全文获取类型
收费全文 | 3795篇 |
免费 | 366篇 |
国内免费 | 1篇 |
专业分类
4162篇 |
出版年
2024年 | 5篇 |
2023年 | 12篇 |
2022年 | 59篇 |
2021年 | 84篇 |
2020年 | 54篇 |
2019年 | 46篇 |
2018年 | 88篇 |
2017年 | 82篇 |
2016年 | 127篇 |
2015年 | 233篇 |
2014年 | 237篇 |
2013年 | 269篇 |
2012年 | 340篇 |
2011年 | 364篇 |
2010年 | 230篇 |
2009年 | 189篇 |
2008年 | 271篇 |
2007年 | 273篇 |
2006年 | 255篇 |
2005年 | 174篇 |
2004年 | 170篇 |
2003年 | 162篇 |
2002年 | 142篇 |
2001年 | 24篇 |
2000年 | 19篇 |
1999年 | 30篇 |
1998年 | 32篇 |
1997年 | 15篇 |
1996年 | 11篇 |
1995年 | 12篇 |
1994年 | 11篇 |
1993年 | 11篇 |
1992年 | 13篇 |
1991年 | 9篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 10篇 |
1987年 | 8篇 |
1986年 | 5篇 |
1985年 | 8篇 |
1984年 | 6篇 |
1983年 | 4篇 |
1982年 | 8篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1976年 | 4篇 |
1975年 | 4篇 |
1972年 | 4篇 |
1969年 | 4篇 |
1968年 | 3篇 |
排序方式: 共有4162条查询结果,搜索用时 15 毫秒
961.
Jenkins CE Swiatoniowski A Power MR Lin TJ 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(11):8000-8007
Mast cells play a critical role in the host defense against bacterial infection. Recently, apoptosis has been demonstrated to be essential in the regulation of host response to Pseudomonas aeruginosa. In this study we show that human mast cell line HMC-1 and human cord blood-derived mast cells undergo apoptosis as determined by the ssDNA formation after infection with P. aeruginosa. P. aeruginosa induced activation of caspase-3 in mast cells as evidenced by the cleavage of D4-GDI, an endogenous caspase-3 substrate and the generation of an active form of caspase-3. Interestingly, P. aeruginosa treatment induced up-regulation of Bcl-x(S) and down-regulation of Bcl-x(L). Bcl-x(S), and Bcl-x(L) are alternative variants produced from the same Bcl-x pre-mRNA. The former is proapoptotic and the latter is antiapoptotic likely through regulating mitochondrial membrane integrity. Treatment of mast cells with P. aeruginosa induced release of cytochrome c from mitochondria and loss of mitochondrial membrane potentials. Moreover, P. aeruginosa treatment reduced levels of Fas-associated death domain protein-like IL-1beta-converting enzyme-inhibitory proteins (FLIPs) that are endogenous apoptosis inhibitors through counteraction with caspase-8. Thus, human mast cells undergo apoptosis after encountering P. aeruginosa through a mechanism that likely involves both the Bcl family protein mitochondrial-dependent and the FLIP-associated caspase-8 pathways. 相似文献
962.
Strehl B Joeris T Rieger M Visekruna A Textoris-Taube K Kaufmann SH Kloetzel PM Kuckelkorn U Steinhoff U 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(9):6238-6244
Microbial infections induce the replacement of constitutive proteasomes by immunoproteasomes (I-proteasomes). I-proteasomes support efficient generation of MHC class I epitopes and influence immunodominance hierarchies of CD8(+) T cells. Recently, the function of I-proteasomes in antimicrobial responses was challenged by showing that the lack of I-proteasomes has no effect on induction and function of lymphocytic choriomeningitis virus-specific CD8(+) T cells. Here, we show that infection with Listeria monocytogenes rapidly induces I-proteasomes in nonlymphoid tissues, which leads to enhanced generation of protection relevant CD8(+) T cell epitopes. I-proteasome-deficient mice (beta5i(-/-) mice) exhibited normal frequencies of L. monocytogenes-specific CD8(+) T cells. However, clearance of L. monocytogenes in liver but not spleen was significantly impaired in I-proteasome-deficient mice. In summary, our studies demonstrate that induction of I-proteasomes is required for CD8(+) T cell-mediated elimination of L. monocytogenes from nonlymphoid but not lymphoid tissues. 相似文献
963.
Eckert M Wittmann I Röllinghoff M Gessner A Schnare M 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(1):522-528
964.
965.
Catimel B Layton M Church N Ross J Condron M Faux M Simpson RJ Burgess AW Nice EC 《Analytical biochemistry》2006,357(2):277-288
Phosphorylation is a key posttranslational modification for modulating biological interactions. Biosensor technology is ideally suited for examining in real time the role of phosphorylation on protein-protein interactions in signaling pathways. We have developed processes for on-chip phosphorylation of immobilized receptors on biosensor surfaces. These processes have been used to analyze E-cadherin/beta-catenin interactions. Phosphorylation of the intracellular domain (ICD) of E-cadherin modulates its affinity to beta-catenin and consequently the strength of cell-cell adhesion. We have phosphorylated immobilized E-cadherin ICD in situ using casein kinase 1 (CK1), casein kinase 2 (CK2), and src. On-chip phosphorylation of E-cadherin was confirmed using anti-phosphoserine and anti-phosphotyrosine antibodies. The binding of beta-catenin to E-cadherin was analyzed quantitatively. CK1 phosphorylation of E-cadherin increased the binding affinity to beta-catenin from approximately 230 to 4 nM. A similar increase in affinity, from 260 to 4 nM, was obtained with CK2 phosphorylation of E-cadherin. However, phosphorylation by src kinase decreased the affinity constant from approximately 260 nM to 4 microM. Interestingly, phosphorylation of E-cadherin by CK1 or CK2 prevented the inhibition of beta-catenin binding by src phosphorylation. 相似文献
966.
967.
968.
Functional effects of intramembranous proline substitutions in the staphylococcal multidrug transporter QacA 总被引:3,自引:0,他引:3
The QacA multidrug transporter is encoded on Staphylococcus aureus multidrug resistance plasmids and confers broad-range antimicrobial resistance to more than 30 monovalent and bivalent lipophilic, cationic compounds from at least 12 different chemical classes. QacA contains 10 proline residues predicted to be within transmembrane regions, several of which are conserved in related export proteins. Proline residues are classically known as helix-breakers and are highly represented within the transmembrane helices of membrane transport proteins, where they can mediate the formation of structures essential for protein stability and transport function. The importance of these 10 intramembranous proline residues for QacA-mediated transport function was determined by examining the functional effect of substituting these residues with glycine, alanine or serine. Several proline-substituted QacA mutants failed to confer high-level resistance to selected QacA substrates. However, no single proline mutation, including those at conserved positions, significantly disrupted QacA protein expression or QacA-mediated resistance to all representative substrates, suggesting that these residues are not essential for the formation of structures requisite to the QacA substrate transport mechanism. 相似文献
969.
RGS2, one of the small members of the regulator of G protein signaling (RGS) family, is highly expressed in brain and regulates G(i/o) as well as G(q)-coupled receptor pathways. RGS2 modulates anxiety, aggression, and blood pressure in mice, suggesting that RGS2 regulates synaptic circuits underlying animal physiology and behavior. How RGS2 in brain influences synaptic activity is unknown. We therefore analyzed the synaptic function of RGS2 in hippocampal neurons by comparing electrophysiological recordings from RGS2 knockout and wild-type mice. Our study provides a general mechanism of the action of the RGS family containing RGS2 by demonstrating that RGS2 increases synaptic vesicle release by downregulating the G(i/o)-mediated presynaptic Ca(2+) channel inhibition and therefore provides an explanation of how regulation of RGS2 expression can modulate the function of neuronal circuits underlying behavior. 相似文献
970.
DNA replication occurs at discrete sites in the cell. To gain insight into the spatial and temporal organization of the Bacillus subtilis replication cycle, we simultaneously visualized replication origins and the replication machinery (replisomes) inside live cells. We found that the origin of replication is positioned near midcell prior to replication. After initiation, the replisome colocalizes with the origin, confirming that replication initiates near midcell. The replisome remains near midcell after duplicated origins separate. Artificially mispositioning the origin region leads to mislocalization of the replisome indicating that the location of the origin at the time of initiation establishes the position of the replisome. Time-lapse microscopy revealed that a single replisome focus reversibly splits into two closely spaced foci every few seconds in many cells, including cells that recently initiated replication. Thus, sister replication forks are likely not intimately associated with each other throughout the replication cycle. Fork dynamics persisted when replication elongation was halted, and is thus independent of the relative movement of DNA through the replisome. Our results provide new insights into how the replisome is positioned in the cell and refine our current understanding of the spatial and temporal events of the B. subtilis replication cycle. 相似文献