全文获取类型
收费全文 | 1070篇 |
免费 | 115篇 |
出版年
2021年 | 13篇 |
2020年 | 9篇 |
2018年 | 12篇 |
2017年 | 12篇 |
2016年 | 17篇 |
2015年 | 29篇 |
2014年 | 35篇 |
2013年 | 49篇 |
2012年 | 42篇 |
2011年 | 48篇 |
2010年 | 29篇 |
2009年 | 37篇 |
2008年 | 39篇 |
2007年 | 38篇 |
2006年 | 31篇 |
2005年 | 27篇 |
2004年 | 32篇 |
2003年 | 25篇 |
2002年 | 45篇 |
2001年 | 43篇 |
2000年 | 40篇 |
1999年 | 21篇 |
1998年 | 16篇 |
1997年 | 17篇 |
1996年 | 16篇 |
1995年 | 12篇 |
1994年 | 10篇 |
1993年 | 15篇 |
1992年 | 18篇 |
1991年 | 23篇 |
1990年 | 16篇 |
1989年 | 20篇 |
1988年 | 26篇 |
1987年 | 23篇 |
1986年 | 18篇 |
1985年 | 29篇 |
1984年 | 16篇 |
1983年 | 16篇 |
1982年 | 16篇 |
1981年 | 8篇 |
1979年 | 15篇 |
1978年 | 10篇 |
1977年 | 9篇 |
1975年 | 13篇 |
1974年 | 17篇 |
1973年 | 10篇 |
1972年 | 19篇 |
1968年 | 8篇 |
1967年 | 8篇 |
1966年 | 7篇 |
排序方式: 共有1185条查询结果,搜索用时 31 毫秒
991.
Peng X Cebra JJ Adler MW Meissler JJ Cowan A Feng P Eisenstein TK 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(7):3677-3681
In this study, we investigated the effect of morphine on the mucosal immune system using fragment cultures of ileal segments, Peyer's patches (PPs), and mesenteric lymph nodes. Mice were implanted s.c. with a morphine slow release pellet. Control groups received a naltrexone slow release pellet, a placebo pellet, or both a morphine and a naltrexone pellet. After 48 h, mice were orally immunized with cholera toxin (CT) and were boosted orally 1 wk later. Animals were sacrificed 1 wk after the booster immunization, and PPs, mesenteric lymph nodes, and ileal segments were cultured in 24-well plates for 12 days. Morphine resulted in a highly significant inhibition of CT-specific IgA and IgG production in fragment culture supernatants of all three tissues compared with placebo. Naltrexone blocked the reduction in Ab levels induced by morphine, indicating that the effect is opioid receptor mediated. Morphine did not significantly alter total IgA levels in any of the tissue culture supernatants. Morphine also inhibited CT-specific IgA and IgG levels in serum. By flow cytometry, morphine did not alter the lymphoid cell composition in PPs compared with placebo. The effect of morphine on TGF-beta, IL-5, and IL-6 mRNA expression in PPs and ileal segments was determined following oral immunization with CT. Morphine significantly decreased TGF-beta mRNA compared with that in the placebo group, and naltrexone blocked this effect. These results indicate that morphine inhibits Ag-specific IgA responses in gut-associated lymphoid tissue at least partially through the inhibition of TGF-beta, a putative IgA switch factor, in the gastrointestinal tract. 相似文献
992.
Musso DL Andersen MW Andrews RC Austin R Beaudet EJ Becherer JD Bubacz DG Bickett DM Chan JH Conway JG Cowan DJ Gaul MD Glennon KC Hedeen KM Lambert MH Leesnitzer MA McDougald DL Mitchell JL Moss ML Rabinowitz MH Rizzolio MC Schaller LT Stanford JB Tippin T Warner JR Whitesell LG Wiethe RW 《Bioorganic & medicinal chemistry letters》2001,11(16):2147-2151
N-Hydroxyformamide-class metalloprotease inhibitors were designed and synthesized, which have potent broad-spectrum activity versus matrix metalloproteases and TNF-alpha converting enzyme (TACE). Compound 13c possesses good oral and intravenous pharmacokinetics in the rat and dog. 相似文献
993.
994.
Outside-in signaling mediated by the integrin alpha(IIb)beta(3) (GPIIbIIIa) is critical to platelet function and has been shown to involve the phosphorylation of tyrosine residues on the cytoplasmic tail of beta(3). To identify proteins that bind directly to phosphorylated beta(3), we utilized an affinity column consisting of a peptide modeled on the tyrosine-phosphorylated cytoplasmic domain of beta(3). Tandem mass spectrometric sequencing and immunoblotting demonstrated that Shc was the primary protein binding to phosphorylated beta(3). To determine the involvement of Shc in outside-in alpha(IIb)beta(3) signaling, the phosphorylation of Shc during platelet aggregation was examined; transient Shc phosphorylation was observed when thrombin-stimulated platelets were allowed to aggregate or when aggregation was induced by an LIBS (ligand-induced binding site) antibody, D3. Moreover, Shc was co-immunoprecipitated with tyrosine-phosphorylated beta(3) in detergent lysates of aggregated platelets. Using purified, recombinant protein, it was found that the binding of Shc to monophosphorylated (C-terminal tyrosine) and diphosphorylated beta(3) peptides was direct, demonstrating Shc recognition motifs on phospho-beta(3). Aggregation-induced Shc phosphorylation was also observed to be robust in platelets from wild-type mice, but not in those from mice expressing (Y747F,Y759F) beta(3), which are defective in outside-in alpha(IIb)beta(3) signaling. Thus, Shc is the primary downstream signaling partner of beta(3) in its tyrosine phosphorylation outside-in signaling pathway. 相似文献
995.
ADP ribosylation factor-like protein 2 (Arl2) regulates the interaction of tubulin-folding cofactor D with native tubulin 总被引:9,自引:0,他引:9
The ADP ribosylation factor-like proteins (Arls) are a family of small monomeric G proteins of unknown function. Here, we show that Arl2 interacts with the tubulin-specific chaperone protein known as cofactor D. Cofactors C, D, and E assemble the alpha/beta- tubulin heterodimer and also interact with native tubulin, stimulating it to hydrolyze GTP and thus acting together as a beta-tubulin GTPase activating protein (GAP). We find that Arl2 downregulates the tubulin GAP activity of C, D, and E, and inhibits the binding of D to native tubulin in vitro. We also find that overexpression of cofactors D or E in cultured cells results in the destruction of the tubulin heterodimer and of microtubules. Arl2 specifically prevents destruction of tubulin and microtubules by cofactor D, but not by cofactor E. We generated mutant forms of Arl2 based on the known properties of classical Ras-family mutations. Experiments using these altered forms of Arl2 in vitro and in vivo demonstrate that it is GDP-bound Arl2 that interacts with cofactor D, thereby averting tubulin and microtubule destruction. These data establish a role for Arl2 in modulating the interaction of tubulin-folding cofactors with native tubulin in vivo. 相似文献
996.
Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts 总被引:9,自引:0,他引:9
Williams MA Trambley J Ha J Adams AB Durham MM Rees P Cowan SR Pearson TC Larsen CP 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(12):6849-6857
Simultaneous blockade of the CD40 and CD28 T cell costimulatory pathways effectively promotes skin allograft survival in C3H/HeJ mice, extending median survival times (MSTs) beyond 100 days. This strategy is markedly less effective in C57BL/6 mice, with MSTs ranging between 20 and 30 days. In this study, we investigate the underlying genetic causes of these distinct phenotypes. Using H-2 congenic mice, we show that the genetic basis for the varied responses between these two strains is independent of the H-2 locus and T cell precursor frequency. C57BL/6 mice treated with costimulation blockade are able to generate allospecific CTL- and IFN-gamma-producing T cells within 3-4 wk posttransplant, whereas mice with a C3H background generate neither CTL- nor IFN-gamma-producing cells. Thus, differences appear to be in the generation of the immune response and not T cell homing. Strain differences in costimulation blockade-induced hyporesponsiveness persist in the absence of CD4(+) T cells, implying a direct effect on CD8(+) T cells. We demonstrate that genetic differences are important in cells of hemopoietic origin and that the costimulation blockade-resistant phenotype is dominant. Analysis of BXH recombinant inbred strains indicates that multiple loci contribute to the phenotype, and that the blockade resistance loci are preliminarily linked to 17 markers on four chromosomes. We conclude that strain variation in allograft MSTs following CD40/CD28 blockade results from the ability of CD8(+) T cells in some strains to use alternative modes of costimulation to mount an effective alloresponse. 相似文献
997.
Microbial genomes--the untapped resource 总被引:8,自引:0,他引:8
Cowan DA 《Trends in biotechnology》2000,18(1):14-16
Although the 1990s have ushered in the genome, they have also exposed our limitations for deriving structural and functional information. In parallel, molecular phylogeny has demonstrated that the majority of microbial genomes are currently inaccessible. Key objectives for the next century are the development of techniques for accessing 'unculturable' genomes, exploiting their biotechnologically valuable genes and products, and linking genome-sequence data to molecular structure and function. 相似文献
998.
A conditioned taste aversion (CTA) is acquired through an association between the taste of a food and a feeling of illness experienced after ingestion. It can be induced deliberately by the addition of an undetectable illness-inducing chemical to food. Harnessing the CTA response could provide humane and effective means of controlling vertebrate pest problems. For field use, the ideal illness-inducing chemical should induce a robust CTA after a single oral dose, at which it must cause neither chronic illness nor persistent detrimental effects in the target or any non-target species at risk of exposure; it must also be undetectable and physically stable in the bait substrate. At present, no compound that satisfactorily meets all of these criteria has been identified. 17alpha ethinyl oestradiol meets most but, as a synthetic oestrogenic hormone, it can affect reproductive processes. The ability of two potentially safe compounds, cinnamamide (160 mg/kg) and thiabendazole (100 and 200 mg/kg) to generate a CTA in the laboratory rat Rattus norvegicus11 post-treatment tests (6 months). Thiabendazole at 200 mg/kg induced the next best CTA, persisting for five post-treatment tests. Cinnamamide and thiabendazole could provide safe alternative CTA agents to 17alpha ethinyl oestradiol for field use; the use of a second dose of these compounds to improve longevity of the CTA warrants further study. 相似文献
999.
Based on a hypothesis of neural system involvement in the initial absorption and further processing of the millimeter electromagnetic waves (MW) signal, we reproduced, quantitatively assessed and compared the analgesic effect of a single MW treatment, exposing areas of skin possessing different innervation densities. The cold water tail flick test (cTFT) was used to assess experimental pain in mice. Three areas of exposure were used: the nose, the glabrous skin of the right footpad, and the hairy skin of the mid back at the level of T5-T10. The MW exposure characteristics were: frequency = 61.22 GHz; incident power density = 15mW/cm2; and duration = 15 min. The maximum hypoalgesic effect was achieved by exposing to MW the more densely innervated skin areas--the nose and the footpad. The hypoalgesic effect in the cTFT after MW exposure to the murine back, which is less densely innervated, was not statistically significant. These results support the hypothesis of neural system involvement in the systemic response to MW. 相似文献
1000.