全文获取类型
收费全文 | 448573篇 |
免费 | 52936篇 |
国内免费 | 170篇 |
出版年
2018年 | 3799篇 |
2017年 | 3498篇 |
2016年 | 5440篇 |
2015年 | 8141篇 |
2014年 | 9144篇 |
2013年 | 12851篇 |
2012年 | 14829篇 |
2011年 | 14941篇 |
2010年 | 9860篇 |
2009年 | 9122篇 |
2008年 | 13042篇 |
2007年 | 13519篇 |
2006年 | 12201篇 |
2005年 | 12033篇 |
2004年 | 11798篇 |
2003年 | 11239篇 |
2002年 | 10731篇 |
2001年 | 21604篇 |
2000年 | 21728篇 |
1999年 | 17248篇 |
1998年 | 6041篇 |
1997年 | 6279篇 |
1996年 | 6069篇 |
1995年 | 5681篇 |
1994年 | 5743篇 |
1993年 | 5561篇 |
1992年 | 13634篇 |
1991年 | 12956篇 |
1990年 | 12627篇 |
1989年 | 12487篇 |
1988年 | 11152篇 |
1987年 | 10775篇 |
1986年 | 9860篇 |
1985年 | 9642篇 |
1984年 | 8177篇 |
1983年 | 7061篇 |
1982年 | 5518篇 |
1981年 | 4996篇 |
1980年 | 4642篇 |
1979年 | 7678篇 |
1978年 | 5910篇 |
1977年 | 5421篇 |
1976年 | 5056篇 |
1975年 | 5359篇 |
1974年 | 5803篇 |
1973年 | 5653篇 |
1972年 | 5095篇 |
1971年 | 4725篇 |
1970年 | 3920篇 |
1969年 | 3848篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
1.
Bo R. Park Ryszard A. Zielke Igor H. Wierzbicki Kristie C. Mitchell Jeffrey H. Withey Aleksandra E. Sikora 《Journal of bacteriology》2015,197(6):1051-1064
Vibrio cholerae is autochthonous to various aquatic niches and is the etiological agent of the life-threatening diarrheal disease cholera. The persistence of V. cholerae in natural habitats is a crucial factor in the epidemiology of cholera. In contrast to the well-studied V. cholerae-chitin connection, scarce information is available about the factors employed by the bacteria for the interaction with collagens. Collagens might serve as biologically relevant substrates, because they are the most abundant protein constituents of metazoan tissues and V. cholerae has been identified in association with invertebrate and vertebrate marine animals, as well as in a benthic zone of the ocean where organic matter, including collagens, accumulates. Here, we describe the characterization of the V. cholerae putative collagenase, VchC, encoded by open reading frame VC1650 and belonging to the subfamily M9A peptidases. Our studies demonstrate that VchC is an extracellular collagenase degrading native type I collagen of fish and mammalian origin. Alteration of the predicted catalytic residues coordinating zinc ions completely abolished the protein enzymatic activity but did not affect the translocation of the protease by the type II secretion pathway into the extracellular milieu. We also show that the protease undergoes a maturation process with the aid of a secreted factor(s). Finally, we propose that V. cholerae is a collagenovorous bacterium, as it is able to utilize collagen as a sole nutrient source. This study initiates new lines of investigations aiming to uncover the structural and functional components of the V. cholerae collagen utilization program. 相似文献
2.
Ryan Roth Richard Swanson Gonzalo Izaguirre Susan C. Bock Peter G. W. Gettins Steven T. Olson 《The Journal of biological chemistry》2015,290(47):28020-28036
Past studies have suggested that a key feature of the mechanism of heparin allosteric activation of the anticoagulant serpin, antithrombin, is the release of the reactive center loop P14 residue from a native state stabilizing interaction with the hydrophobic core. However, more recent studies have indicated that this structural change plays a secondary role in the activation mechanism. To clarify this role, we expressed and characterized 15 antithrombin P14 variants. The variants exhibited basal reactivities with factors Xa and IXa, heparin affinities and thermal stabilities that were dramatically altered from wild type, consistent with the P14 mutations perturbing native state stability and shifting an allosteric equilibrium between native and activated states. Rapid kinetic studies confirmed that limiting rate constants for heparin allosteric activation of the mutants were altered in conjunction with the observed shifts of the allosteric equilibrium. However, correlations of the P14 mutations'' effects on parameters reflecting the allosteric activation state of the serpin were inconsistent with a two-state model of allosteric activation and suggested multiple activated states. Together, these findings support a minimal three-state model of allosteric activation in which the P14 mutations perturb equilibria involving distinct native, intermediate, and fully activated states wherein the P14 residue retains an interaction with the hydrophobic core in the intermediate state but is released from the core in the fully activated state, and the bulk of allosteric activation has occurred in the intermediate. 相似文献
3.
4.
5.
Cortney C. Winkle Leslie M. McClain Juli G. Valtschanoff Charles S. Park Christopher Maglione Stephanie L. Gupton 《The Journal of cell biology》2014,205(2):217-232
Developmental axon branching dramatically increases synaptic capacity and neuronal surface area. Netrin-1 promotes branching and synaptogenesis, but the mechanism by which Netrin-1 stimulates plasma membrane expansion is unknown. We demonstrate that SNARE-mediated exocytosis is a prerequisite for axon branching and identify the E3 ubiquitin ligase TRIM9 as a critical catalytic link between Netrin-1 and exocytic SNARE machinery in murine cortical neurons. TRIM9 ligase activity promotes SNARE-mediated vesicle fusion and axon branching in a Netrin-dependent manner. We identified a direct interaction between TRIM9 and the Netrin-1 receptor DCC as well as a Netrin-1–sensitive interaction between TRIM9 and the SNARE component SNAP25. The interaction with SNAP25 negatively regulates SNARE-mediated exocytosis and axon branching in the absence of Netrin-1. Deletion of TRIM9 elevated exocytosis in vitro and increased axon branching in vitro and in vivo. Our data provide a novel model for the spatial regulation of axon branching by Netrin-1, in which localized plasma membrane expansion occurs via TRIM9-dependent regulation of SNARE-mediated vesicle fusion. 相似文献
6.
Hemant Kulkarni Peter J. Meikle Manju Mamtani Jacquelyn M. Weir Marcio Almeida Vincent Diego Juan Manuel Peralta Christopher K. Barlow Claire Bellis Thomas D. Dyer Laura Almasy Michael C. Mahaney Anthony G. Comuzzie Harald H. H. G?ring Joanne E. Curran John Blangero 《Journal of lipid research》2014,55(5):939-946
Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high-resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS. 相似文献
7.
8.
9.
10.