全文获取类型
收费全文 | 3660篇 |
免费 | 323篇 |
国内免费 | 479篇 |
出版年
2024年 | 16篇 |
2023年 | 55篇 |
2022年 | 147篇 |
2021年 | 244篇 |
2020年 | 167篇 |
2019年 | 204篇 |
2018年 | 178篇 |
2017年 | 161篇 |
2016年 | 187篇 |
2015年 | 248篇 |
2014年 | 283篇 |
2013年 | 337篇 |
2012年 | 349篇 |
2011年 | 297篇 |
2010年 | 190篇 |
2009年 | 195篇 |
2008年 | 192篇 |
2007年 | 149篇 |
2006年 | 155篇 |
2005年 | 116篇 |
2004年 | 76篇 |
2003年 | 72篇 |
2002年 | 50篇 |
2001年 | 40篇 |
2000年 | 36篇 |
1999年 | 48篇 |
1998年 | 26篇 |
1997年 | 25篇 |
1996年 | 22篇 |
1995年 | 35篇 |
1994年 | 25篇 |
1993年 | 23篇 |
1992年 | 21篇 |
1991年 | 12篇 |
1990年 | 10篇 |
1989年 | 8篇 |
1988年 | 11篇 |
1987年 | 10篇 |
1986年 | 6篇 |
1985年 | 14篇 |
1984年 | 5篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1974年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有4462条查询结果,搜索用时 797 毫秒
211.
Miao EA Brittnacher M Haraga A Jeng RL Welch MD Miller SI 《Molecular microbiology》2003,48(2):401-415
A family of nine Salmonella typhimurium type III secretion effectors with a conserved amino-terminus have been defined. Three family members (SifA, SifB and SseJ) have previously been demonstrated to localize to the Salmonella-containing vacuole and to Salmonella-induced filaments. In contrast, we demonstrate that two other family members, SspH2 and SseI, co-localized with the polymerizing actin cytoskeleton. These proteins also interacted with the mammalian actin cross-linking protein filamin in the yeast two-hybrid assay through their highly conserved amino-terminal domains. This amino-terminus was sufficient to direct localization to the polymerizing actin cytoskeleton, suggesting that the interaction with filamin is important for this subcellular localization. In addition, SspH2 co-localized with vacuole-associated actin polymerizations (VAP) induced by intracellular bacteria through the Salmonella pathogenicity island (SPI)-2 type III secretion system (TTSS). SspH2 interacted with the actin-binding protein profilin in the yeast two-hybrid assay and by affinity chromatography. This interaction was highly specific to SspH2 and was mediated by its carboxy-terminus. Furthermore, SspH2 inhibited the rate of actin polymerization in vitro, suggesting that it functions to reduce or remodel VAP. Strains with mutations in sspH2 and sseI retained the ability to form VAP. However, a third intracellular virulence factor, spvB, which ADP-ribosylates actin, strongly inhibited VAP formation in HeLa cells, suggesting a more subtle effect for SspH2 and SseI on the actin cytoskeleton. 相似文献
212.
Genome-based analysis of virulence genes in a non-biofilm-forming Staphylococcus epidermidis strain (ATCC 12228) 总被引:3,自引:0,他引:3
Zhang YQ Ren SX Li HL Wang YX Fu G Yang J Qin ZQ Miao YG Wang WY Chen RS Shen Y Chen Z Yuan ZH Zhao GP Qu D Danchin A Wen YM 《Molecular microbiology》2003,49(6):1577-1593
Staphylococcus epidermidis strains are diverse in their pathogenicity; some are invasive and cause serious nosocomial infections, whereas others are non-pathogenic commensal organisms. To analyse the implications of different virulence factors in Staphylococcus epidermidis infections, the complete genome of Staphylococcus epidermidis strain ATCC 12228, a non-biofilm forming, non-infection associated strain used for detection of residual antibiotics in food products, was sequenced. This strain showed low virulence by mouse and rat experimental infections. The genome consists of a single 2499 279 bp chromosome and six plasmids. The chromosomal G + C content is 32.1% and 2419 protein coding sequences (CDS) are predicted, among which 230 are putative novel genes. Compared to the virulence factors in Staphylococcus aureus, aside from delta-haemolysin and beta-haemolysin, other toxin genes were not found. In contrast, the majority of adhesin genes are intact in ATCC 12228. Most strikingly, the ica operon coding for the enzymes synthesizing interbacterial cellular polysaccharide is missing in ATCC 12228 and rearrangements of adjacent genes are shown. No mec genes, IS256, IS257, were found in ATCC 12228. It is suggested that the absence of the ica operon is a genetic marker in commensal Staphylococcus epidermidis strains which are less likely to become invasive. 相似文献
213.
The mechanisms that establish DNA methylation in eukaryotes are poorly understood. In principle, methylation in a particular chromosomal region may reflect the presence of a "signal" that recruits methylation, the absence of a signal that prevents methylation, or both. Experiments were carried out to address these possibilities for the 1.6 kb zeta-eta (zeta-eta) region, a relict of repeat-induced point mutation (RIP) in the fungus Neurospora crassa. The zeta-eta region directs its own de novo methylation at a variety of chromosomal locations. We tested the methylation potential of a nested set of fragments with deletions from one end of the zeta-eta region, various internal fragments of this region, chimeras of eta and the homologous unmutated allele, theta (theta), and various synthetic variants, integrated precisely in single copy at the am locus on linkage group (LG) VR or the his-3 locus on LG IR. We found that: (1) the zeta-eta region contains at least two non-overlapping methylation signals; (2) different fragments of the region can induce different levels of methylation; (3) methylation induced by zeta-eta sequences can spread far into flanking sequences; (4) fragments as small as 171 bp can trigger methylation; (5) methylation signals behave similarly, but not identically, at different chromosomal sites; (6) mutation density, per se, does not determine whether sequences become methylated; and (7) neither A:T-richness nor high densities of TpA dinucleotides, typical attributes of methylated sequences in Neurospora, are essential features of methylation signals, but both promote de novo methylation. We conclude that de novo methylation of zeta-eta sequences does not simply reflect the absence of signals that prevent methylation; rather, the region contains multiple, positive signals that trigger methylation. These findings conflict with earlier models for the control of DNA methylation, including the simplest version of the collapsed chromatin model. 相似文献
214.
Clee SM Bissada N Miao F Miao L Marais AD Henderson HE Steures P McManus J McManus B LeBoeuf RC Kastelein JJ Hayden MR 《Journal of lipid research》2000,41(4):521-531
Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization. Decreased plasma LPL activity is associated with the high triglyceride (TG);-low HDL phenotype that is often observed in patients with premature vascular disease. In contrast, in the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of variations in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL(+/-)E(-/-)) was associated with increased TG and increased total cholesterol (TC) compared with LPL(+/+)E(-/-) sibs. However despite their dyslipidemia, LPL(+/-)E(-/-) mice had significantly reduced lesion areas compared to the LPL(+/+)E(-/-) mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast, transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and thus the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL(+/+)E(-/-) mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis.Taken together, these results provide in vivo evidence that the contribution of LPL to atherogenesis is significantly influenced by the balance between vessel wall protein (pro-atherogenic) and plasma activity (anti-atherogenic). 相似文献
215.
Interactions between receptor tyrosine kinases of the Eph family and their ligands, ephrins, are implicated in establishment of organ boundaries and repulsive guidance of cell migration during development, but the mechanisms by which this is achieved are unclear. Here we show that activation of endogenous EphA2 kinase induces an inactive conformation of integrins and inhibits cell spreading, migration and integrin-mediated adhesion. Moreover, EphA2 is constitutively associated with focal-adhesion kinase (FAK) in resting cells. Within one minute after stimulation of EphA2 with its ligand, ephrin-A1, the protein tyrosine phosphatase SHP2 is recruited to EphA2; this is followed by dephosphorylation of FAK and paxillin, and dissociation of the FAK-EphA2 complex. We conclude that Eph kinases mediate some of their functions by negatively regulating integrins and FAK. 相似文献
216.
217.
218.
219.
中国株丙型肝炎病毒(HCV)结构区蛋白在昆虫细胞中的表达及加工 总被引:4,自引:1,他引:3
利用杆状病毒表达系统在昆虫细胞中表达了完整的中国河北株丙丙型肝炎病毒结构蛋白。免疫印迹实验结果显示,表达产物中有一系列分子量不同、可以与HCV抗体阳性病人血清反应的蛋白,表明结构蛋白被宿主细胞蛋白酶切割与加工,相应分别为20kD的核心蛋白、32kD糖基化的E1蛋白40kD的未糖化的E2蛋白和70kD糖基化的E2蛋白,另有80kD及100kD的两组前体蛋白。利用表达产物检测慢性HCV感染者血清,发现 相似文献
220.
Yiting Qiao Yunxin Pei Miao Luo Muthukumar Rajasekaran Kam M Hui Jianxiang Chen 《Experimental biology and medicine (Maywood, N.J.)》2021,246(12):1343
Cytokinesis, the final step of mitosis, is critical for maintaining the ploidy level of cells. Cytokinesis is a complex, highly regulated process and its failure can lead to genetic instability and apoptosis, contributing to the development of cancer. Human hepatocellular carcinoma is often accompanied by a high frequency of aneuploidy and the DNA ploidy pattern observed in human hepatocellular carcinoma results mostly from impairments in cytokinesis. Many key regulators of cytokinesis are abnormally expressed in human hepatocellular carcinoma, and their expression levels are often correlated with patient prognosis. Moreover, preclinical studies have demonstrated that the inhibition of key cytokinesis regulators can suppress the growth of human hepatocellular carcinoma. Here, we provide an overview of the current understanding of the signaling networks regulating cytokinesis, the key cytokinesis regulators involved in the initiation and development of human hepatocellular carcinoma, and their applications as potential diagnostic and therapeutic biomarkers. 相似文献