全文获取类型
收费全文 | 7481篇 |
免费 | 529篇 |
国内免费 | 3篇 |
出版年
2023年 | 25篇 |
2022年 | 48篇 |
2021年 | 125篇 |
2020年 | 89篇 |
2019年 | 123篇 |
2018年 | 201篇 |
2017年 | 145篇 |
2016年 | 280篇 |
2015年 | 411篇 |
2014年 | 458篇 |
2013年 | 498篇 |
2012年 | 661篇 |
2011年 | 626篇 |
2010年 | 407篇 |
2009年 | 385篇 |
2008年 | 504篇 |
2007年 | 452篇 |
2006年 | 417篇 |
2005年 | 354篇 |
2004年 | 373篇 |
2003年 | 346篇 |
2002年 | 254篇 |
2001年 | 104篇 |
2000年 | 115篇 |
1999年 | 86篇 |
1998年 | 39篇 |
1997年 | 44篇 |
1996年 | 33篇 |
1995年 | 25篇 |
1994年 | 17篇 |
1993年 | 21篇 |
1992年 | 29篇 |
1991年 | 20篇 |
1990年 | 18篇 |
1989年 | 20篇 |
1988年 | 18篇 |
1987年 | 20篇 |
1986年 | 21篇 |
1985年 | 15篇 |
1984年 | 16篇 |
1983年 | 14篇 |
1982年 | 13篇 |
1981年 | 12篇 |
1980年 | 12篇 |
1979年 | 11篇 |
1978年 | 9篇 |
1976年 | 10篇 |
1975年 | 12篇 |
1974年 | 10篇 |
1972年 | 9篇 |
排序方式: 共有8013条查询结果,搜索用时 31 毫秒
871.
Lee JC Lee EJ Lee JH Jun SH Choi CW Kim SI Kang SS Hyun S 《FEMS microbiology letters》2012,331(1):17-24
Outer membrane vesicles (OMVs) derived from pathogenic Gram-negative bacteria are an important vehicle for delivery of effector molecules to host cells, but the production of OMVs from Klebsiella pneumoniae, an opportunistic pathogen of both nosocomial and community-acquired infections, and their role in bacterial pathogenesis have not yet been determined. In the present study, we examined the production of OMVs from K. pneumoniae and determined the induction of the innate immune response against K. pneumoniae OMVs. Klebsiella pneumoniae ATCC 13883 produced and secreted OMVs during in vitro culture. Proteomic analysis revealed that 159 different proteins were associated with K. pneumoniae OMVs. Klebsiella pneumoniae OMVs did not inhibit cell growth or induce cell death. However, these vesicles induced expression of proinflammatory cytokine genes such as interleukin (IL)-1β and IL-8 in epithelial cells. An intratracheal challenge of K. pneumoniae OMVs in neutropenic mice resulted in severe lung pathology similar to K. pneumoniae infection. In conclusion, K. pneumoniae produces OMVs like other pathogenic Gram-negative bacteria and K. pneumoniae OMVs are a molecular complex that induces the innate immune response. 相似文献
872.
Kang YH Ji NY Han SR Lee CI Kim JW Yeom YI Kim YH Chun HK Kim JW Chung JW Ahn DK Lee HG Song EY 《Cellular signalling》2012,24(10):1940-1949
In our previous study, we reported that endothelial cell specific molecule-1 (ESM-1) was increased in tissue and serum from colorectal cancer patients and suggested that ESM-1 can be used as a potential serum marker for early detection of colorectal cancer. The aim of this study was to evaluate the role of ESM-1 as an intracellular molecule in colorectal cancer. ESM-1 expression was knocked down by small interfering RNA (siRNA) in colorectal cancer cells. Expression of ESM-1 siRNA decreased cell survival through the Akt-dependent inhibition of NF-κB/IκB pathway and an interconnected reduction in phospho-Akt, -p38, -ERK1, -RSK1, -GSK-3α/β and -HSP27, as determined by a phospho-MAPK array. ESM-1 silencing induced G(1) phase cell cycle arrest by induction of PTEN, resulting in the inhibition of cyclin D1 and inhibited cell migration and invasion of COLO205 cells. Consistently, ESM-1 overexpression in HCT-116 cells enhanced cell proliferation through the Akt-dependent activation of NF-κB pathway. In addition, ESM-1 interacted with NF-κB and activated NF-κB promoter. This study demonstrates that ESM-1 is involved in cell survival, cell cycle progression, migration, invasion and EMT during tumor invasion in colorectal cancer. Based on our results, ESM-1 may be a useful therapeutic target for colorectal cancer. 相似文献
873.
874.
Kim N Yoo JC Han JY Hwang EM Kim YS Jeong EY Sun CH Yi GS Roh GS Kim HJ Kang SS Cho GJ Park JY Choi WS 《Journal of cellular physiology》2012,227(3):1157-1167
Clusterin (CLU), a glycoprotein, is involved in apoptosis, producing two alternatively spliced isoforms in various cell types. The pro-apoptotic CLU appears to be a nuclear isoform (nuclear clusterin; nCLU), and the secretory CLU (sCLU) is thought to be anti-apoptotic. The detailed molecular mechanism of nCLU as a pro-apoptotic molecule has not yet been clear. In the current study, overexpressed nCLU induced apoptosis in human kidney cells. Biochemical studies revealed that nCLU sequestered Bcl-XL via a putative BH3 motif in the C-terminal coiled coil (CC2) domain, releasing Bax, and promoted apoptosis accompanied by activation of caspase-3 and cytochrome c release. These results suggest a novel mechanism of apoptosis mediated by nCLU as a pro-apoptotic molecule. 相似文献
875.
Syk is a 72-kDa protein-tyrosine kinase that regulates signaling through multiple cell surface receptors including those for antigens, immunoglobulins and proteins of the extracellular matrix. As part of its function, Syk binds a variety of downstream effectors through interactions that are often mediated by motifs that recognize phosphotyrosines. In a search for novel Syk-interacting proteins by yeast two-hybrid analysis, we identified tensin2 as a Syk-binding protein. Syk interacts with a fragment of tensin2 located near the C-terminus that contains SH2 and PTB domains. In epithelial cells, tensin2 localizes both to focal adhesions and to large cytoplasmic puncta. It is within these punctuate structures that Syk and tensin2 are co-localized. The clustering of Syk within these structures leads to its phosphorylation on tyrosine. 相似文献
876.
Within a discrete scheme, the process of population migration is set by some nonnegative Markov matrix. In studying an appropriate class of competition models, nonlinear methods of convex analysis (monotone operator theory) prove to be highly effective. For special matrices (cyclic and perron ones), conditions of steady coexistence in and of competitor displacement from the community have been found. Model mechanisms of migration route adaptation for a separate population and for a family of populations from one vertical trophic chain have been proposed. The major characteristic of a migration route turns out to be the relative time of population dwelling in one or another region. Specific (perron) vectors of migration matrices correspond to these populations. It is revealed that in the course of co-adaptation the perron vectors of predator and prey migration matrixes practically coincide. 相似文献
877.
878.
879.
Kim SI Na HJ Ding Y Wang Z Lee SJ Choi ME 《The Journal of biological chemistry》2012,287(15):11677-11688
Autophagy is a highly conserved cellular process regulating turnover of cytoplasmic proteins via a lysosome-dependent pathway. Here we show that kidneys from mice deficient in autophagic protein Beclin 1 exhibited profibrotic phenotype, with increased collagen deposition. Reduced Beclin 1 expression, through genetic disruption of beclin 1 or knockdown by specific siRNA in primary mouse mesangial cells (MMC), resulted in increased protein levels of type I collagen (Col-I). Inhibition of autolysosomal protein degradation by bafilomycin A(1) also increased Col-I protein levels and colocalization of Col-I with LC3, an autophagy marker, or LAMP-1, a lysosome marker, whereas treatment with TFP, an inducer of autophagy, resulted in decreased Col-I protein levels induced by TGF-β1, without alterations in Col-I α1 mRNA. Heterozygous deletion of beclin 1 increased accumulation of aggregated Col-I under nonstimulated conditions, and stimulation with TGF-β1 further increased aggregated Col-I. These data indicate that Col-I and aggregated, insoluble procollagen I undergo intracellular degradation via autophagy. A cytoprotective role of autophagy is implicated in kidney injury, and we demonstrate that low-dose carbon monoxide, shown to exert cytoprotection against renal fibrosis, induces autophagy to suppress accumulation of Col-I induced by TGF-β1. We also show that TGF-β1 induces autophagy in MMC via TAK1-MKK3-p38 signaling pathway. The dual functions of TGF-β1, as both an inducer of Col-I synthesis and an inducer of autophagy and Col-I degradation, underscore the multifunctional nature of TGF-β1. Our findings suggest a novel role of autophagy as a cytoprotective mechanism to negatively regulate and prevent excess collagen accumulation in the kidney. 相似文献
880.
The putative capsule O-acetyltransferase gene wcjE is highly conserved across various Streptococcus pneumoniae serotypes, but the role of the gene in capsule biosynthesis and bacterial fitness remains largely unclear. Isolates expressing pneumococcal serotype 9A arise from precursors expressing wcjE-associated serotype 9V through loss-of-function mutation to wcjE. To define the biosynthetic role of 9V wcjE, we characterized the structure and serological properties of serotype 9V and 9A capsule polysaccharide (PS). NMR data revealed that both 9V and 9A PS are composed of an identical pentasaccharide repeat unit, as reported previously. However, in sharp contrast to previous studies on 9A PS being devoid of any O-acetylation, we identified O-acetylation of α-glucuronic acid and α-glucose in 9A PS. In addition, 9V PS also contained -CH(2) O-acetylation of β-N-acetylmannosamine, a modification that disappeared following in vitro recombinatorial deletion of wcjE. We also show that serotyping sera and monoclonal antibodies specific for 9V and 9A bound capsule PS in an O-acetate-dependent manner. Furthermore, IgG and to a lesser extent IgM from human donors immunized with serotype 9V PS displayed stronger binding to 9V compared with 9A PS. We conclude that serotype 9V wcjE mediates 6-O-acetylation of β-N-acetylmannosamine. This PS modification can be selectively targeted by antibodies in immunized individuals, identifying a potential selective advantage for wcjE inactivation and serotype 9A emergence. 相似文献