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排序方式: 共有61条查询结果,搜索用时 15 毫秒
1.
Molecular architecture of the ribosome‐bound Hepatitis C Virus internal ribosomal entry site RNA 下载免费PDF全文
Justus Loerke Jochen Ismer Andrea Schmidt Tarek Hilal Thiemo Sprink Kaori Yamamoto Thorsten Mielke Jörg Bürger Tanvir R Shaikh Marylena Dabrowski Peter W Hildebrand Patrick Scheerer Christian MT Spahn 《The EMBO journal》2015,34(24):3042-3058
Internal ribosomal entry sites (IRESs) are structured cis‐acting RNAs that drive an alternative, cap‐independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo‐EM reconstructions of the ribosome 80S‐ and 40S‐bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S•HCV IRES complex reveals dynamic conformational modes of the complex. At a global resolution of 3.9 Å for the most stable complex, a derived atomic model reveals a complex fold of the IRES RNA and molecular details of its interaction with the ribosome. The comparison of obtained structures explains how a modular architecture facilitates mRNA loading and tRNA binding to the P‐site. This information provides the structural foundation for understanding the mechanism of HCV IRES RNA‐driven translation initiation. 相似文献
2.
Cellular stress regulates the nucleocytoplasmic distribution of the protein-tyrosine phosphatase TCPTP 总被引:5,自引:0,他引:5
Lam MH Michell BJ Fodero-Tavoletti MT Kemp BE Tonks NK Tiganis T 《The Journal of biological chemistry》2001,276(40):37700-37707
Specific cellular stresses, including hyperosmotic stress, caused a dramatic but reversible cytoplasmic accumulation of the otherwise nuclear 45-kDa variant of the protein-tyrosine phosphatase TCPTP (TC45). In the cytoplasm, TC45 dephosphorylated the epidermal growth factor receptor and down-regulated the hyperosmotic stress-induced activation of the c-Jun N-terminal kinase. The hyperosmotic stress-induced nuclear exit of TC45 was not inhibited by leptomycin B, indicating that TC45 nuclear exit was independent of the exportin CRM-1. Moreover, hyperosmotic stress did not induce the cytoplasmic accumulation of a green fluorescent protein-TC45 fusion protein that was too large to diffuse across the nuclear pore. Our results indicate that TC45 nuclear exit may occur by passive diffusion and that cellular stress may induce the cytoplasmic accumulation of TC45 by inhibiting nuclear import. Neither p42(Erk2) nor the stress-activated c-Jun N-terminal kinase or p38 mediated the stress-induced redistribution of TC45. We found that only those stresses that stimulated the metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) induced the redistribution of TC45. In addition, specific pharmacological activation of the AMPK was sufficient to cause the accumulation of TC45 in the cytoplasm. Our studies indicate that specific stress-activated signaling pathways that involve the AMPK can alter the nucleocytoplasmic distribution of TC45 and thus regulate TC45 function in vivo. 相似文献
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Jennifer MP Woo Zhuofeng Lin Mohamad Navab Casey Van Dyck Yvette Trejo-Lopez Krystal MT Woo Hongyun Li Lawrence W Castellani Xuping Wang Noriko Iikuni Ornella J Rullo Hui Wu Antonio La Cava Alan M Fogelman Aldons J Lusis Betty P Tsao 《Arthritis research & therapy》2010,12(3):R93
Introduction
The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.Methods
Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.Results
In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (PL, LP < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (PL < 0.05) and oxidized phospholipids (oxPLs) (PL, LP < 0.005), and elevated total and vertebral bone mineral density (PL, LP < 0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68+ macrophages (PLP < 0.01), significantly increased mean α-actin stained area (PLP < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (PL, LP < 0.0005) and VCAM-1 (PL < 0.0002).Conclusions
L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis. 相似文献4.
Falsone SF Meyer NH Schrank E Leitinger G Pham CL Fodero-Tavoletti MT Holmberg M Dulle M Scicluna B Gesslbauer B Rückert HM Wagner GE Merle DA Nollen EA Kungl AJ Hill AF Cappai R Zangger K 《Cell reports》2012,2(2):358-371
The inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn) complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway. 相似文献
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Renato M Salgado Luciane P Capelo Rodolfo R Favaro Jocelyn D Glazier John D Aplin Telma MT Zorn 《Reproductive biology and endocrinology : RB&E》2009,7(1):60
Background
Remodeling of the extracellular matrix is one of the most striking features observed in the uterus during the estrous cycle and after hormone replacement. Versican (VER) is a hyaluronan-binding proteoglycan that undergoes RNA alternative splicing, generating four distinct isoforms. This study analyzed the synthesis and distribution of VER in mouse uterine tissues during the estrous cycle, in ovariectomized (OVX) animals and after 17beta-estradiol (E2) and medroxyprogesterone (MPA) treatments, either alone or in combination. 相似文献8.
Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP 总被引:3,自引:0,他引:3 下载免费PDF全文
Galic S Klingler-Hoffmann M Fodero-Tavoletti MT Puryer MA Meng TC Tonks NK Tiganis T 《Molecular and cellular biology》2003,23(6):2096-2108
The human protein tyrosine phosphatase TCPTP exists as two forms: an endoplasmic reticulum-targeted 48-kDa form (TC48) and a nuclear 45-kDa form (TC45). Although targeted to the nucleus, TC45 can exit in response to specific stimuli to dephosphorylate cytoplasmic substrates. In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A "substrate-trapping" mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells. Moreover, in response to insulin stimulation, the TC45-D182A mutant accumulated in the cytoplasm of cells overexpressing the IR and in part colocalized with the IR beta-subunit at the cell periphery. These results indicate that the IR may serve as a cellular substrate for both TC48 and TC45. In immortalized TCPTP(-/-) murine embryo fibroblasts, insulin-induced IR beta-subunit tyrosine phosphorylation and protein kinase PKB/Akt activation were enhanced relative to the values in TCPTP(+/+) cells. Importantly, the expression of TC45 or TC48 to physiological levels suppressed the enhanced insulin-induced signaling in TCPTP(-/-) cells. These results indicate that the differentially localized variants of TCPTP may dephosphorylate the IR and downregulate insulin-induced signaling in vivo. 相似文献
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Josué I. Beltrán-López Andrea Romero-Maldonado Elizabeth Monreal-Escalante Bernardo Bañuelos-Hernández Luz MT Paz-Maldonado Sergio Rosales-Mendoza 《Plant cell reports》2016,35(5):1133-1141