estimate when population homogeneity is violated. 相似文献
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Eller MA Koehler RN Kijak GH Eller LA Guwatudde D Marovich MA Michael NL de Souza MS Wabwire-Mangen F Robb ML Currier JR Sandberg JK 《Journal of virology》2011,85(10):4802-4811
Natural killer (NK) cells are important innate effector cells controlled by an array of activating and inhibitory receptors. Some alleles of the inhibitory killer-cell immunoglobulin-like receptor KIR3DL1 in combination with its HLA class I ligand Bw4 have been genetically associated with slower HIV-1 disease progression. Here, we observed that the presence of HLA-B Bw4 was associated with elevated frequencies of KIR3DL1(+) CD56(dim) NK cells in chronically HIV-1-infected individuals from the rural district of Kayunga, Uganda. In contrast, levels of KIR2DL1(+) CD56(dim) NK cells were decreased, and levels of KIR2DL3(+) CD56(dim) NK cells were unchanged in infected subjects carrying their respective HLA-C ligands. Furthermore, the size of the KIR3DL1(+) NK cell subset correlated directly with viral load, and this effect occurred only in HLA-B Bw4(+) patients, suggesting that these cells expand in response to viral replication but may have relatively poor antiviral capacity. In contrast, no association with viral load was present for KIR2DL1(+) and KIR2DL3(+) NK cells. Interestingly, chronic HIV-1 infection was associated with an increased polyfunctional response in the NK cell compartment, and, upon further investigation, KIR3DL1(+) CD56(dim) NK cells exhibited a significantly increased functional response in the patients carrying HLA-B Bw4. These results indicate that chronic HIV-1 infection is associated with increased NK cell polyfunctionality and elevated levels of KIR3DL1(+) NK cells in Ugandans carrying the HLA-B Bw4 motif. 相似文献
137.
Resource availability, dispersal and infection genetics all have the potential to fundamentally alter the coevolutionary dynamics of bacteria–bacteriophage interactions. However, it remains unclear how these factors synergise to shape diversity within bacterial populations. We used a combination of laboratory experiments and mathematical modeling to test how the structure of a dispersal network affects host phenotypic diversity in a coevolving bacteria-phage system in communities of differential resource input. Unidirectional dispersal of bacteria and phage from high to low resources consistently increased host diversity compared with a no dispersal regime. Bidirectional dispersal, on the other hand, led to a marked decrease in host diversity. Our mathematical model predicted these opposing outcomes when we incorporated modified gene-for-gene infection genetics. To further test how host diversity depended on the genetic underpinnings of the bacteria-phage interaction, we expanded our mathematical model to include different infection mechanisms. We found that the direction of dispersal had very little impact on bacterial diversity when the bacteria-phage interaction was mediated by matching alleles, gene-for-gene or related infection mechanisms. Our experimental and theoretical results demonstrate that the effects of dispersal on diversity in coevolving host–parasite systems depend on an intricate interplay of the structure of the underlying dispersal network and the specifics of the host–parasite interaction. 相似文献
138.
Melissa M. Page Amy Sinclair Ellen L. Robb Jeffrey A. Stuart Dominic J. Withers Colin Selman 《Aging cell》2014,13(5):962-964
Reduced signalling through the insulin/insulin-like growth factor-1 signalling (IIS) pathway is a highly conserved lifespan determinant in model organisms. The precise mechanism underlying the effects of the IIS on lifespan and health is currently unclear, although cellular stress resistance may be important. We have previously demonstrated that mice globally lacking insulin receptor substrate 1 (Irs1−/−) are long-lived and enjoy a greater period of their life free from age-related pathology compared with wild-type (WT) controls. In this study, we show that primary dermal fibroblasts and primary myoblasts derived from Irs1−/− mice are no more resistant to a range of oxidant and nonoxidant chemical stressors than cells derived from WT mice. 相似文献
139.
We present a new software package (hzar ) that provides functions for fitting molecular genetic and morphological data from hybrid zones to classic equilibrium cline models using the Metropolis–Hastings Markov chain Monte Carlo (MCMC) algorithm. The software applies likelihood functions appropriate for different types of data, including diploid and haploid genetic markers and quantitative morphological traits. The modular design allows flexibility in fitting cline models of varying complexity. To facilitate hypothesis testing, an autofit function is included that allows automated model selection from a set of nested cline models. Cline parameter values, such as cline centre and cline width, are estimated and may be compared statistically across clines. The package is written in the R language and is available through the Comprehensive R Archive Network (CRAN; http://cran.r-project.org/ ). Here, we describe hzar and demonstrate its use with a sample data set from a well‐studied hybrid zone in western Panama between white‐collared (Manacus candei) and golden‐collared manakins (M. vitellinus). Comparisons of our results with previously published results for this hybrid zone validate the hzar software. We extend analysis of this hybrid zone by fitting additional models to molecular data where appropriate. 相似文献
140.
Paul J. Feldblum Sónia Enosse Karine Dubé Paulo Arnaldo Chadreque Muluana Reginaldo Banze Aristides Nhanala Joana Cunaca Pai-Lien Chen Merlin L. Robb Ricardo Thompson 《PloS one》2014,9(5)