全文获取类型
收费全文 | 1142篇 |
免费 | 97篇 |
国内免费 | 1篇 |
出版年
2023年 | 9篇 |
2022年 | 24篇 |
2021年 | 41篇 |
2020年 | 21篇 |
2019年 | 30篇 |
2018年 | 25篇 |
2017年 | 25篇 |
2016年 | 35篇 |
2015年 | 62篇 |
2014年 | 71篇 |
2013年 | 86篇 |
2012年 | 109篇 |
2011年 | 108篇 |
2010年 | 57篇 |
2009年 | 60篇 |
2008年 | 70篇 |
2007年 | 49篇 |
2006年 | 69篇 |
2005年 | 45篇 |
2004年 | 46篇 |
2003年 | 38篇 |
2002年 | 31篇 |
2001年 | 6篇 |
2000年 | 6篇 |
1999年 | 11篇 |
1998年 | 22篇 |
1997年 | 6篇 |
1996年 | 7篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 5篇 |
1992年 | 4篇 |
1991年 | 3篇 |
1990年 | 5篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 3篇 |
1980年 | 2篇 |
1978年 | 3篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1969年 | 2篇 |
1964年 | 2篇 |
1962年 | 1篇 |
1961年 | 1篇 |
1960年 | 1篇 |
排序方式: 共有1240条查询结果,搜索用时 16 毫秒
111.
112.
113.
Jonathan P. Belman Rachel R. Bian Estifanos N. Habtemichael Don T. Li Michael J. Jurczak Abel Alcázar-Román Leah J. McNally Gerald I. Shulman Jonathan S. Bogan 《The Journal of biological chemistry》2015,290(7):4447-4463
Insulin causes the exocytic translocation of GLUT4 glucose transporters to stimulate glucose uptake in fat and muscle. Previous results support a model in which TUG traps GLUT4 in intracellular, insulin-responsive vesicles termed GLUT4 storage vesicles (GSVs). Insulin triggers TUG cleavage to release the GSVs; GLUT4 then recycles through endosomes during ongoing insulin exposure. The TUG C terminus binds a GSV anchoring site comprising Golgin-160 and possibly other proteins. Here, we report that the TUG C terminus is acetylated. The TUG C-terminal peptide bound the Golgin-160-associated protein, ACBD3 (acyl-CoA-binding domain-containing 3), and acetylation reduced binding of TUG to ACBD3 but not to Golgin-160. Mutation of the acetylated residues impaired insulin-responsive GLUT4 trafficking in 3T3-L1 adipocytes. ACBD3 overexpression enhanced the translocation of GSV cargos, GLUT4 and insulin-regulated aminopeptidase (IRAP), and ACBD3 was required for intracellular retention of these cargos in unstimulated cells. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, bound TUG and deacetylated the TUG peptide. SIRT2 overexpression reduced TUG acetylation and redistributed GLUT4 and IRAP to the plasma membrane in 3T3-L1 adipocytes. Mutation of the acetylated residues in TUG abrogated these effects. In mice, SIRT2 deletion increased TUG acetylation and proteolytic processing. During glucose tolerance tests, glucose disposal was enhanced in SIRT2 knock-out mice, compared with wild type controls, without any effect on insulin concentrations. Together, these data support a model in which TUG acetylation modulates its interaction with Golgi matrix proteins and is regulated by SIRT2. Moreover, acetylation of TUG enhances its function to trap GSVs within unstimulated cells and enhances insulin-stimulated glucose uptake. 相似文献
114.
115.
Prolactin (PRL) regulates cytoskeletal rearrangement and cell motility. PRL-activated Janus tyrosine kinase 2 (JAK2) phosphorylates the p21-activated serine-threonine kinase (PAK)1 and the Src homology 2 (SH2) domain-containing adapter protein SH2B1β. SH2B1β is an actin-binding protein that cross-links actin filaments, whereas PAK1 regulates the actin cytoskeleton by different mechanisms, including direct phosphorylation of the actin-binding protein filamin A (FLNa). Here, we have used a FLNa-deficient human melanoma cell line (M2) and its derivative line (A7) that stably expresses FLNa to demonstrate that SH2B1β and FLNa are required for maximal PRL-dependent cell ruffling. We have found that in addition to two actin-binding domains, SH2B1β has a FLNa-binding domain (amino acids 200-260) that binds directly to repeats 17-23 of FLNa. The SH2B1β-FLNa interaction participates in PRL-dependent actin rearrangement. We also show that phosphorylation of the three tyrosines of PAK1 by JAK2, as well as the presence of FLNa, play a role in PRL-dependent cell ruffling. Finally, we show that the actin- and FLNa-binding-deficient mutant of SH2B1β (SH2B1β 3Δ) abolished PRL-dependent ruffling and PRL-dependent cell migration when expressed along with PAK1 Y3F (JAK2 tyrosyl-phosphorylation-deficient mutant). Together, these data provide insight into a novel mechanism of PRL-stimulated regulation of the actin cytoskeleton and cell motility via JAK2 signaling through FLNa, PAK1, and SH2B1β. We propose a model for PRL-dependent regulation of the actin cytoskeleton that integrates our findings with previous studies. 相似文献
116.
117.
118.
Methods were developed to perform precipitation photopolymerization of PEG-diacrylate. Previously, comonomers have been added to PEG when precipitation polymerization was desired. In the present method, the LCST of the PEG itself was lowered by the addition of the kosmotropic salt sodium sulfate to an aqueous solution. Typical of a precipitation polymerization, small microparticles or microspheres (1-5 μm) resulted with relatively low polydispersity. However, aggregate formation was often severe, presumably because of a lack of stabilization of the phase-separated colloids. Microparticles were also produced by copoymerization of PEG-diacrylate with acrylic acid or aminoethylmethacrylate. The comonomers affected the zeta potential of the formed microparticles but not the size. The carboxyl groups of acrylic-acid-containing PEG microparticles were activated, and scaffolds were formed by mixing with amine-containing PEG microparticles. Although the scaffolds were relatively weak, human hepatoma cells showed excellent viability when present during microparticle cross-linking. 相似文献
119.
Lissina E Young B Urbanus ML Guan XL Lowenson J Hoon S Baryshnikova A Riezman I Michaut M Riezman H Cowen LE Wenk MR Clarke SG Giaever G Nislow C 《PLoS genetics》2011,7(10):e1002332
Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors. 相似文献
120.
Koh YY Wang Y Qiu C Opperman L Gross L Tanaka Hall TM Wickens M 《RNA (New York, N.Y.)》2011,17(4):718-727
Stacking interactions between amino acids and bases are common in RNA-protein interactions. Many proteins that regulate mRNAs interact with single-stranded RNA elements in the 3' UTR (3'-untranslated region) of their targets. PUF proteins are exemplary. Here we focus on complexes formed between a Caenorhabditis elegans PUF protein, FBF, and its cognate RNAs. Stacking interactions are particularly prominent and involve every RNA base in the recognition element. To assess the contribution of stacking interactions to formation of the RNA-protein complex, we combine in vivo selection experiments with site-directed mutagenesis, biochemistry, and structural analysis. Our results reveal that the identities of stacking amino acids in FBF affect both the affinity and specificity of the RNA-protein interaction. Substitutions in amino acid side chains can restrict or broaden RNA specificity. We conclude that the identities of stacking residues are important in achieving the natural specificities of PUF proteins. Similarly, in PUF proteins engineered to bind new RNA sequences, the identity of stacking residues may contribute to "target" versus "off-target" interactions, and thus be an important consideration in the design of proteins with new specificities. 相似文献