全文获取类型
收费全文 | 4664篇 |
免费 | 358篇 |
出版年
2023年 | 28篇 |
2022年 | 20篇 |
2021年 | 124篇 |
2020年 | 70篇 |
2019年 | 83篇 |
2018年 | 122篇 |
2017年 | 85篇 |
2016年 | 150篇 |
2015年 | 249篇 |
2014年 | 241篇 |
2013年 | 335篇 |
2012年 | 375篇 |
2011年 | 338篇 |
2010年 | 240篇 |
2009年 | 217篇 |
2008年 | 302篇 |
2007年 | 310篇 |
2006年 | 259篇 |
2005年 | 224篇 |
2004年 | 226篇 |
2003年 | 206篇 |
2002年 | 155篇 |
2001年 | 39篇 |
2000年 | 39篇 |
1999年 | 44篇 |
1998年 | 56篇 |
1997年 | 29篇 |
1996年 | 30篇 |
1995年 | 34篇 |
1994年 | 24篇 |
1993年 | 20篇 |
1992年 | 21篇 |
1991年 | 25篇 |
1990年 | 25篇 |
1989年 | 16篇 |
1988年 | 13篇 |
1987年 | 11篇 |
1986年 | 12篇 |
1985年 | 20篇 |
1984年 | 25篇 |
1983年 | 15篇 |
1982年 | 20篇 |
1981年 | 15篇 |
1979年 | 15篇 |
1978年 | 11篇 |
1977年 | 15篇 |
1974年 | 10篇 |
1973年 | 11篇 |
1972年 | 8篇 |
1968年 | 5篇 |
排序方式: 共有5022条查询结果,搜索用时 31 毫秒
1.
2.
3.
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
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.
Adrian C. Kanaar 《BMJ (Clinical research ed.)》1941,1(4188):549-552
7.
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
8.
9.
Site-selective cAMP analogs, depending on the position of their substituents on the adenine ring, selectively bind to either site 1 or site 2 of the known cAMP binding sites of protein kinase. Treatment of Harvey murine sarcoma virus-transformed NIH/3T3 cells with such site-selective analogs results in growth inhibition and phenotypic reversion, and the combination of a C-8 thio or halogen analog (site 1 selective) with an N6 analog (site 2 selective) produces a synergistic effect. We report here that the growth inhibitory effect of the analogs correlates with the nuclear translocation of the RII cAMP receptor protein, the regulatory subunit of protein kinase type II. The transformed NIH/3T3 cells contained no detectable level of RII in the nucleus, whereas nontransformed NIH/3T3 cells exhibited a high level of nuclear RII. Within 30 min after treatment of the transformed cells with the site-selective analogs, immunofluorescence against the RII protein markedly increased in the cell nucleus. The nuclear translocation of the RII cAMP receptor protein is an early event in the reverse transformation of the fibroblasts treated with site-selective cAMP analogs. 相似文献
10.
Comparative organization of nitrogen fixation-specific genes from Azotobacter vinelandii and Klebsiella pneumoniae: DNA sequence of the nifUSV genes. 总被引:10,自引:8,他引:2 下载免费PDF全文
J Beynon A Ally M Cannon F Cannon M Jacobson V Cash D Dean 《Journal of bacteriology》1987,169(9):4024-4029
In the facultative anaerobe Klebsiella pneumoniae 17 nitrogen fixation-specific genes (nif genes) have been identified. Homologs to 12 of these genes have now been isolated from the aerobic diazotroph Azotobacter vinelandii. Comparative studies have indicated that these diverse microorganisms share striking similarities in the genetic organization of their nif genes and in the primary structure of their individual nif gene products. In this study the complete nucleotide sequence of the nifUSV gene clusters from both K. pneumoniae and A. vinelandii were determined. These genes are identically organized on their respective genomes, and the individual genes and their products exhibit a high degree of interspecies sequence homology. 相似文献