全文获取类型
收费全文 | 931篇 |
免费 | 60篇 |
出版年
2023年 | 8篇 |
2022年 | 6篇 |
2021年 | 16篇 |
2020年 | 15篇 |
2019年 | 20篇 |
2018年 | 33篇 |
2017年 | 19篇 |
2016年 | 51篇 |
2015年 | 46篇 |
2014年 | 43篇 |
2013年 | 58篇 |
2012年 | 69篇 |
2011年 | 67篇 |
2010年 | 57篇 |
2009年 | 37篇 |
2008年 | 49篇 |
2007年 | 58篇 |
2006年 | 53篇 |
2005年 | 55篇 |
2004年 | 44篇 |
2003年 | 37篇 |
2002年 | 33篇 |
2001年 | 12篇 |
2000年 | 14篇 |
1999年 | 12篇 |
1998年 | 9篇 |
1997年 | 11篇 |
1996年 | 5篇 |
1995年 | 10篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1966年 | 1篇 |
1961年 | 1篇 |
1942年 | 1篇 |
排序方式: 共有991条查询结果,搜索用时 15 毫秒
91.
Lemierre's syndrome, or necrobacillosis, is a life-threatening septic thrombophlebitis of the internal jugular vein. The causative organism is Fusobacterium necrophorum. Here we report a case of Lemierre's syndrome in a young male and describe the clinical presentations and treatment. Epstein-Barr virus (EBV) was a suspected predisposing factor in this case. 相似文献
92.
A basic peptide within the juxtamembrane region is required for EGF receptor dimerization 总被引:9,自引:0,他引:9
Aifa S Aydin J Nordvall G Lundström I Svensson SP Hermanson O 《Experimental cell research》2005,302(1):108-114
The epidermal growth factor receptor (EGFR) is fundamental for normal cell growth and organ development, but has also been implicated in various pathologies, notably tumors of epithelial origin. We have previously shown that the initial 13 amino acids (P13) within the intracellular juxtamembrane region (R645-R657) are involved in the interaction with calmodulin, thus indicating an important role for this region in EGFR function. Here we show that P13 is required for proper dimerization of the receptor. We expressed either the intracellular domain of EGFR (TKJM) or the intracellular domain lacking P13 (DeltaTKJM) in COS-7 cells that express endogenous EGFR. Only TKJM was immunoprecipitated with an antibody directed against the extracellular part of EGFR, and only TKJM was tyrosine phosphorylated by endogenous EGFR. Using SK-N-MC cells, which do not express endogenous EGFR, that were stably transfected with either wild-type EGFR or recombinant full-length EGFR lacking P13 demonstrated that P13 is required for appropriate receptor dimerization. Furthermore, mutant EGFR lacking P13 failed to be autophosphorylated. P13 is rich in basic amino acids and in silico modeling of the EGFR in conjunction with our results suggests a novel role for the juxtamembrane domain (JM) of EGFR in mediating intracellular dimerization and thus receptor kinase activation and function. 相似文献
93.
94.
95.
Ipek MS Zenciroglu A Aydin M Okumus N Orun UA Uner C 《Genetic counseling (Geneva, Switzerland)》2010,21(3):289-292
We report a case of VACTERL complex which had concomitant horseshoe lung, laryngeal cleft, and hypertrophic pyloric stenosis, which has not been previously reported. 相似文献
96.
Daryl A. Bosco Elan Zohar Eisenmesser Michael W. Clarkson Wladimir Labeikovsky Oscar Millet Dorothee Kern 《Journal of molecular biology》2010,403(5):723-738
Peptidyl-prolyl isomerases (PPIases) are emerging as key regulators of many diverse biological processes. Elucidating the role of PPIase activity in vivo has been challenging because mutagenesis of active-site residues not only reduces the catalytic activity of these enzymes but also dramatically affects substrate binding. Employing the cyclophilin A PPIase together with its biologically relevant and natively folded substrate, the N-terminal domain of the human immunodeficiency virus type 1 capsid (CAN) protein, we demonstrate here how to dissect residue-specific contributions to PPIase catalysis versus substrate binding utilizing NMR spectroscopy. Surprisingly, a number of cyclophilin A active-site mutants previously assumed to be strongly diminished in activity toward biological substrates based only on a peptide assay catalyze the human immunodeficiency virus capsid with wild-type activity but with a change in the rate-limiting step of the enzymatic cycle. The results illustrate that a quantitative analysis of catalysis using the biological substrates is critical when interpreting the effects of PPIase mutations in biological assays. 相似文献
97.
Hanschmann EM Lönn ME Schütte LD Funke M Godoy JR Eitner S Hudemann C Lillig CH 《The Journal of biological chemistry》2010,285(52):40699-40705
The proteins from the thioredoxin family are crucial actors in redox signaling and the cellular response to oxidative stress. The major intracellular source for oxygen radicals are the components of the respiratory chain in mitochondria. Here, we show that the mitochondrial 2-Cys peroxiredoxin (Prx3) is not only substrate for thioredoxin 2 (Trx2), but can also be reduced by glutaredoxin 2 (Grx2) via the dithiol reaction mechanism. Grx2 reduces Prx3 exhibiting catalytic constants (K(m), 23.8 μmol·liter(-1); V(max), 1.2 μmol·(mg·min)(-1)) similar to Trx2 (K(m), 11.2 μmol·liter(-1); V(max), 1.1 μmol·(mg·min)(-1)). The reduction of the catalytic disulfide of the atypical 2-Cys Prx5 is limited to the Trx system. Silencing the expression of either Trx2 or Grx2 in HeLa cells using specific siRNAs did not change the monomer:dimer ratio of Prx3 detected by a specific 2-Cys Prx redox blot. Only combined silencing of the expression of both proteins led to an accumulation of oxidized protein. We further demonstrate that the distribution of Prx3 in different mouse tissues is either linked to the distribution of Trx2 or Grx2. These results introduce Grx2 as a novel electron donor for Prx3, providing further insights into pivotal cellular redox signaling mechanisms. 相似文献
98.
99.
Jutta Walstab Christian Hammer Felix Lasitschka Dorothee M?ller Christopher N. Connolly Gudrun Rappold Michael Brüss Heinz B?nisch Beate Niesler 《The Journal of biological chemistry》2010,285(35):26956-26965
Although five 5-hydroxytryptamine type 3 (5-HT3) subunits (A–E) have been cloned, knowledge on the regulation of their assembly is limited. RIC-3 has been identified as a chaperone specific for the pentameric ligand-gated nicotinic acetylcholine and 5-HT3 receptors. Therefore, we examined the impact of RIC-3 on differently composed 5-HT3 receptors with the focus on 5-HT3C, -D, and -E subunits. The influence of RIC-3 on these receptor subtypes is supported by the presence of RIC3 mRNA in tissues expressing at least one of the subunits 5-HT3C, -D, and -E. Furthermore, immunocytochemical studies on transfected mammalian cells revealed co-localization in the endoplasmic reticulum and direct interaction of RIC-3 with 5-HT3A, -C, -D, and -E. Functional and pharmacological characterization was performed using HEK293 cells expressing 5-HT3A or 5-HT3A + 5-HT3B (or -C, -D, or -E) in the presence or absence of RIC-3. Ca2+ influx analyses revealed that RIC-3 does not influence the 5-HT concentration-response relationship on 5-HT3A receptors but leads to differential increases of 5-HT-induced maximum response (Emax) on cells expressing different subunits. Increases of Emax were due to analogously enhanced Bmax values for binding of the 5-HT3 receptor antagonist [3H]GR65630. The observed enhanced cell surface expression of the tested 5-HT3 subunit combinations correlated with the increased surface expression of 5-HT3A as determined by flow cytometry. In conclusion, we showed that RIC-3 can interact with 5-HT3A, -C, -D, and -E subunits and predominantly enhances the surface expression of homomeric 5-HT3A receptors in HEK293 cells. These data implicate a possible role of RIC-3 in determining 5-HT3 receptor composition in vivo. 相似文献
100.
Tailspike Interactions with Lipopolysaccharide Effect DNA Ejection from Phage P22 Particles in Vitro
Dorothee Andres Christin Hanke Ulrich Baxa Ana?t Seul Stefanie Barbirz Robert Seckler 《The Journal of biological chemistry》2010,285(47):36768-36775
Initial attachment of bacteriophage P22 to the Salmonella host cell is known to be mediated by interactions between lipopolysaccharide (LPS) and the phage tailspike proteins (TSP), but the events that subsequently lead to DNA injection into the bacterium are unknown. We used the binding of a fluorescent dye and DNA accessibility to DNase and restriction enzymes to analyze DNA ejection from phage particles in vitro. Ejection was specifically triggered by aggregates of purified Salmonella LPS but not by LPS with different O-antigen structure, by lipid A, phospholipids, or soluble O-antigen polysaccharide. This suggests that P22 does not use a secondary receptor at the bacterial outer membrane surface. Using phage particles reconstituted with purified mutant TSP in vitro, we found that the endorhamnosidase activity of TSP degrading the O-antigen polysaccharide was required prior to DNA ejection in vitro and DNA replication in vivo. If, however, LPS was pre-digested with soluble TSP, it was no longer able to trigger DNA ejection, even though it still contained five O-antigen oligosaccharide repeats. Together with known data on the structure of LPS and phage P22, our results suggest a molecular model. In this model, tailspikes position the phage particles on the outer membrane surface for DNA ejection. They force gp26, the central needle and plug protein of the phage tail machine, through the core oligosaccharide layer and into the hydrophobic portion of the outer membrane, leading to refolding of the gp26 lazo-domain, release of the plug, and ejection of DNA and pilot proteins. 相似文献