首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   905篇
  免费   97篇
  2023年   2篇
  2022年   8篇
  2021年   14篇
  2020年   8篇
  2019年   9篇
  2018年   12篇
  2017年   17篇
  2016年   24篇
  2015年   21篇
  2014年   42篇
  2013年   49篇
  2012年   66篇
  2011年   66篇
  2010年   47篇
  2009年   39篇
  2008年   45篇
  2007年   71篇
  2006年   61篇
  2005年   61篇
  2004年   57篇
  2003年   61篇
  2002年   45篇
  2001年   11篇
  2000年   18篇
  1999年   11篇
  1998年   15篇
  1997年   8篇
  1996年   9篇
  1995年   15篇
  1994年   7篇
  1993年   3篇
  1992年   9篇
  1991年   8篇
  1990年   6篇
  1989年   7篇
  1988年   4篇
  1987年   4篇
  1986年   2篇
  1985年   6篇
  1984年   2篇
  1983年   3篇
  1982年   5篇
  1980年   2篇
  1979年   3篇
  1978年   2篇
  1976年   2篇
  1975年   2篇
  1974年   2篇
  1957年   1篇
  1916年   1篇
排序方式: 共有1002条查询结果,搜索用时 15 毫秒
81.
TRPM8 is a cold sensor that is highly expressed in the prostate as well as in other non-temperature-sensing organs, and is regulated by downstream receptor–activated signaling pathways. However, little is known about the intracellular proteins necessary for channel function. Here, we identify two previously unknown proteins, which we have named “TRP channel–associated factors” (TCAFs), as new TRPM8 partner proteins, and we demonstrate that they are necessary for channel function. TCAF1 and TCAF2 both bind to the TRPM8 channel and promote its trafficking to the cell surface. However, they exert opposing effects on TRPM8 gating properties. Functional interaction of TCAF1/TRPM8 also leads to a reduction in both the speed and directionality of migration of prostate cancer cells, which is consistent with an observed loss of expression of TCAF1 in metastatic human specimens, whereas TCAF2 promotes migration. The identification of TCAFs introduces a novel mechanism for modulation of TRPM8 channel activity.  相似文献   
82.
83.
Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1(lacZ) and Msx2(lacZ) are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1(lacZ), Msx2(lox) and Sm22α-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1(CreERT2) allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.  相似文献   
84.
Mice deficient in α-sarcoglycan (Sgca-null mice) develop progressive muscular dystrophy and serve as a model for human limb girdle muscular dystrophy type 2D. Sgca-null mice suffer a more severe myopathy than that of mdx mice, the model for Duchenne muscular dystrophy. This is the opposite of what is observed in humans and the reason for this is unknown. In an attempt to understand the cellular basis of this severe muscular dystrophy, we isolated clonal populations of myogenic progenitor cells (MPCs), the resident postnatal muscle progenitors of dystrophic and wild-type mice. MPCs from Sgca-null mice generated much smaller clones than MPCs from wild-type or mdx dystrophic mice. Impaired proliferation of Sgca-null myogenic precursors was confirmed by single fiber analysis and this difference correlated with Sgca expression during MPC proliferation. In the absence of dystrophin and associated proteins, which are only expressed after differentiation, SGCA complexes with and stabilizes FGFR1. Deficiency of Sgca leads to an absence of FGFR1 expression at the membrane and impaired MPC proliferation in response to bFGF. The low proliferation rate of Sgca-null MPCs was rescued by transduction with Sgca-expressing lentiviral vectors. When transplanted into dystrophic muscle, Sgca-null MPCs exhibited reduced engraftment. The reduced proliferative ability of Sgca-null MPCs explains, at least in part, the severity of this muscular dystrophy and also why wild-type donor progenitor cells engraft efficiently and consequently ameliorate disease.  相似文献   
85.
86.
Long-distance flights can cause a number of clinical problems due to mild hypoxia resulting from cabin pressurization. Using a chronobiological approach, the aim of this work was to assess the clinical tolerance and biological impact of daytime exposure to hypobaric hypoxia on markers of iron metabolism and plasma proteins. Fourteen healthy, male volunteers, ages 23 to 39 yrs, spent 8.5 h in a hypobaric chamber (from 07:45 to 16:15 h) simulating an altitude of 8000 ft. This was followed by another 8.5-h session 4 wks later simulating conditions at an altitude of 12,000 ft. Biological variables were assayed every 2 h over two 24-h spans (control and hypoxia spans, respectively) per simulated altitude. Whereas most of the subjects tolerated the 8000 ft exposure well, eight subjects (57%) presented clear clinical signs of hypoxic intolerance at 12,000 ft. The 24-h blood iron profile showed a biphasic pattern at both altitude simulations, with a significant (~40%) increase during hypoxia, followed by a (~25%) decrease during the first hours of recovery. The iron circadian rhythm showed a significant phase delay during the hypoxic exposure at 8000 ft vs. reference. Mean 24-h ferritin levels decreased at both altitudes, but mainly during the nighttime after the 12,000 ft exposure in accordance with Cosinor analysis. The transferrin and total plasma proteins 24-h profiles did not show significant change. Moreover, significant differences, mainly in iron, ferritin, and transferrin, were found at 12,000 ft according to the clinical tolerance to hypoxia, and significant correlations were found between the mid-range crossing times, i.e., here half-descent times (d-T(50)), for ferritin and total plasma proteins and the reported level of clinical discomfort under hypoxia. This study shows that an 8.5-h exposure to mild hypoxia is able to alter very quickly the 24-h pattern of iron and ferritin. These alterations seem to depend, at least in part, on the clinical tolerance to hypoxia and may help explain the interindividual differences observed in the tolerance to hypoxia.  相似文献   
87.
p53 regulates several biological processes, including senescence. Its protein stability is regulated by ubiquitination and proteasomal degradation, mainly mediated by Mdm2. However, other E3 ligases have been identified, such as the chaperone-associated ligase CHIP, although their precise function regarding p53 degradation remains elusive. Interestingly, CHIP deficiency has been recently shown to result in accelerated aging in mice, although the molecular basis of this phenotype was not completely understood. In this study, we explore the role of CHIP in regulating p53 in senescence. We demonstrate that in senescent human fibroblasts, CHIP is up-regulated concomitant with a significant down-regulation of p53. Moreover, CHIP partially translocates to the nucleus and acquires higher ubiquitination levels in senescent cells. Notably, CHIP overexpression in young cells, to levels similar to those recorded during senescence, leads to p53 degradation to below its basal levels. In addition, whereas CHIP silencing has no effect on p53 stability in young cells, a considerable p53 accumulation occurs in their senescent counterparts. Finally, we have observed an attenuation of the CHIP-associated molecular folding-refolding machinery during senescence, and supportively, inhibition of Hsp90 activity leads to rapid p53 degradation only in senescent cells. Taking these results together, we conclude that CHIP-dependent p53 regulation occurs specifically during senescence.  相似文献   
88.
89.
Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.  相似文献   
90.
The temporal prevalence of the widespread boring sponge Cliona celata and its effects were analysed in a population of the invasive mollusc Crepidula fornicata. This mollusc produces extra shell material when infested with the endolithic sponge, suggesting that infestation may be detrimental for C. fornicata growth and/or reproduction. For 37 months, size, sex, female reproductive status and sponge-infestation stage were recorded for 300 individuals sampled every month in the Bay of Morlaix (France). In the 12,049 individuals examined, the prevalence of C. celata was high with a monthly average of 43.1% of the individuals hosting the sponge. The relative proportion of heavily infested individuals generally increased over time. Nevertheless, a cyclic decrease occurred every 10 months, suggesting putative episodes of mortality of heavily infested individuals. The gregarious behaviour of the mollusc seemed to promote the high prevalence of the sponge, which may propagate through contact between neighbouring C. fornicata individuals. Due to the sex-size relationship in protandrous C. fornicata, females were far more infested than males. We did not find evidence for a cost of producing extra shell material on somatic growth or on female fertility, and the boring sponge is unlikely to substantially affect the sex-change patterns in C. fornicata. The limited effects of the endolithic sponge on C. fornicata contrasts with the documented damage to some local species, including commercially exploited shellfish, suggesting that C. fornicata may alter the infestation dynamics in the surrounding native community. Dedicated studies are now needed to investigate the extent and mechanisms of these species interactions.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号