全文获取类型
收费全文 | 4258篇 |
免费 | 296篇 |
国内免费 | 6篇 |
专业分类
4560篇 |
出版年
2023年 | 21篇 |
2022年 | 48篇 |
2021年 | 78篇 |
2020年 | 41篇 |
2019年 | 50篇 |
2018年 | 108篇 |
2017年 | 80篇 |
2016年 | 131篇 |
2015年 | 218篇 |
2014年 | 236篇 |
2013年 | 287篇 |
2012年 | 315篇 |
2011年 | 323篇 |
2010年 | 190篇 |
2009年 | 176篇 |
2008年 | 224篇 |
2007年 | 190篇 |
2006年 | 220篇 |
2005年 | 180篇 |
2004年 | 174篇 |
2003年 | 171篇 |
2002年 | 153篇 |
2001年 | 94篇 |
2000年 | 99篇 |
1999年 | 73篇 |
1998年 | 37篇 |
1997年 | 28篇 |
1996年 | 28篇 |
1995年 | 21篇 |
1994年 | 30篇 |
1993年 | 24篇 |
1992年 | 44篇 |
1991年 | 33篇 |
1990年 | 31篇 |
1989年 | 28篇 |
1988年 | 21篇 |
1987年 | 25篇 |
1986年 | 17篇 |
1985年 | 17篇 |
1984年 | 17篇 |
1983年 | 20篇 |
1979年 | 18篇 |
1977年 | 15篇 |
1975年 | 16篇 |
1974年 | 21篇 |
1973年 | 17篇 |
1972年 | 20篇 |
1970年 | 13篇 |
1969年 | 13篇 |
1967年 | 13篇 |
排序方式: 共有4560条查询结果,搜索用时 15 毫秒
101.
Suzuki Y Gómez-Guerrero C Shirato I López-Franco O Gallego-Delgado J Sanjuán G Lázaro A Hernández-Vargas P Okumura K Tomino Y Ra C Egido J 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(6):3243-3253
In immune complex (IC) diseases, FcR are essential molecules facilitating polymorphonuclear cell (PMN) recruitment and effector functions at the IC site. Although FcR-dependent initial tethering and FcR/integrin-dependent PMN accumulation were postulated, their underlying mechanisms remain unclear. We here addressed potential mechanisms involved in PMN recruitment in acute IC glomerulonephritis (nephrotoxic nephritis). Since some renal cells may be recruited from bone marrow (BM) lineages, reconstitution studies with BM chimeras and PMN transfer between wild-type (WT) and FcR-deficient mice (gamma(-/-)) were performed. Severe glomerular damage was induced in WT and W gamma chimeras (BM from WT to irradiated gamma(-/-)), while it was absent in gamma(-/-) and gamma W chimeras (gamma(-/-) BM to WT). Moreover, WT PMN transfer, but not gamma(-/-) PMN, reconstituted the disease in gamma(-/-), indicating that FcR on resident cells is not a prerequisite for PMN recruitment in this disease. Surprisingly, transferred WT PMN were recruited coincidentally with NF-kappa B activation and TNF-alpha overexpression even in glomeruli with preformed IC (nephrotoxic Ab administered 3 days previously), suggesting that PMN can initially be recruited via its own FcR without previous chemoattractant release. Furthermore, H(2)O(2) inhibition by catalase attenuated the acute WT PMN recruitment and the induction of NF-kappa B and TNF-alpha much more than integrin (CD18) blockade, indicating a role for the respiratory burst before integrin-dependent accumulation. In coculture experiments with IC-stimulated PMN and glomeruli, PMN caused acute glomerular TNF-alpha expression predominantly via FcR-mediated H(2)O(2) production. In conclusion, glomerular IC, even preformed, can cause PMN recruitment and injury through PMN FcR-mediated respiratory burst during initial PMN tethering to IC. 相似文献
102.
The role of interleukin-4 (IL-4) in the inflammatory process has emerged recently. In this study, we investigated the effect of IL-4 on the angiogenic process in an in vitro experimental system. IL-4 significantly inhibited the proliferation of human umbilical vein endothelial cells (HUVEC) that was induced by the vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF- or bFGF-induced HUVEC chemotaxis was abrogated by the IL-4 treatment. In addition, the formation of tube-like structures by HUVEC in the presence of VEGF or bFGF was also severely down-regulated by IL-4. The inhibitory effects on the critical steps of angiogenesis were not observed with IL-6 that is abundantly found in the inflamed tissue. Our results suggest that IL-4 may play a regulatory role in normal physiology and provide the potential possibility for IL-4 as a therapeutic agent in the intervention of angiogenesis-related diseases. 相似文献
103.
Kayagaki N Yamaguchi N Abe M Hirose S Shirai T Okumura K Yagita H 《Cellular immunology》2002,219(2):82-91
TNF-related apoptosis-inducing ligand (TRAIL), a type II membrane protein belonging to the TNF family, induces apoptotic cell death in various types of tumor cells. However, little is known about its pathological and physiological functions in the immune system. In this study, we showed that administration of neutralizing anti-TRAIL mAb markedly increased serum auto-Ab levels, particularly of IgG1 subclass, in autoimmune-prone C3H/HeJ gld/gld mice without affecting lymphocytosis and lymphocytes populations. In an experimental system where TNP-specific Ab production was induced by immunization with TNP-modified syngeneic B lymphoma cells, expression of TRAIL on these cells significantly reduced TNP-specific Ab production, especially of IgG1 subclass, without affecting T cell priming. These results suggest a new role for TRAIL in the suppression of Ab production. 相似文献
104.
105.
Supajatura V Ushio H Wada A Yahiro K Okumura K Ogawa H Hirayama T Ra C 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(6):2603-2607
Mucosal mast cells strategically located at the optimal site interact with invading bacteria. Presence of VacA, the virulent Helicobacter pylori cytotoxin, is correlated with the severity of H. pylori-induced gastritis. To examine the mechanisms of inflammation in H. pylori-induced gastritis, we administered VacA to the mice. Inoculation of VacA resulted in epithelium vacuolization and marked infiltrations of mast cells and mononuclear cells into the mucosal epithelium within 24 h. In an in vitro study using bone marrow-derived mast cells, VacA directly bound and showed a chemotactic activity to the mast cell. In addition, VacA induced bone marrow-derived mast cells to produce proinflammatory cytokines, TNF-alpha, macrophage-inflammatory protein-1alpha, IL-1beta, IL-6, IL-10, and IL-13 in a dose-dependent manner without causing degranulation. The present study suggests that early activation of mast cells by VacA may be the host early response to clear the bacteria and also may contribute to the pathogenesis of H. pylori-induced gastritis. 相似文献
106.
Effect of shear stress on cultivation of Bacillus thuringiensis for thuringiensin production 总被引:2,自引:0,他引:2
Cultivation of Bacillus thuringiensis for thuringiensin production is a mixed-growth-associated system. Cultivation conditions should be different during the cell growth stage and production stage. In this study, agitation speed and aeration rate were varied during the exponential growth phase and stationary phase in order to investigate the effect of shear stress via agitation on cultivation of B. thuringiensis for thuringiensin production. It was found that shear stress had a significant effect on thuringiensin production during the stationary phase. By decreasing the agitation speed during the stationary phase, product formation was increased up to 43%. 相似文献
107.
Bong Cho Kim Hyung Chul Lee Je‐Jung Lee Chang‐Min Choi Dong‐Kwan Kim Jae Cheol Lee Young‐Gyu Ko Jae‐Seon Lee 《The EMBO journal》2012,31(22):4289-4303
Premature senescence, a key strategy used to suppress carcinogenesis, can be driven by p53/p21 proteins in response to various stresses. Here, we demonstrate that Wig1 plays a critical role in this process through regulation of p21 mRNA stability. Wig1 controls the association of Argonaute2 (Ago2), a central component of the RNA‐induced silencing complex (RISC), with target p21 mRNA via binding of the stem‐loop structure near the microRNA (miRNA) target site. Depletion of Wig1 prohibited miRNA‐mediated p21 mRNA decay and resulted in premature senescence. Wig1 plays an essential role in cell proliferation, as demonstrated in tumour xenografts in mice, and Wig1 and p21 mRNA levels are inversely correlated in human normal and cancer tissues. Together, our data indicate a novel role of Wig1 in RISC target accessibility, which is a key step in RNA‐mediated gene silencing. In addition, these findings indicate that fine‐tuning of p21 levels by Wig1 is essential for the prevention of cellular senescence. 相似文献
108.
Ernst WA Thoma-Uszynski S Teitelbaum R Ko C Hanson DA Clayberger C Krensky AM Leippe M Bloom BR Ganz T Modlin RL 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(12):7102-7108
Granulysin, a protein located in the acidic granules of human NK cells and cytotoxic T cells, has antimicrobial activity against a broad spectrum of microbial pathogens. A predicted model generated from the nuclear magnetic resonance structure of a related protein, NK lysin, suggested that granulysin contains a four alpha helical bundle motif, with the alpha helices enriched for positively charged amino acids, including arginine and lysine residues. Denaturation of the polypeptide reduced the alpha helical content from 49 to 18% resulted in complete inhibition of antimicrobial activity. Chemical modification of the arginine, but not the lysine, residues also blocked the antimicrobial activity and interfered with the ability of granulysin to adhere to Escherichia coli and Mycobacterium tuberculosis. Granulysin increased the permeability of bacterial membranes, as judged by its ability to allow access of cytosolic ss-galactosidase to its impermeant substrate. By electron microscopy, granulysin triggered fluid accumulation in the periplasm of M. tuberculosis, consistent with osmotic perturbation. These data suggest that the ability of granulysin to kill microbial pathogens is dependent on direct interaction with the microbial cell wall and/or membrane, leading to increased permeability and lysis. 相似文献
109.
Characterization of the distal tail fiber locus and determination of the receptor for phage AR1, which specifically infects Escherichia coli O157:H7 总被引:1,自引:0,他引:1 下载免费PDF全文
Phage AR1 is similar to phage T4 in several essential genes but differs in host range. AR1 infects various isolates of Escherichia coli O157:H7 but does not infect K-12 strains that are commonly infected by T4. We report here the determinants that confer this infection specificity. In T-even phages, gp37 and gp38 are components of the tail fiber that are critical for phage-host interaction. The counterparts in AR1 may be similarly important and, therefore, were characterized. The AR1 gp37 has a sequence that differs totally from those of T2 and T4, except for a short stretch at the N terminus. The gp38 sequence, however, has some conservation between AR1 and T2 but not between AR1 and T4. The sequences that are most closely related to the AR1 gp37 and gp38 are those of phage Ac3 in the T2 family. To identify the AR1-specific receptor, E. coli O157:H7 was mutated by Tn10 insertion and selected for an AR1-resistant phenotype. A mutant so obtained has an insertion occurring at ompC that encodes an outer membrane porin. To confirm the role of OmpC in the AR1 infection, homologous replacement was used to create an ompC disruption mutant (RM). When RM was complemented with OmpC originated from an O157:H7 strain, but not from K-12, its AR1 susceptibility was fully restored. Our results suggest that the host specificity of AR1 is mediated at least in part through the OmpC molecule. 相似文献
110.
Ko Nakamura Kunihiko Higashiura Naoharu Nishimura Atsushi Yamamoto Ikuo Tooyama Hiroshi Kimura Kazuharu Ienaga 《Journal of neurochemistry》1990,55(3):1064-1066
We isolated a glutamyltaurine from bovine brains and determined its structure as gamma-glutamyltaurine (gamma-Glu-Tau; glutaurine) by use of a new mass spectrometric technique [B/E linked scan sputtered ion mass spectrometry (SIMS)], which we have recently shown to be useful for distinguishing the gamma- from the alpha-isomer of glutamyl-dipeptides. Neither the alpha-isomer of glutamyltaurine nor any aspartyltaurines could be detected in bovine brain. 相似文献