全文获取类型
收费全文 | 641篇 |
免费 | 41篇 |
国内免费 | 117篇 |
出版年
2024年 | 3篇 |
2023年 | 9篇 |
2022年 | 15篇 |
2021年 | 31篇 |
2020年 | 20篇 |
2019年 | 29篇 |
2018年 | 18篇 |
2017年 | 16篇 |
2016年 | 21篇 |
2015年 | 42篇 |
2014年 | 41篇 |
2013年 | 45篇 |
2012年 | 59篇 |
2011年 | 47篇 |
2010年 | 52篇 |
2009年 | 34篇 |
2008年 | 43篇 |
2007年 | 27篇 |
2006年 | 32篇 |
2005年 | 29篇 |
2004年 | 22篇 |
2003年 | 19篇 |
2002年 | 14篇 |
2001年 | 13篇 |
2000年 | 8篇 |
1999年 | 10篇 |
1998年 | 9篇 |
1997年 | 11篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1990年 | 7篇 |
1989年 | 11篇 |
1988年 | 6篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1979年 | 3篇 |
1977年 | 1篇 |
1958年 | 1篇 |
1956年 | 1篇 |
1954年 | 3篇 |
1953年 | 1篇 |
1951年 | 1篇 |
排序方式: 共有799条查询结果,搜索用时 46 毫秒
61.
CHIP is a ubiquitin ligase implicated in the degradation of misfolded proteins. In the November 23 issue of Molecular Cell, identified CHIP as a protein that interacts with the ubiquitin E2 complex Ubc13-Uev1A, which catalyzes the synthesis of Lys-63-linked polyubiquitin chains. Although the ubiquitin ligase activity of CHIP requires its dimerization through the U box domain, the crystal structure of the CHIP-E2 complex reveals that the protomers in the CHIP homodimer adopt distinct conformations such that only one U box of CHIP interacts with Ubc13. 相似文献
62.
Lu Z Bohn J Rano T Rutkowski CA Simcoe AL Olsen DB Schleif WA Carella A Gabryelski L Jin L Lin JH Emini E Chapman K Tata JR 《Bioorganic & medicinal chemistry letters》2005,15(23):5311-5314
Efforts directed to identifying potent HIV protease inhibitors (PI) have yielded a class of compounds that are not only very active against wild-type (NL4-3) HIV virus but also very potent against a panel of PI-resistant viral isolates. Chemistry and biology are described. 相似文献
63.
We developed and evaluated simple sequence repeat (SSR) markers derived from expressed sequence tags (ESTs) of Liriodendron tulipifera. Characteristics of 15 EST‐SSR loci were investigated using 33 L. tulipifera individuals. The number of alleles per locus ranged from two to five. The expected and observed heterozygosities ranged from 0.216 to 0.751 and from 0.182 to 0.97, respectively. These loci were further tested for their cross‐species transferability to Liriodendron Chinense. Because of their high level of polymorphism and transferability, our 15 single‐locus EST‐SSR markers will be valuable tools for research on mating system, population genetics and systemic evolution of Liriodendron. 相似文献
64.
65.
Franco J. Vizeacoumar Nydia van Dyk Frederick S.Vizeacoumar Vincent Cheung Jingjing Li Yaroslav Sydorskyy Nicolle Case Zhijian Li Alessandro Datti Corey Nislow Brian Raught Zhaolei Zhang Brendan Frey Kerry Bloom Charles Boone Brenda J. Andrews 《The Journal of cell biology》2010,188(1):69-81
We describe the application of a novel screening approach that combines automated yeast genetics, synthetic genetic array (SGA) analysis, and a high-content screening (HCS) system to examine mitotic spindle morphogenesis. We measured numerous spindle and cellular morphological parameters in thousands of single mutants and corresponding sensitized double mutants lacking genes known to be involved in spindle function. We focused on a subset of genes that appear to define a highly conserved mitotic spindle disassembly pathway, which is known to involve Ipl1p, the yeast aurora B kinase, as well as the cell cycle regulatory networks mitotic exit network (MEN) and fourteen early anaphase release (FEAR). We also dissected the function of the kinetochore protein Mcm21p, showing that sumoylation of Mcm21p regulates the enrichment of Ipl1p and other chromosomal passenger proteins to the spindle midzone to mediate spindle disassembly. Although we focused on spindle disassembly in a proof-of-principle study, our integrated HCS-SGA method can be applied to virtually any pathway, making it a powerful means for identifying specific cellular functions. 相似文献
66.
67.
Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO 总被引:7,自引:0,他引:7
The receptor interacting protein kinase 1 (RIP1) is essential for the activation of nuclear factor kappaB (NF-kappaB) by tumor necrosis factor alpha (TNFalpha). Here, we present evidence that TNFalpha induces the polyubiquitination of RIP1 at Lys-377 and that this polyubiquitination is required for the activation of IkappaB kinase (IKK) and NF-kappaB. A point mutation of RIP1 at Lys-377 (K377R) abolishes its polyubiquitination as well as its ability to restore IKK activation in a RIP1-deficient cell line. The K377R mutation of RIP1 also prevents the recruitment of TAK1 and IKK complexes to TNF receptor. Interestingly, polyubiquitinated RIP1 recruits IKK through the binding between the polyubiquitin chains and NEMO, a regulatory subunit of the IKK complex. Mutations of NEMO that disrupt its polyubiquitin binding also abolish IKK activation. These results reveal the biochemical mechanism underlying the essential signaling function of NEMO and provide direct evidence that signal-induced site-specific ubiquitination of RIP1 is required for IKK activation. 相似文献
68.
Lu Z Bohn J Bergeron R Deng Q Ellsworth KP Geissler WM Harris G McCann PE McKeever B Myers RW Saperstein R Willoughby CA Yao J Chapman K 《Bioorganic & medicinal chemistry letters》2003,13(22):4125-4128
A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed. 相似文献
69.
Lin DH Yue P Rinehart J Sun P Wang Z Lifton R Wang WH 《American journal of physiology. Renal physiology》2012,303(1):F110-F119
With-no-Lysine kinase 4 (WNK4) inhibited ROMK (Kir1.1) channels and the inhibitory effect of WNK4 was abolished by serum-glucocorticoid-induced kinase 1 (SGK1) but restored by c-Src. The aim of the present study is to explore the mechanism by which Src-family tyrosine kinase (SFK) modulates the effect of SGK1 on WNK4 and to test the role of SFK-WNK4-SGK1 interaction in regulating ROMK channels in the kidney. Immunoprecipitation demonstrated that protein phosphatase 1 (PP1) binds to WNK4 at amino acid (aa) residues 695-699 (PP1(#1)) and at aa 1211-1215 (PP1(#2)). WNK4(-PP1#1) and WNK4(-PP1#2), in which the PP1(#1) or PP1(#2) binding site was deleted or mutated, inhibited ROMK channels as potently as WNK4. However, c-Src restored the inhibitory effect of WNK4 but not WNK4(-PP1#1) on ROMK channels in the presence of SGK1. Moreover, expression of c-Src inhibited SGK1-induced phosphorylation of WNK4 but not WNK4(-PP1#1) at serine residue 1196 (Ser(1196)). In contrast, coexpression of c-Src restored the inhibitory effect of WNK4(-PP1#2) on ROMK in the presence of SGK1 and diminished SGK1-induced WNK4 phosphorylation at Ser(1196) in cells transfected with WNK4(-PP1#2). This suggests the possibility that c-Src regulates the interaction between WNK4 and SGK1 through activating PP1 binding to aa 695-9 thereby decreasing WNK4 phosphorylation and restoring the inhibitory effect of WNK4. This mechanism plays a role in suppressing ROMK channel activity during the volume depletion because inhibition of SFK or serine/threonine phosphatases increases ROMK channel activity in the cortical collecting duct of rats on a low-Na diet. We conclude that regulation of phosphatase activity by SFK plays a role in determining the effect of aldosterone on ROMK channels and on renal K secretion. 相似文献
70.
Clingan JM Ostrow K Hosiawa KA Chen ZJ Matloubian M 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(9):4432-4440
The necessity for pathogen recognition of viral infection by the innate immune system in initiating early innate and adaptive host defenses is well documented. However, little is known about the role these receptors play in the maintenance of adaptive immune responses and their contribution to resolution of persistent viral infections. In this study, we demonstrate a nonredundant functional requirement for both nucleic acid-sensing TLRs and RIG-I-like receptors in the control of a mouse model of chronic viral infection. Whereas the RIG-I-like receptor pathway was important for production of type I IFNs and optimal CD8(+) T cell responses, nucleic acid-sensing TLRs were largely dispensable. In contrast, optimal anti-viral Ab responses required intact signaling through nucleic acid-sensing TLRs, and the absence of this pathway correlated with less virus-specific Ab and deficient long-term virus control of a chronic infection. Surprisingly, absence of the TLR pathway had only modest effects on Ab production in an acute infection with a closely related virus strain, suggesting that persistent TLR stimulation may be necessary for optimal Ab responses in a chronic infection. These results indicate that innate virus recognition pathways may play critical roles in the outcome of chronic viral infections through distinct mechanisms. 相似文献