全文获取类型
收费全文 | 376篇 |
免费 | 51篇 |
国内免费 | 70篇 |
出版年
2024年 | 2篇 |
2023年 | 2篇 |
2022年 | 7篇 |
2021年 | 13篇 |
2020年 | 13篇 |
2019年 | 10篇 |
2018年 | 18篇 |
2017年 | 11篇 |
2016年 | 20篇 |
2015年 | 18篇 |
2014年 | 22篇 |
2013年 | 26篇 |
2012年 | 26篇 |
2011年 | 31篇 |
2010年 | 19篇 |
2009年 | 18篇 |
2008年 | 21篇 |
2007年 | 22篇 |
2006年 | 27篇 |
2005年 | 23篇 |
2004年 | 23篇 |
2003年 | 29篇 |
2002年 | 23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 |
1990年 | 1篇 |
1982年 | 2篇 |
1969年 | 1篇 |
排序方式: 共有497条查询结果,搜索用时 62 毫秒
41.
The JIL-1 kinase localizes to interband regions of Drosophila polytene chromosomes and phosphorylates histone H3 Ser10. Analysis of JIL-1 hypomorphic alleles demonstrated that reduced levels of JIL-1 protein lead to global changes in polytene chromatin structure.
Here we have performed a detailed ultrastructural and cytological analysis of the defects in JIL-1 mutant chromosomes. We show that all autosomes and the female X chromosome are similarly affected, whereas the defects in
the male X chromosome are qualitatively different. In polytene autosomes, loss of JIL-1 leads to misalignment of interband
chromatin fibrils and to increased ectopic contacts between nonhomologous regions. Furthermore, there is an abnormal coiling
of the chromosomes with an intermixing of euchromatic regions and the compacted chromatin characteristic of banded regions.
In contrast, coiling of the male X polytene chromosome was not observed. Instead, the shortening of the male X chromosome
appeared to be caused by increased dispersal of the chromatin into a diffuse network without any discernable banded regions.
To account for the observed phenotypes we propose a model in which JIL-1 functions to establish or maintain the parallel alignment
of interband chromosome fibrils as well as to repress the formation of contacts and intermingling of nonhomologous chromatid
regions.
Electronic Supplementary Material Supplementary material is available for this article at and accessible for authorised users 相似文献
42.
JIL-1 kinase, a member of the male-specific lethal (MSL) complex, is necessary for proper dosage compensation of eye pigmentation in Drosophila 总被引:2,自引:0,他引:2
Lerach S Zhang W Deng H Bao X Girton J Johansen J Johansen KM 《Genesis (New York, N.Y. : 2000)》2005,43(4):213-215
The upregulation of the JIL-1 kinase on the male X chromosome and its association with the male-specific lethal (MSL) complex suggest that JIL-1 may play a role in regulating dosage compensation. To directly test this hypothesis we measured eye pigment levels of mutants in the X-linked white gene in an allelic series of JIL-1 hypomorphic mutants. We show that dosage compensation of w(a) alleles that normally do exhibit dosage compensation was severely impaired in the JIL-1 mutant backgrounds. As a control we also examined a hypomorphic white allele w(e) that fails to dosage compensate in males due to a pogo element insertion. In this case the relative pigment level measured in males as compared to females remained approximately the same even in the most severe JIL-1 hypomorphic background. These results indicate that proper dosage compensation of eye pigment levels in males controlled by X-linked white alleles requires normal JIL-1 function. 相似文献
43.
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
44.
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
45.
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
46.
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
47.
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
48.
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
49.
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
50.