全文获取类型
收费全文 | 890篇 |
免费 | 93篇 |
出版年
2022年 | 8篇 |
2021年 | 9篇 |
2018年 | 12篇 |
2017年 | 12篇 |
2016年 | 16篇 |
2015年 | 28篇 |
2014年 | 34篇 |
2013年 | 44篇 |
2012年 | 60篇 |
2011年 | 45篇 |
2010年 | 32篇 |
2009年 | 30篇 |
2008年 | 41篇 |
2007年 | 33篇 |
2006年 | 35篇 |
2005年 | 33篇 |
2004年 | 27篇 |
2003年 | 37篇 |
2002年 | 25篇 |
2001年 | 24篇 |
2000年 | 29篇 |
1999年 | 26篇 |
1998年 | 14篇 |
1997年 | 17篇 |
1996年 | 7篇 |
1995年 | 10篇 |
1994年 | 12篇 |
1993年 | 7篇 |
1992年 | 19篇 |
1991年 | 15篇 |
1990年 | 20篇 |
1989年 | 17篇 |
1988年 | 21篇 |
1987年 | 20篇 |
1986年 | 10篇 |
1985年 | 6篇 |
1984年 | 15篇 |
1983年 | 7篇 |
1982年 | 9篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1979年 | 10篇 |
1977年 | 6篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1974年 | 5篇 |
1973年 | 6篇 |
1972年 | 7篇 |
1971年 | 6篇 |
1970年 | 9篇 |
排序方式: 共有983条查询结果,搜索用时 15 毫秒
111.
112.
Vendeville S Lin TI Hu L Tahri A McGowan D Cummings MD Amssoms K Canard M Last S Van den Steen I Devogelaere B Rouan MC Vijgen L Berke JM Dehertogh P Fransen E Cleiren E van der Helm L Fanning G Van Emelen K Nyanguile O Simmen K Raboisson P 《Bioorganic & medicinal chemistry letters》2012,22(13):4437-4443
Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC(50) of 82 nM) with minimal associated cell toxicity (CC(50)>20 μM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic. 相似文献
113.
Stark JH Sharma R Ostroff S Cummings DA Ermentrout B Stebbins S Burke DS Wisniewski SR 《PloS one》2012,7(3):e34245
Background
Influenza is a contagious respiratory disease responsible for annual seasonal epidemics in temperate climates. An understanding of how influenza spreads geographically and temporally within regions could result in improved public health prevention programs. The purpose of this study was to summarize the spatial and temporal spread of influenza using data obtained from the Pennsylvania Department of Health''s influenza surveillance system.Methodology and Findings
We evaluated the spatial and temporal patterns of laboratory-confirmed influenza cases in Pennsylvania, United States from six influenza seasons (2003–2009). Using a test of spatial autocorrelation, local clusters of elevated risk were identified in the South Central region of the state. Multivariable logistic regression indicated that lower monthly precipitation levels during the influenza season (OR = 0.52, 95% CI: 0.28, 0.94), fewer residents over age 64 (OR = 0.27, 95% CI: 0.10, 0.73) and fewer residents with more than a high school education (OR = 0.76, 95% CI: 0.61, 0.95) were significantly associated with membership in this cluster. In addition, time series analysis revealed a temporal lag in the peak timing of the influenza B epidemic compared to the influenza A epidemic.Conclusions
These findings illustrate a distinct spatial cluster of cases in the South Central region of Pennsylvania. Further examination of the regional transmission dynamics within these clusters may be useful in planning public health influenza prevention programs. 相似文献114.
Kaltenbrunner O Cao S Freydell E Keener N Zhu L Jiao N Williamson B Snyder MA Cummings LJ 《Biotechnology journal》2012,7(10):1288-1296
Ceramic hydroxyapatite (CHT) is a multimodal chromatographic medium widely used in the pharmaceutical industry for the purification of biomolecules. CHT is a sintered form of hydroxyapatite crystals with moderate stability at acidic conditions. This moderate stability may lead to underperformance of CHT packed bed lifetime, especially under acidic conditions, which should be monitored by diagnostic tools to design optimal buffer systems for the step. This study presents the application of dynamic image analysis (DIA) and uniaxial confined bulk compression (UCBC) to monitor CHT particle degradation as a function of buffer composition. DIA was used to evaluate changes in solidity and morphology, while UCBC was used to evaluate changes in resistance to uniaxial compression. All properties were studied as a function of bed position and operational parameters. Results show that when CHT is exposed to acidic pH, adding phosphate and/or calcium at concentrations of 1 mM minimizes changes in particle solidity and mechanical strength. Changes in CHT morphological properties (i.e., convexity, aspect ratio) are also affected by the presence of calcium and/or phosphate in the inlet buffers. Furthermore, calcium and phosphate have a positive effect on the mechanical behavior of CHT, which is related to changes in the CHT particle solidity. 相似文献
115.
Ayres DL Darling A Zwickl DJ Beerli P Holder MT Lewis PO Huelsenbeck JP Ronquist F Swofford DL Cummings MP Rambaut A Suchard MA 《Systematic biology》2012,61(1):170-173
Phylogenetic inference is fundamental to our understanding of most aspects of the origin and evolution of life, and in recent years, there has been a concentration of interest in statistical approaches such as Bayesian inference and maximum likelihood estimation. Yet, for large data sets and realistic or interesting models of evolution, these approaches remain computationally demanding. High-throughput sequencing can yield data for thousands of taxa, but scaling to such problems using serial computing often necessitates the use of nonstatistical or approximate approaches. The recent emergence of graphics processing units (GPUs) provides an opportunity to leverage their excellent floating-point computational performance to accelerate statistical phylogenetic inference. A specialized library for phylogenetic calculation would allow existing software packages to make more effective use of available computer hardware, including GPUs. Adoption of a common library would also make it easier for other emerging computing architectures, such as field programmable gate arrays, to be used in the future. We present BEAGLE, an application programming interface (API) and library for high-performance statistical phylogenetic inference. The API provides a uniform interface for performing phylogenetic likelihood calculations on a variety of compute hardware platforms. The library includes a set of efficient implementations and can currently exploit hardware including GPUs using NVIDIA CUDA, central processing units (CPUs) with Streaming SIMD Extensions and related processor supplementary instruction sets, and multicore CPUs via OpenMP. To demonstrate the advantages of a common API, we have incorporated the library into several popular phylogenetic software packages. The BEAGLE library is free open source software licensed under the Lesser GPL and available from http://beagle-lib.googlecode.com. An example client program is available as public domain software. 相似文献
116.
Borgert A Heimburg-Molinaro J Song X Lasanajak Y Ju T Liu M Thompson P Ragupathi G Barany G Smith DF Cummings RD Live D 《ACS chemical biology》2012,7(6):1031-1039
Mucin glycoproteins present a complex structural landscape arising from the multiplicity of glycosylation patterns afforded by their numerous serine and threonine glycosylation sites, often in clusters, and with variations in respective glycans. To explore the structural complexities in such glycoconjugates, we used NMR to systematically analyze the conformational effects of glycosylation density within a cluster of sites. This allows correlation with molecular recognition through analysis of interactions between these and other glycopeptides, with antibodies, lectins, and sera, using a glycopeptide microarray. Selective antibody interactions with discrete conformational elements, reflecting aspects of the peptide and disposition of GalNAc residues, are observed. Our results help bridge the gap between conformational properties and molecular recognition of these molecules, with implications for their physiological roles. Features of the native mucin motifs impact their relative immunogenicity and are accurately encoded in the antibody binding site, with the conformational integrity being preserved in isolated glycopeptides, as reflected in the antibody binding profile to array components. 相似文献
117.
Differential roles of galectin-1 and galectin-3 in regulating leukocyte viability and cytokine secretion 总被引:4,自引:0,他引:4
Stowell SR Qian Y Karmakar S Koyama NS Dias-Baruffi M Leffler H McEver RP Cummings RD 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(5):3091-3102
Galectin-1 (Gal-1) and galectin-3 (Gal-3) exhibit profound but unique immunomodulatory activities in animals but their molecular mechanisms are incompletely understood. Early studies suggested that Gal-1 inhibits leukocyte function by inducing apoptotic cell death and removal, but recent studies show that some galectins induce exposure of the common death signal phosphatidylserine (PS) independently of apoptosis. In this study, we report that Gal-3, but not Gal-1, induces both PS exposure and apoptosis in primary activated human T cells, whereas both Gal-1 and Gal-3 induce PS exposure in neutrophils in the absence of cell death. Gal-1 and Gal-3 bind differently to the surfaces of T cells and only Gal-3 mobilizes intracellular Ca2+ in these cells, although Gal-1 and Gal-3 bind their respective T cell ligands with similar affinities. Although Gal-1 does not alter T cell viability, it induces IL-10 production and attenuates IFN-gamma production in activated T cells, suggesting a mechanism for Gal-1-mediated immunosuppression in vivo. These studies demonstrate that Gal-1 and Gal-3 induce differential responses in T cells and neutrophils, and identify the first factor, Gal-3, capable of inducing PS exposure with or without accompanying apoptosis in different leukocytes, thus providing a possible mechanism for galectin-mediated immunomodulation in vivo. 相似文献
118.
Leukocyte trafficking involves specific recognition between P-selectin and L-selectin and PSGL-1 containing core 2-based O-glycans expressing sialyl Lewis x (SLe(x)) antigen. However, the structural identity of the glycan component(s) displayed by murine neutrophil PSGL-1 that contributes to its P-selectin counter-receptor activity has been uncertain, since these cells express little if any SLe(x) antigen, and because there have been no direct studies to examine murine PSGL-1 glycosylation. To address this uncertainty, we studied PSGL-1 glycosylation in the murine cell line WEHI-3 using metabolic-radiolabeling with (3)H-monosaccharide precursors to detect low-abundance O-glycan structures. We report that PSGL-1 from WEHI-3 cells expresses a di-sialylated core 2 O-glycan containing the SLe(x) antigen. This fucosylated O-glycan is scarce on PSGL-1 and essentially undetectable in total leukocyte glycoproteins from WEHI-3 cells. These results demonstrate that WEHI-3 cells selectively fucosylate PSGL-1 to generate functionally important core 2-based O-glycans containing the SLe(x) antigen. 相似文献
119.
120.
As conservation reserves expand, the likelihood that they will capture areas degraded by previous land use increases. Ecological
restoration of such areas will therefore play an increasing role in biodiversity conservation. On the New South Wales North
Coast, recent expansion in the conservation estate has captured over 300 softwood and hardwood plantations, many with understoreys
dominated by exotic weeds. Here we present an overview of the practices we have adopted in managing flooded gum (Eucalyptus grandis) plantations infested with lantana (Lantana camara) to enhance their biodiversity value. Experiments designed to overcome barriers limiting regeneration of native forest in
conjunction with measurement of soil and plant responses yielded insights into the management of former timber plantations
for biodiversity. Canonical Correspondence Analysis indicated that the level of canopy retention (or logging intensity) within
sites consistently explained the greatest amount of variation in plant community composition (32–38% post-treatment). Thinning
and burning stimulated regeneration of native species. Retained canopy cover was proportional to the richness or abundance
of native woody shrubs, understorey trees and native perennial herbs, indicating that management intensity can be varied to
promote a range of conservation values. A state-and-transition model summarising purported management actions and likely outcomes
for these plantations is presented. This is the first time plantations have been managed solely for biodiversity. Logging
income means that plantation restoration can be cost-neutral, and the positive influence of a cover crop of trees means that
plantation management may generally be manipulated to promote biodiversity conservation. 相似文献