全文获取类型
收费全文 | 494篇 |
免费 | 65篇 |
国内免费 | 1篇 |
出版年
2021年 | 6篇 |
2020年 | 3篇 |
2019年 | 5篇 |
2016年 | 8篇 |
2015年 | 11篇 |
2014年 | 14篇 |
2013年 | 11篇 |
2012年 | 22篇 |
2011年 | 40篇 |
2010年 | 27篇 |
2009年 | 16篇 |
2008年 | 26篇 |
2007年 | 33篇 |
2006年 | 23篇 |
2005年 | 26篇 |
2004年 | 29篇 |
2003年 | 22篇 |
2002年 | 26篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 10篇 |
1998年 | 10篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1994年 | 4篇 |
1993年 | 13篇 |
1992年 | 18篇 |
1991年 | 7篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 4篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 3篇 |
1981年 | 7篇 |
1980年 | 6篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1976年 | 4篇 |
1975年 | 8篇 |
1974年 | 2篇 |
1973年 | 7篇 |
1972年 | 3篇 |
1969年 | 3篇 |
1968年 | 2篇 |
排序方式: 共有560条查询结果,搜索用时 15 毫秒
81.
82.
83.
84.
Scherzer R Gdalevsky GY Goldgur Y Cohen-Luria R Bittner S Parola AH 《Journal of enzyme inhibition and medicinal chemistry》2009,24(2):350-355
Tryptophanase (tryptophan indole-lyase, Tnase, EC 4.1.99.1), a bacterial enzyme with no counterpart in eukaryotic cells, produces from L-tryptophan pyruvate, ammonia and indole. It was recently suggested that indole signaling plays an important role in the stable maintenance of multicopy plasmids. In addition, Tnase was shown to be capable of binding Rcd, a short RNA molecule involved in resolution of plasmid multimers. Binding of Rcd increases the affinity of Tnase for tryptophan, and it was proposed that indole is involved in bacteria multiplication and biofilm formation. Biofilm-associated bacteria may cause serious infections, and biofilm contamination of equipment and food, may result in expensive consequences. Thus, optimal and specific factors that interact with Tnase can be used as a tool to study the role of this multifunctional enzyme as well as antibacterial agents that may affect biofilm formation. Most known quasi-substrates inhibit Tnase at the mM range. In the present work, the mode of Tnase inhibition by the following compounds and the corresponding Ki values were: S-phenylbenzoquinone-L-tryptophan, uncompetitively, 101 microM; alpha-amino-2-(9,10-anthraquinone)-propanoic acid, noncompetitively, 174 microM; L-tryptophane-ethylester, competitively, 52 microM; N-acetyl-L-tryptophan, noncompetitively, 48 microM. S-phenylbenzoquinone-L-tryptophan and alpha-amino-2-(9,10-anthraquinone)-propanoic acid were newly synthesized. 相似文献
85.
86.
Iris Alchanati Carmit Teicher Galit Cohen Vivian Shemesh Haim M. Barr Philippe Nakache Danny Ben-Avraham Anna Idelevich Itzchak Angel Nurit Livnah Shmuel Tuvia Yuval Reiss Daniel Taglicht Omri Erez 《PloS one》2009,4(12)
Background
The topoisomerases Top1, Top2α and Top2β are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2β are subject to proteasomal degradation, this phenomena was not demonstrated for Top2α.Methodology/Principal Findings
We show here that Top2α is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2β. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2α degradation, increases the persistence of Top2α-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2α in-vitro and cellular overexpression of Bmi1 increases drug induced Top2α ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2α ubiquitination and drug-induced Top2α degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner.Conclusions/Significance
The discovery that poisoned Top2α is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1. 相似文献87.
88.
Citri A Harari D Shohat G Ramakrishnan P Gan J Lavi S Eisenstein M Kimchi A Wallach D Pietrokovski S Yarden Y 《The Journal of biological chemistry》2006,281(20):14361-14369
Hsp90 is a highly abundant chaperone whose clientele includes hundreds of cellular proteins, many of which are central players in key signal transduction pathways and the majority of which are protein kinases. In light of the variety of Hsp90 clientele, the mechanism of selectivity of the chaperone toward its client proteins is a major open question. Focusing on human kinases, we have demonstrated that the chaperone recognizes a common surface in the amino-terminal lobe of kinases from diverse families, including two newly identified clients, NFkappaB-inducing kinase and death-associated protein kinase, and the oncoprotein HER2/ErbB-2. Surface electrostatics determine the interaction with the Hsp90 chaperone complex such that introduction of a negative charge within this region disrupts recognition. Compiling information on the Hsp90 dependence of 105 protein kinases, including 16 kinases whose relationship to Hsp90 is first examined in this study, reveals that surface features, rather than a contiguous amino acid sequence, define the capacity of the Hsp90 chaperone machine to recognize client kinases. Analyzing Hsp90 regulation of two major signaling cascades, the mitogen-activated protein kinase and phosphatidylinositol 3-kinase, leads us to propose that the selectivity of the chaperone to specific kinases is functional, namely that Hsp90 controls kinases that function as hubs integrating multiple inputs. These lessons bear significance to pharmacological attempts to target the chaperone in human pathologies, such as cancer. 相似文献
89.
Kim JY Zeng W Kiselyov K Yuan JP Dehoff MH Mikoshiba K Worley PF Muallem S 《The Journal of biological chemistry》2006,281(43):32540-32549
Store-operated Ca(2+) channels (SOCs) mediate receptor-stimulated Ca(2+) influx. Accumulating evidence indicates that members of the transient receptor potential (TRP) channel family are components of SOCs in mammalian cells. Agonist stimulation activates SOCs and TRP channels directly and by inducing translocation of channels in intracellular vesicles to the plasma membrane (PM). The mechanism of TRP channel translocation in response to store depletion and agonist stimulation is not known. Here we use TRPC3 as a model to show that IP(3) and the scaffold Homer 1 (H1) regulate the rate of translocation and retrieval of TRPC3 from the PM. In resting cells, TRPC3 exists in TRPC3-H1b/c-IP(3)Rs complexes that are located in part at the PM and in part in intracellular vesicles. Binding of IP(3) to the IP(3)Rs dissociates the interaction between IP(3)Rs and H1 but not between H1 and TRPC3 to form IP(3)Rs-TRPC3-H1b/c. TIRFM and biotinylation assays show robust receptor- and store-dependent translocation of the TRPC3 to the PM and their retrieval upon termination of cell stimulation. The translocation requires depletion of stored Ca(2+) and is prevented by inhibition of the IP(3)Rs. In HEK293, dissociating the H1b/c-IP(3)R complex with H1a results in TRPC3 translocation to the PM, where it is spontaneously active. The TRPC3-H1b/c-IP(3)Rs complex is reconstituted by infusing H1c into these cells. Reconstitution is inhibited by IP(3). Deletion of H1 in mice markedly reduces the rates of translocation and retrieval of TRPC3. Conversely, infusion of H1c into H1(-/-) cells eliminates spontaneous channel activity and increases the rate of channel activation by agonist stimulation. The effects of H1c are inhibited by IP(3). These findings together with our earlier studies demonstrating gating of TRPC3 by IP(3)Rs were used to develop a model in which assembly of the TRPC3-H1b/c-IP(3)Rs complexes by H1b/c mediates both the translocation of TRPC3-containing vesicles to the PM and gating of TRPC3 by IP(3)Rs. 相似文献
90.