全文获取类型
收费全文 | 364篇 |
免费 | 51篇 |
国内免费 | 67篇 |
出版年
2024年 | 2篇 |
2023年 | 2篇 |
2022年 | 7篇 |
2021年 | 13篇 |
2020年 | 12篇 |
2019年 | 10篇 |
2018年 | 18篇 |
2017年 | 11篇 |
2016年 | 20篇 |
2015年 | 17篇 |
2014年 | 22篇 |
2013年 | 26篇 |
2012年 | 26篇 |
2011年 | 30篇 |
2010年 | 18篇 |
2009年 | 18篇 |
2008年 | 19篇 |
2007年 | 19篇 |
2006年 | 26篇 |
2005年 | 21篇 |
2004年 | 23篇 |
2003年 | 28篇 |
2002年 | 22篇 |
2001年 | 15篇 |
2000年 | 16篇 |
1999年 | 10篇 |
1998年 | 7篇 |
1997年 | 8篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1982年 | 2篇 |
1969年 | 1篇 |
排序方式: 共有482条查询结果,搜索用时 156 毫秒
41.
Bacterial lipoprotein induces resistance to Gram-negative sepsis in TLR4-deficient mice via enhanced bacterial clearance 总被引:1,自引:0,他引:1
TLRs are highly conserved pathogen recognition receptors. As a result, TLR4-deficient C3H/HeJ mice are highly susceptible to Gram-negative sepsis. We have previously demonstrated that tolerance induced by bacterial lipoprotein (BLP) protects wild-type mice against polymicrobial sepsis-induced lethality. In this study, we assessed whether pretreatment of C3H/HeJ mice with BLP could induce resistance to a subsequent Gram-negative Salmonella typhimurium infection. Pretreatment with BLP resulted in a significant survival benefit in TLR4-deficient C3H/HeJ mice (p < 0.0002 vs control C3H/HeJ) after challenge with live S. typhimurium (0.25 x 10(6) CFU/mouse). This survival benefit was associated with enhanced bacterial clearance from the circulation and in the visceral organs (p < 0.05 vs control C3H/HeJ). Furthermore, pretreatment with BLP resulted in significant increases in complement receptor type 3 (CR3) and FcgammaIII/IIR expression on polymorphonuclear neutrophils (PMNs) and macrophages (p < 0.05 vs control C3H/HeJ). There was impaired bacterial recognition and phagocytosis in TLR4-deficient mice compared with wild-type mice. However, a significant augmented uptake, ingestion, and intracellular killing of S. typhimurium by PMNs and peritoneal macrophages was evident in BLP-pretreated C3H/HeJ mice (p < 0.05 vs control C3H/HeJ). An up-regulation of inducible NO synthase and increased production of intracellular NO were observed in peritoneal macrophages from BLP-pretreated C3H/HeJ mice (p < 0.05 vs control C3H/HeJ). Depletion of PMNs did not diminish the beneficial effects of BLP with regard to both animal survival and bacterial clearance. These results indicate that BLP, a TLR2 ligand, protects highly susceptible TLR4-deficient mice from Gram-negative sepsis via enhanced bacterial clearance. 相似文献
42.
An embryo-defective mutant of Arabidopsis thaliana was isolated that arrests development at a variety of stages, from as early as the globular stage of embryogenesis to as late as formation of an abnormal bent cotyledon stage embryo. Defects in the suspensor, a normally transient structure derived from the fertilized egg, were often associated with the arrested embryo. The lesion was within a gene encoding a protein with domains characteristic of lariat debranching enzymes, which has been named AtDBR1 (for Arabidopsis thaliana Debranching enzyme 1). Cleavage of the 2'-5'-phosphodiester bond found in excised intron lariats ("debranching") is essential for turnover of intronic sequences as well as generation of some small nucleolar RNAs. The mutation within AtDBR1 was confirmed by complementation as being responsible for the embryo-lethal phenotype, and the activity of the encoded protein in cleavage of 2'-5'-phosphodiester bonds was verified using an in vitro debranching assay. 相似文献
43.
大量研究表明,TGF-β作为一种具有多种功能的生长因子,是全身瘢痕愈合的重要刺激因素.在人眼部参与多种眼部纤维化的过程。尤其在促进青光眼滤过术后结膜瘢痕形成中起重要作用。Smad蛋白家族在TGF-β超家族的信号转导中具有重要的作用。Smad7主要通过抑制TGF书受体介导的Smad2、Smad3磷酸化来拮抗TGF-β的信号转导,被认为是TGF-β超家族信号转导自我调节的一种负反馈信号。 相似文献
44.
Shields CJ Winter DC Geibel JP O'Sullivan GC Wang JH Redmond HP 《The Journal of membrane biology》2006,211(1):35-42
Hypertonic saline (HTS) suppresses tumor cell-endothelial interactions by reducing integrin expression. This translates into
reduced adhesion, migration and metastatic potential. This study determined the relative contributions of hyperosmolarity
and sodium-specific hypertonicity on the inhibitory effects of HTS, the intracellular pH and sodium responses to HTS and the
role of cytoskeletal remodeling in these changes. Human colonic tumor cells (LS174T) were exposed to lipopolysaccharide under
isotonic, hypertonic, sodium-free (N-methyl- D-glucamine), hyperosmolar (mannitol or urea), disrupted cytoskeletal (10 μg/ml cytochalasin D) conditions or in the presence
of 5-(N-ethyl-N-isopropyl)amiloride (EIPA). β1 integrin expression was measured flow-cytometrically. Intracellular sodium and pH were measured with confocal laser microscopic
imaging. Statistical analysis was performed with analysis of variance, and P < 0.05 was considered significant. Data are represented as mean ± SEM. Hypertonic exposure attenuated integrin expression (62.03 ± 4.7% of control, P < 0.04). No discernible effect was observed with sodium-free or hyperosmolar solutions. HTS evoked a cellular alkalinization
(by a mean 0.2 pH units) and an increase in cytosolic sodium concentration (by a mean 12.4 mM, P < 0.001) via upregulation of sodium-hydrogen exchange. Disassembly of actin microfilaments by cytochalasin D and antiporter
inhibition with EIPA abrogated the effect of hypertonicity on integrin expression and intracellular sodium and pH (P < 0.05). HTS downregulates adhesion molecule expression via a hypertonic, sodium-specific, cytoskeletally mediated mechanism
that involves activation of sodium-hydrogen exchange with associated changes in intracellular pH and sodium concentrations. 相似文献
45.
Systematic intervention of transcription for identifying network response to disease and cellular phenotypes 总被引:1,自引:0,他引:1
MOTIVATION: A major challenge in post-genomic research has been to understand how physiological and pathological phenotypes arise from the networks of expressed genes. Here, we addressed this issue by developing an algorithm to mimic the behavior of regulatory networks in silico and to identify the dynamic response to disease and changing cellular conditions. RESULTS: With regulatory pathway and gene expression data as input, the algorithm provides quantitative assessments of a wide range of responses, including susceptibility to disease, potential usefulness of a given drug, or consequences to such external stimuli as pharmacological interventions or caloric restriction. The algorithm is particularly amenable to the analysis of systems that are difficult to recapitulate in vitro, yet they may have important clinical value. The hypotheses derived from the algorithm were biologically relevant and were successfully validated via independent experiments, as illustrated here in the analysis of the leukemia-associated BCR-ABL pathway and the insulin/IGF pathway related to longevity. The algorithm correctly identified the leukemia drug target and genes important for longevity, and also provided new insights into our understanding of these two processes. AVAILABILITY: The software package is available upon request to the authors. 相似文献
46.
The present study investigated the effects of raloxifene, a second generation selective estrogen receptor modulator (SERM), plus 17-betaE2 on aortic atherosclerosis and mammary gland hyperplasia in ovariectomized, cholesterol-fed rabbits. Following 10 weeks of raloxifene, 17-betaE2, or raloxifene plus 17-betaE2 administration, serum total cholesterol, triglyceride, low density lipoprotein were significantly decreased in the drug groups compared to the placebo group. Consistent with serum lipid results, the total lesion area for each aorta of the drug groups decreased significantly as compared to the placebo group. HE staining of aorta paraffin section showed that in the drug groups the endothelial monolayer was almost continuous. While in mammary gland, HE staining of paraffin sections indicated the hyperplasia of epithelial cells (in 17-betaE2 group) was obviously inhibited in raloxifene plus 17-betaE2 group. In cultured vascular smooth muscle cell (VSMC), the results of MTT and [3H]TdR incorporation showed that the drug groups could inhibit AngII-induced proliferation of VSMC. Western blotting proved that raloxifene plus 17-betaE2 inhibited the expression of phosphorylated ERK protein, similar to 17-betaE2 but different from raloxifene. This effect was inhibited by PD98059 (inhibitor of MAPK) or ICI182780 (ER antagonist). In conclusion, this study suggests that SERM raloxifene plus 17-betaE2 improves the lipid metabolism and relieves the aorta changes of female experimental atherosclerosis rabbits, which are partly implemented by the inhibition of VSMC growth through ERK cascade. The hyperplasia of mammary gland epithelial cells could be significantly inhibited by raloxifene plus 17-betaE2. 相似文献
47.
Chen X Quinn EM Ni H Wang J Blankson S Redmond HP Wang JH Feng X 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(1):347-355
In addition to a well-documented role in regulating T cell-mediated immune responses, B7-H3, a newly discovered member of the B7 superfamily, has been recently identified as a costimulator in the innate immunity-mediated inflammatory response. In this study, we further report that B7-H3 participates in the development of pneumococcal meningitis in a murine model. Exogenous administration of B7-H3 strongly amplified the inflammatory response, exacerbated blood-brain barrier disruption, and aggravated the clinical disease status in Streptococcus pneumoniae-infected C3H/HeN wild-type mice. Consistent with the in vivo findings, B7-H3 substantially augmented proinflammatory cytokine and chemokine production, upregulated NF-κB p65 and MAPK p38 phosphorylation, and enhanced the nuclear transactivation of NF-κB p65 at both TNF-α and IL-6 promoters in S. pneumoniae-stimulated primary murine microglia cells. These B7-H3-associated in vitro and in vivo effects appeared to be dependent on TLR2 signaling, as B7-H3 almost completely lost its amplifying actions in both TLR2-deficient microglial cells and TLR2-deficient mice. Furthermore, administration of the anti-B7-H3 mAb (MIH35) attenuated the inflammatory response and ameliorated blood-brain barrier disruption in S. pneumoniae-infected wild-type mice. Collectively, our results indicate that B7-H3 plays a contributory role in the development of S. pneumoniae infection-induced bacterial meningitis. 相似文献
48.
49.
(2R)-2-[4-(4-Cyano-2-fluorophenoxy)phenoxy]butylpropanoate (cyhalofop-butyl, CyB) was synthesized by a chemoenzymatic route involving
enantioselective transesterification with Candida antarctica lipase B (Novozym 435). The optimum organic solvent, acyl donor, a
w
, reaction temperature and shaking rate for the transesterification were acetonitrile, n-butanol, 0.11, 45°C and 200 rpm, respectively. Under the optimum conditions, the maximum substrate conversion and the enantiomeric
purity of the product were 96.9 and >99%, respectively. The total yield and enantiomeric purity of CyB by this chemoenzymatic
synthesis were 60.4 and >99%, respectively; 15.3 and 21% higher than that of the traditional way (45 and 78%). 相似文献
50.
The combined effects of warming and drying suppress CO2 and N2O emission rates in an alpine meadow of the eastern Tibetan Plateau 总被引:1,自引:0,他引:1
The eastern Tibetan Plateau has become increasingly warmer and drier since the 1990s. Such warming and drying has a great impact on ecosystem processes on the eastern Tibetan Plateau. To determine their combined effects on CO2 and N2O emission rates, we conducted a field manipulative experiment in an alpine meadow of the eastern Tibetan Plateau during the growing season of 2009. The experiment showed that warming manipulation increased soil temperature by 1?°C, and drying manipulation decreased soil water content by 6.8?%. We found that by counteracting the effect of low temperature in the area, experimental warming significantly increased soil microbial biomass, the number of bacteria, fungi, actinomycetes, ammonifying bacteria, nitrobacteria and denitrifying bacteria, and facilitated the emission rates of CO2 and N2O by 33.4 and 31.5?%, respectively. However, decreased precipitation further aggravated soil water stress and inhibited the numbers of these organisms, and reduced the emission rates of CO2 and N2O by 47.4 and 37.9?%, respectively. So decreased soil water content tended to offset the positive effect of warming. Compared to the positive effects of warming, decreased soil water content was shown in our study to have even greater impact on the eastern Tibetan Plateau during the growing season. Therefore, inhibition of CO2 and N2O emission rates (32.3 and 29.3?%, respectively) by warming and drying will intensify if the combined effects of these climatic trends persist in the region. 相似文献