全文获取类型
收费全文 | 8033篇 |
免费 | 844篇 |
国内免费 | 3篇 |
专业分类
8880篇 |
出版年
2023年 | 56篇 |
2022年 | 145篇 |
2021年 | 272篇 |
2020年 | 137篇 |
2019年 | 180篇 |
2018年 | 206篇 |
2017年 | 195篇 |
2016年 | 343篇 |
2015年 | 531篇 |
2014年 | 531篇 |
2013年 | 543篇 |
2012年 | 697篇 |
2011年 | 725篇 |
2010年 | 462篇 |
2009年 | 360篇 |
2008年 | 507篇 |
2007年 | 511篇 |
2006年 | 385篇 |
2005年 | 379篇 |
2004年 | 391篇 |
2003年 | 335篇 |
2002年 | 306篇 |
2001年 | 57篇 |
2000年 | 42篇 |
1999年 | 55篇 |
1998年 | 74篇 |
1997年 | 32篇 |
1996年 | 46篇 |
1995年 | 29篇 |
1994年 | 23篇 |
1993年 | 18篇 |
1992年 | 17篇 |
1991年 | 18篇 |
1990年 | 16篇 |
1989年 | 8篇 |
1987年 | 6篇 |
1986年 | 10篇 |
1985年 | 11篇 |
1984年 | 17篇 |
1983年 | 10篇 |
1982年 | 12篇 |
1981年 | 23篇 |
1980年 | 13篇 |
1979年 | 9篇 |
1978年 | 10篇 |
1977年 | 7篇 |
1976年 | 7篇 |
1904年 | 5篇 |
1900年 | 5篇 |
1899年 | 5篇 |
排序方式: 共有8880条查询结果,搜索用时 15 毫秒
971.
Passero CJ Mueller GM Myerburg MM Carattino MD Hughey RP Kleyman TR 《American journal of physiology. Renal physiology》2012,302(1):F1-F8
The epithelial sodium channel (ENaC) is activated by a unique mechanism, whereby inhibitory tracts are released by proteolytic cleavage within the extracellular loops of two of its three homologous subunits. While cleavage by furin within the biosynthetic pathway releases one inhibitory tract from the α-subunit and moderately activates the channel, full activation through release of a second inhibitory tract from the γ-subunit requires cleavage once by furin and then at a distal site by a second protease, such as prostasin, plasmin, or elastase. We now report that coexpression of mouse transmembrane protease serine 4 (TMPRSS4) with mouse ENaC in Xenopus oocytes was associated with a two- to threefold increase in channel activity and production of a unique ~70-kDa carboxyl-terminal fragment of the γ-subunit, similar to the ~70-kDa γ-subunit fragment that we previously observed with prostasin-dependent channel activation. TMPRSS4-dependent channel activation and production of the ~70-kDa fragment were partially blocked by mutation of the prostasin-dependent cleavage site (γRKRK186QQQQ). Complete inhibition of TMPRSS4-dependent activation of ENaC and γ-subunit cleavage was observed when three basic residues between the furin and prostasin cleavage sites were mutated (γK173Q, γK175Q, and γR177Q), in addition to γRKRK186QQQQ. Mutation of the four basic residues associated with the furin cleavage site (γRKRR143QQQQ) also prevented TMPRSS4-dependent channel activation. We conclude that TMPRSS4 primarily activates ENaC by cleaving basic residues within the tract γK173-K186 distal to the furin cleavage site, thereby releasing a previously defined key inhibitory tract encompassing γR158-F168 from the γ-subunit. 相似文献
972.
973.
Layton AT Gilbert RL Pannabecker TL 《American journal of physiology. Renal physiology》2012,302(7):F830-F839
Recent anatomic findings indicate that in the upper inner medulla of the rodent kidney, tubules, and vessels are organized around clusters of collecting ducts (CDs). Within CD clusters, CDs and some of the ascending vasa recta (AVR) and ascending thin limbs (ATLs), when viewed in transverse sections, form interstitial nodal spaces, which are arrayed at structured intervals throughout the inner medulla. These spaces, or microdomains, are bordered on one side by a single CD, on the opposite side by one or more ATLs, and on the other two sides by AVR. To study the interactions among these CDs, ATLs, and AVR, we have developed a mathematical compartment model, which simulates steady-state solute exchange through the microdomain at a given inner medullary level. Fluid in all compartments contains Na(+), Cl(-), urea and, in the microdomain, negative fixed charges that represent macromolecules (e.g., hyaluronan) balanced by Na(+). Fluid entry into AVR is assumed to be driven by hydraulic and oncotic pressures. Model results suggest that the isolated microdomains facilitate solute and fluid mixing among the CDs, ATLs, and AVR, promote water withdrawal from CDs, and consequently may play an important role in generating the inner medullary osmotic gradient. 相似文献
974.
Light-evoked responses of all three major classes of?retinal ganglion cells (RGCs) are mediated by NMDA receptors (NMDARs) and AMPA receptors (AMPARs). Although synaptic activity at RGC synapses is highly dynamic, synaptic plasticity has not been observed in adult RGCs. Here, using patch-clamp recordings in dark-adapted mouse retina, we report a retina-specific form of AMPAR plasticity. Both chemical and light activation of NMDARs caused the selective endocytosis of GluA2-containing, Ca(2+)-impermeable AMPARs on RGCs and replacement with GluA2-lacking, Ca(2+)-permeable AMPARs. The plasticity was expressed in ON but not OFF RGCs and was restricted solely to the ON responses in ON-OFF RGCs. Finally, the plasticity resulted in a shift in the light responsiveness of ON RGCs. Thus, physiologically relevant light stimuli can induce a change in synaptic receptor composition of ON RGCs, providing a mechanism by which the sensitivity of RGC responses may be modified under scotopic conditions. 相似文献
975.
976.
The pro-apoptotic BH3 only protein BIMEL is phosphorylated by ERK1/2 and this targets it for proteasome-dependent degradation. A recent study has shown that ERK5, an ERK1/2-related MAPK, is activated during mitosis and phosphorylates BIMEL to promote cell survival. Here we show that treatment of cells with nocodazole or paclitaxel does cause phosphorylation of BIMEL, which is independent of ERK1/2. However, this was not due to ERK5-catalysed phosphorylation, since it was not reversed by the MEK5 inhibitor BIX02189 and proceeded normally in ERK5−/− fibroblasts. Indeed, although ERK5 is phosphorylated at multiple sites in the C-terminal transactivation region during mitosis, these do not include the activation-loop and ERK5 kinase activity does not increase. Mitotic phosphorylation of BIMEL occurred at proline-directed phospho-acceptor sites and was abolished by selective inhibition of CDK1. Furthermore, cyclin B1 was able to interact with BIM and cyclin B1/CDK1 complexes could phosphorylate BIM in vitro. Finally, we show that CDK1-dependent phosphorylation of BIMEL drives its polyubiquitylation and proteasome-dependent degradation to protect cells during mitotic arrest. These results provide new insights into the regulation of BIMEL and may be relevant to the therapeutic use of agents such as paclitaxel. 相似文献
977.
Rebecca Keller Jeanine de Keyzer Arnold J.M. Driessen Tracy Palmer 《The Journal of cell biology》2012,199(2):303-315
Membrane protein assembly is a fundamental process in all cells. The membrane-bound Rieske iron-sulfur protein is an essential component of the cytochrome bc1 and cytochrome b6f complexes, and it is exported across the energy-coupling membranes of bacteria and plants in a folded conformation by the twin arginine protein transport pathway (Tat) transport pathway. Although the Rieske protein in most organisms is a monotopic membrane protein, in actinobacteria, it is a polytopic protein with three transmembrane domains. In this work, we show that the Rieske protein of Streptomyces coelicolor requires both the Sec and the Tat pathways for its assembly. Genetic and biochemical approaches revealed that the initial two transmembrane domains were integrated into the membrane in a Sec-dependent manner, whereas integration of the third transmembrane domain, and thus the correct orientation of the iron-sulfur domain, required the activity of the Tat translocase. This work reveals an unprecedented co-operation between the mechanistically distinct Sec and Tat systems in the assembly of a single integral membrane protein. 相似文献
978.
Elizabeth J. Haining Jing Yang Rebecca L. Bailey Kabir Khan Richard Collier Schickwann Tsai Steve P. Watson Jon Frampton Paloma Garcia Michael G. Tomlinson 《The Journal of biological chemistry》2012,287(47):39753-39765
A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions from over 40 different transmembrane target proteins, including Notch and amyloid precursor protein. ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. However, ADAM10 regulation remains poorly understood. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which are a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane “partner” proteins. This is achieved by specific tetraspanin-partner interactions, but it is not clear which tetraspanins specifically interact with ADAM10. The aims of this study were to identify which tetraspanins interact with ADAM10 and how they regulate this metalloprotease. Co-immunoprecipitation identified specific ADAM10 interactions with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the largely unstudied TspanC8 subgroup of tetraspanins, all six of which promoted ADAM10 maturation. Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33-deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. These results define TspanC8 tetraspanins as essential regulators of ADAM10 maturation and trafficking to the cell surface. This finding has therapeutic implications because focusing on specific TspanC8-ADAM10 complexes may allow cell type- and/or substrate-specific ADAM10 targeting. 相似文献
979.
980.