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   1798篇
  免费   118篇
  2023年   8篇
  2022年   9篇
  2021年   36篇
  2020年   15篇
  2019年   42篇
  2018年   44篇
  2017年   27篇
  2016年   41篇
  2015年   80篇
  2014年   110篇
  2013年   129篇
  2012年   135篇
  2011年   150篇
  2010年   91篇
  2009年   87篇
  2008年   118篇
  2007年   113篇
  2006年   107篇
  2005年   108篇
  2004年   106篇
  2003年   79篇
  2002年   67篇
  2001年   13篇
  2000年   10篇
  1999年   14篇
  1998年   17篇
  1997年   12篇
  1996年   10篇
  1995年   16篇
  1994年   14篇
  1993年   9篇
  1992年   10篇
  1991年   7篇
  1990年   5篇
  1989年   5篇
  1988年   6篇
  1987年   3篇
  1986年   4篇
  1985年   5篇
  1984年   11篇
  1983年   4篇
  1982年   8篇
  1981年   3篇
  1980年   3篇
  1979年   6篇
  1978年   3篇
  1976年   2篇
  1975年   4篇
  1972年   2篇
  1970年   2篇
排序方式: 共有1916条查询结果,搜索用时 687 毫秒
991.
992.
IFN-β inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-γ decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases.  相似文献   
993.
The NSAID (non-steroidal anti-inflammatory drug) indomethacin, a cyclo-oxygenase-1 and -2 inhibitor with anti-inflammatory and analgesic properties, is known to possess anticancer activity against CRC (colorectal cancer) and other malignancies in humans; however, the mechanism underlying the anticancer action remains elusive. In the present study we show that indomethacin selectively activates the dsRNA (double-stranded RNA)-dependent protein kinase PKR in a cyclo-oxygenase-independent manner, causing rapid phosphorylation of eIF2α (the α-subunit of eukaryotic translation initiation factor 2) and inhibiting protein synthesis in colorectal carcinoma and other types of cancer cells. The PKR-mediated translational block was followed by inhibition of CRC cell proliferation and apoptosis induction. Indomethacin did not affect the activity of the eIF2α kinases PERK (PKR-like endoplasmic reticulum-resident kinase), GCN2 (general control non-derepressible-2) and HRI (haem-regulated inhibitor kinase), and induced eIF2α phosphorylation in PERK-knockout and GCN2-knockout cells, but not in PKR-knockout cells or in human PKR-silenced CRC cells, identifying PKR as a selective target for indomethacin-induced translational inhibition. The fact that indomethacin induced PKR activity in vitro, an effect reversed by the PKR inhibitor 2-aminopurine, suggests a direct effect of the drug in kinase activation. The results of the present study identify PKR as a novel target of indomethacin, suggesting new scenarios on the molecular mechanisms underlying the pleiotropic activity of this traditional NSAID.  相似文献   
994.
Transforming growth factor-beta (TGF-β) proteins are a family of structurally related extracellular proteins that trigger their signaling functions through interaction with the extracellular domains of their cognate serine/threonine kinase receptors. The specificity of TGF-β/receptor binding is complex and gives rise to multiple functional roles. Additionally, it is not completely understood at the atomic level. Here, we use the most reliable computational methods currently available to study systems involving activin-like kinase (ALK) receptors ALK4 and ALK7 and their multiple TGF-β ligands. We built models for all these proteins and their complexes for which experimental structures are not available. By analyzing the surfaces of interaction in six different TGF-β/ALK complexes we could infer which are the structural distinctive features of the ligand-receptor binding mode. Furthermore, this study allowed us to rationalize why binding of the growth factors GDF3 and Nodal to the ALK4 receptor requires the Cripto co-factor, whilst binding to the ALK7 receptor does not.  相似文献   
995.
Upon combining bidimensional electrophoresis with monodimensional separation, a more comprehensive analysis of the milk fat globule membrane has been obtained. The proteomic profile of caprine milk fat globules revealed the presence of butyrophilin, lactadherin and perilipin as the major proteins, they were also associated to bovine and human milk fat globule membranes. Xanthine dehydrogenase/oxidase has been detected only in monodimensional gels. Biological activity of milk fat globules has been evaluated in Caco2-cells, as a representative model of the intestinal barrier. The increase of cell viability was indicative of a potential nutraceutical role for the whole milk fat globule, suggesting a possible employment in milk formula preparation.  相似文献   
996.
997.
998.
Dab2ip (DOC-2/DAB2 interacting protein) is a member of the Ras GTPase-activating protein (GAP) family that has been previously shown to function as a tumor suppressor in several systems. Dab2ip is also highly expressed in the brain where it interacts with Dab1, a key mediator of the Reelin pathway that controls several aspects of brain development and function. We found that Dab2ip is highly expressed in the developing cerebral cortex, but that mutations in the Reelin signaling pathway do not affect its expression. To determine whether Dab2ip plays a role in brain development, we knocked down or over expressed it in neuronal progenitor cells of the embryonic mouse neocortex using in utero electroporation. Dab2ip down-regulation severely disrupts neuronal migration, affecting preferentially late-born principal cortical neurons. Dab2ip overexpression also leads to migration defects. Structure-function experiments in vivo further show that both PH and GRD domains of Dab2ip are important for neuronal migration. A detailed analysis of transfected neurons reveals that Dab2ip down- or up-regulation disrupts the transition from a multipolar to a bipolar neuronal morphology in the intermediate zone. Knock down of Dab2ip in neurons ex-vivo indicates that this protein is necessary for proper neurite development and for the expression of several major neuronal microtubule associated proteins (MAPs), which are important for neurite growth and stabilization. Thus, our study identifies, for the first time, a critical role for Dab2ip in mammalian cortical development and begins to reveal molecular mechanisms that underlie this function.  相似文献   
999.
To better understand the proliferation of Calotropis procera in a semi-arid region of northeastern Brazil (Caatinga), we designed two experiments to determine which ecophysiological characteristics contribute to the species adaptive success. The first experiment was conducted with young plants under greenhouse conditions and three water regimes. The second experiment was conducted with adult plants under field conditions subject to regional seasonality. Young plants exhibited a high tolerance to water deficits, mainly because of their strong stomatal control, which was observed before any biochemical alterations in leaf metabolism. Only under full suspension of irrigation did the plants show a reduction in relative water content. Under field conditions, adult plants showed a high resilience to the semi-arid environment with respect to gas exchange and other measured biochemical parameters, including photosynthetic pigment, soluble sugars, amino acids and protein content, even under the low soil water availability of the dry season. This season featured high photosynthetically active radiation, low relative humidity and high temperatures, and thus exposed plants to extreme differences between leaf and air temperatures. Calotropis procera remains green throughout the year, indicating that it has developed several means of tolerating the semi-arid climate. Furthermore, this species maintains a high photosynthetic rate despite reduced stomatal conductance, which increases its water use efficiency, a fundamental characteristic for survival in this ecosystem.  相似文献   
1000.
Abstract

Embryo suspensor in Cruciferae. I. Morphology and structure. — Embryo suspensors in seven species of Cruciferae (Alyssum argenteum All., Brassica nigra (L.) Koch, Capsella bursa-pastoris (L.) Medicus, Diplotaxis erucoides (L.) DC., Eruca sativa Miller, Lepidium graminifolium L., Matthiola tricuspidata (L.) R. Br.) were morphologically investigated. These species have significant differences in their seeds, so that probable differences could be found in the structure of their ovules and therefore of their suspensors. Results indicate that it is impossible to generalize on the suspensor morphology and structure even in the same family. In Eruca sativa and Brassica nigra polyploidy and polyteny were found, suggesting a probably important metabolic function of their suspensors. In the other species polyteny was not present; a various degree of polyploidy could probably be assumed, suggesting a less active function of suspensors, maybe absorption and transport of nutritive material from the integuments to the developing embryo. The development of the endosperm is almost the same in all species, so that seems to be improbable a negative correlation with the suspensor and endosperm function in the early embryogenesis.  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