全文获取类型
收费全文 | 834篇 |
免费 | 61篇 |
专业分类
895篇 |
出版年
2023年 | 7篇 |
2022年 | 12篇 |
2021年 | 29篇 |
2020年 | 19篇 |
2019年 | 15篇 |
2018年 | 17篇 |
2017年 | 12篇 |
2016年 | 32篇 |
2015年 | 52篇 |
2014年 | 52篇 |
2013年 | 73篇 |
2012年 | 68篇 |
2011年 | 88篇 |
2010年 | 53篇 |
2009年 | 40篇 |
2008年 | 44篇 |
2007年 | 43篇 |
2006年 | 50篇 |
2005年 | 33篇 |
2004年 | 42篇 |
2003年 | 36篇 |
2002年 | 29篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 7篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1991年 | 4篇 |
1990年 | 1篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1980年 | 1篇 |
1977年 | 1篇 |
排序方式: 共有895条查询结果,搜索用时 15 毫秒
891.
892.
Yannick F. Fuchs Stephan A. Eisler Gisela Link Oliver Schlicker Gertrude Bunt Klaus Pfizenmaier Angelika Hausser 《Traffic (Copenhagen, Denmark)》2009,10(7):858-867
The protein kinase D (PKD) family comprises multifunctional serine/threonine-specific protein kinases with three mammalian isoforms: PKD1, PKD2 and PKD3. A prominent PKD function is the regulation of basolateral-targeted transport carrier fission from the trans -Golgi network (TGN). To visualize site-specific PKD activation at this organelle, we designed a molecular reporter consisting of a PKD-specific substrate sequence fused to enhanced green fluorescent protein (EGFP), specifically targeted to the TGN via the p230 GRIP domain. Quantitative analyses using a phosphospecific antibody and ratiometric fluorescence imaging revealed that Golgi-specific phosphorylation of the reporter was strictly dependent on stimulation of endogenous PKD or transient expression of active PKD constructs. Conversely, PKD-specific pharmacological inhibitors and siRNA-mediated PKD knockdown suppressed reporter phosphorylation. Using this reporter we investigated a potential role for PKD in the regulation of Golgi complex morphology. Interestingly, nocodazole-induced Golgi complex break-up and dispersal was associated with local PKD activation as measured by reporter phosphorylation and this was efficiently blocked by expression of a dominant-negative PKD mutant or PKD depletion. Our data thus identify a novel link between PKD activity and the microtubule cytoskeleton, whereby Golgi complex integrity is regulated. 相似文献
893.
The innate immune system provides defence against parasites and pathogens. This defence comes at a cost, suggesting that immune function should exhibit plasticity in response to variation in environmental threats. Density-dependent prophylaxis (DDP) has been demonstrated mostly in phase-polyphenic insects, where larval group size determines levels of immune function in either adults or later larval instars. Social insects exhibit extreme sociality, but DDP has been suggested to be absent from these ecologically dominant taxa. Here we show that adult bumble-bee workers (Bombus terrestris) exhibit rapid plasticity in their immune function in response to social context. These results suggest that DDP does not depend upon larval conditions, and is likely to be a widespread and labile response to rapidly changing conditions in adult insect populations. This has obvious ramifications for experimental analysis of immune function in insects, and serious implications for our understanding of the epidemiology and impact of pathogens and parasites in spatially structured adult insect populations. 相似文献
894.
Vinaya Phatak Yannick von Grabowiecki Justyna Janus Leah Officer Caron Behan Lydia Aschauer Lucia Pinon Hannah Mackay Sara Zanivan Jim C. Norman Michael Kelly John Le Quesne Patricia A. J. Muller 《Cell death & disease》2021,12(2)
TP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.Subject terms: Tumour-suppressor proteins, Preclinical research 相似文献