全文获取类型
收费全文 | 5758篇 |
免费 | 512篇 |
专业分类
6270篇 |
出版年
2023年 | 43篇 |
2022年 | 79篇 |
2021年 | 134篇 |
2020年 | 78篇 |
2019年 | 99篇 |
2018年 | 141篇 |
2017年 | 96篇 |
2016年 | 174篇 |
2015年 | 279篇 |
2014年 | 277篇 |
2013年 | 380篇 |
2012年 | 434篇 |
2011年 | 399篇 |
2010年 | 271篇 |
2009年 | 247篇 |
2008年 | 344篇 |
2007年 | 358篇 |
2006年 | 294篇 |
2005年 | 260篇 |
2004年 | 248篇 |
2003年 | 235篇 |
2002年 | 177篇 |
2001年 | 75篇 |
2000年 | 56篇 |
1999年 | 61篇 |
1998年 | 70篇 |
1997年 | 41篇 |
1996年 | 42篇 |
1995年 | 44篇 |
1994年 | 39篇 |
1993年 | 30篇 |
1992年 | 52篇 |
1991年 | 39篇 |
1990年 | 54篇 |
1989年 | 45篇 |
1988年 | 28篇 |
1987年 | 35篇 |
1986年 | 30篇 |
1985年 | 38篇 |
1984年 | 42篇 |
1983年 | 24篇 |
1982年 | 36篇 |
1981年 | 24篇 |
1979年 | 29篇 |
1978年 | 19篇 |
1977年 | 23篇 |
1974年 | 22篇 |
1973年 | 28篇 |
1972年 | 20篇 |
1969年 | 16篇 |
排序方式: 共有6270条查询结果,搜索用时 0 毫秒
1.
2.
This study presents an approach to identifying surface residues on membrane proteins that are exposed toward the membrane-aqueous interface. The method employs a lipid Ni(II) chelate that localizes the metal ion to a region near the membrane-aqueous interface. Lateral diffusion of the lipid chelate results in Heisenberg exchange (HE) with nitroxide side chains in the protein only if direct contact occurs between the paramagnetic species during a collision. Thus, HE serves as a signature for residues facing the bilayer in the neighborhood of the membrane-aqueous interface. To evaluate the method, 13 surface residues on the extracellular half of KcsA, a prokaryotic potassium channel of known structure, were examined for HE with the Ni(II) chelate. The HE rate between the two species is found to depend strongly on the vertical position of the nitroxide with respect to the membrane-aqueous interface. Nitroxides introduced near the interface experience relatively high HE rates, whereas nitroxides that are immersed in the bilayer interior or sterically sheltered from collision experience low or undetectable rates. The results indicate that residues near the interface can be identified on the basis of their high rates of collision with the headgroup region of the bilayer. 相似文献
3.
4.
5.
Alicia P. Higueruelo Adrian Schreyer G. Richard J Bickerton Tom L. Blundell Will R. Pitt 《PloS one》2012,7(12)
Efforts to increase affinity in the design of new therapeutic molecules have tended to lead to greater lipophilicity, a factor that is generally agreed to be contributing to the low success rate of new drug candidates. Our aim is to provide a structural perspective to the study of lipophilic efficiency and to compare molecular interactions created over evolutionary time with those designed by humans. We show that natural complexes typically engage in more polar contacts than synthetic molecules bound to proteins. The synthetic molecules also have a higher proportion of unmatched heteroatoms at the interface than the natural sets. These observations suggest that there are lessons to be learnt from Nature, which could help us to improve the characteristics of man-made molecules. In particular, it is possible to increase the density of polar contacts without increasing lipophilicity and this is best achieved early in discovery while molecules remain relatively small. 相似文献
6.
Yi Ting Zhou Li Li Chew Sheng-cai Lin Boon Chuan Low 《Molecular biology of the cell》2010,21(18):3232-3246
The BNIP-2 and Cdc42GAP homology (BCH) domain is a novel regulator for Rho GTPases, but its impact on p50-Rho GTPase-activating protein (p50RhoGAP or Cdc42GAP) in cells remains elusive. Here we show that deletion of the BCH domain from p50RhoGAP enhanced its GAP activity and caused drastic cell rounding. Introducing constitutively active RhoA or inactivating GAP domain blocked such effect, whereas replacing the BCH domain with endosome-targeting SNX3 excluded requirement of endosomal localization in regulating the GAP activity. Substitution with homologous BCH domain from Schizosaccharomyces pombe, which does not bind mammalian RhoA, also led to complete loss of suppression. Interestingly, the p50RhoGAP BCH domain only targeted RhoA, but not Cdc42 or Rac1, and it was unable to distinguish between GDP and the GTP-bound form of RhoA. Further mutagenesis revealed a RhoA-binding motif (residues 85-120), which when deleted, significantly reduced BCH inhibition on GAP-mediated cell rounding, whereas its full suppression also required an intramolecular interaction motif (residues 169-197). Therefore, BCH domain serves as a local modulator in cis to sequester RhoA from inactivation by the adjacent GAP domain, adding to a new paradigm for regulating p50RhoGAP signaling. 相似文献
7.
8.
We have previously reported that in vitro HCV infection of cells of hepatocyte origin attenuates complement system at multiple steps, and attenuation also occurs in chronically HCV infected liver, irrespective of the disease stage. However, none of these regulations alone completely impaired complement pathways. Modulation of the upstream proteins involved in proteolytic processing of the complement cascade prior to convertase formation is critical in promoting the function of the complement system in response to infection. Here, we examined the regulation of C2 complement expression in hepatoma cells infected in vitro with cell culture grown virus, and validated our observations using randomly selected chronically HCV infected patient liver biopsy specimens. C2 mRNA expression was significantly inhibited, and classical C3 convertase (C4b2a) decreased. In separate experiments for C3 convertase function, C3b deposition onto bacterial membrane was reduced using HCV infected patient sera as compared to uninfected control, suggesting impaired C3 convertase. Further, iC3b level, a proteolytically inactive form of C3b, was lower in HCV infected patient sera, reflecting impairment of both C3 convertase and Factor I activity. The expression level of Factor I was significantly reduced in HCV infected liver biopsy specimens, while Factor H level remained unchanged or enhanced. Together, these results suggested that inhibition of C3 convertase activity is an additional cumulative effect for attenuation of complement system adopted by HCV for weakening innate immune response. 相似文献
9.
10.