全文获取类型
收费全文 | 214篇 |
免费 | 39篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 3篇 |
妇产科学 | 12篇 |
基础医学 | 22篇 |
临床医学 | 5篇 |
内科学 | 115篇 |
皮肤病学 | 6篇 |
神经病学 | 25篇 |
特种医学 | 31篇 |
外科学 | 10篇 |
综合类 | 2篇 |
预防医学 | 8篇 |
眼科学 | 1篇 |
药学 | 8篇 |
肿瘤学 | 4篇 |
出版年
2021年 | 1篇 |
2015年 | 1篇 |
2014年 | 2篇 |
2013年 | 2篇 |
2012年 | 7篇 |
2011年 | 2篇 |
2010年 | 3篇 |
2009年 | 3篇 |
2008年 | 2篇 |
2007年 | 3篇 |
2006年 | 3篇 |
2005年 | 3篇 |
2004年 | 6篇 |
2003年 | 11篇 |
2002年 | 3篇 |
2001年 | 19篇 |
2000年 | 13篇 |
1999年 | 6篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1994年 | 5篇 |
1993年 | 6篇 |
1992年 | 10篇 |
1991年 | 8篇 |
1990年 | 7篇 |
1989年 | 12篇 |
1988年 | 11篇 |
1987年 | 11篇 |
1986年 | 12篇 |
1985年 | 10篇 |
1984年 | 12篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 5篇 |
1977年 | 1篇 |
1976年 | 4篇 |
1975年 | 6篇 |
1974年 | 1篇 |
1972年 | 5篇 |
1970年 | 3篇 |
1969年 | 1篇 |
1967年 | 2篇 |
1965年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有253条查询结果,搜索用时 0 毫秒
251.
Julien Giustiniani Béatrice Chambraud Elodie Sardin Omar Dounane Kevin Guillemeau Hiroko Nakatani Dominik Paquet Amina Kamah Isabelle Landrieu Guy Lippens Etienne-Emile Baulieu Marcel Tawk 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(12):4584-4589
The Tau protein is the major component of intracellular filaments observed in a number of neurodegenerative diseases known as tauopathies. The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) leads to severe human tauopathy. Here, we assess the impact of FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52), an immunophilin protein that interacts with physiological Tau, on Tau-P301L activity. We identify a direct interaction of FKBP52 with Tau-P301L and its phosphorylated forms and demonstrate FKBP52’s ability to induce the formation of Tau-P301L oligomers. EM analysis shows that Tau-P301L oligomers, induced by FKBP52, can assemble into filaments. In the transgenic zebrafish expressing the human Tau-P301L mutant, FKBP52 knockdown is sufficient to redrive defective axonal outgrowth and branching related to Tau-P301L expression in spinal primary motoneurons. This result correlates with a significant reduction of pT181 pathological phosphorylated Tau and with recovery of the stereotypic escape response behavior. Collectively, FKBP52 appears to be an endogenous candidate that directly interacts with the pathogenic Tau-P301L and modulates its function in vitro and in vivo.Tau is a MAP mainly found in neurons (1, 2), which becomes hyperphosphorylated in several neurodegenerative diseases known as tauopathies and forms intraneuronal aggregates called neurofibrillary tangles (NFTs) (3–5). The accumulation of Tau aggregates is a multistep process that involves transient species, and growing evidence suggests that not only the NFTs but equally small oligomeric species contribute to Tau-mediated neurotoxicity (6–8). The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) is identified in frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) (9). Larvae of the zebrafish overexpressing the Tau-P301L mutant protein show defects in motoneuron development early on, and in this model, different Tau phosphoforms are associated with its pathological state (10).The FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52) belongs to the immunophilin family and presents rotamase activity inhibited by FK506 binding (11). This enzymatic activity catalyzes the isomerization of peptidyl-prolyl bonds between cis and trans conformations, and therefore influences target protein folding and function (12, 13). FKBP52 contains additional functional domains, such as a tetratricopeptide repeat domain that serves as a binding site for molecular chaperone heat shock protein with a molecular mass of 90 kDa (14) and for which chaperone activity was observed (15).A novel role of FKBP52 has recently emerged because it binds directly to tubulin and induces tubulin depolymerization in vitro (16). Biochemical characterization of FKBP52 showed that it interacts with Tau, especially its hyperphosphorylated form, and demonstrated an antagonist effect of FKBP52 on Tau’s function in tubulin assembly (17). Here, we show that FKBP52 interacts with the pathological form of Tau-P301L and induces its oligomerization and assembly into filaments. Using a transgenic zebrafish model for Tau-P301L tauopathy (10), we show that FKBP52 knockdown attenuates pathological Tau activity to reestablish axonal outgrowth and branching in defective spinal primary motoneurons. This result confirms the functional implication of FKBP52 in modulating early pathological Tau activity, at least for axonal growth and motility. We propose that FKBP52 is an important regulator of Tau conformational change and assembly, and thus may be instrumental in a therapeutic approach to the disease. 相似文献
252.
253.