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   8864篇
  免费   762篇
  国内免费   1005篇
  2024年   21篇
  2023年   116篇
  2022年   339篇
  2021年   485篇
  2020年   369篇
  2019年   434篇
  2018年   403篇
  2017年   317篇
  2016年   386篇
  2015年   532篇
  2014年   665篇
  2013年   740篇
  2012年   799篇
  2011年   728篇
  2010年   475篇
  2009年   429篇
  2008年   472篇
  2007年   424篇
  2006年   391篇
  2005年   328篇
  2004年   310篇
  2003年   276篇
  2002年   221篇
  2001年   173篇
  2000年   119篇
  1999年   121篇
  1998年   93篇
  1997年   71篇
  1996年   77篇
  1995年   59篇
  1994年   52篇
  1993年   38篇
  1992年   28篇
  1991年   30篇
  1990年   16篇
  1989年   22篇
  1988年   13篇
  1987年   18篇
  1986年   5篇
  1985年   5篇
  1984年   7篇
  1983年   7篇
  1982年   6篇
  1981年   2篇
  1978年   1篇
  1977年   1篇
  1976年   1篇
  1975年   2篇
  1972年   1篇
  1950年   1篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
981.
Overlap of TCR repertoires among individuals provides the molecular basis for public T cell responses. By deep-sequencing the TCRβ repertoires of CD4(+)CD8(+) thymocytes from three individual mice, we observed that a substantial degree of TCRβ overlap, comprising ~10-15% of all unique amino acid sequences and ~5-10% of all unique nucleotide sequences across any two individuals, is already present at this early stage of T cell development. The majority of TCRβ sharing between individual thymocyte repertoires could be attributed to the process of convergent recombination, with additional contributions likely arising from recombinatorial biases; the role of selection during intrathymic development was negligible. These results indicate that the process of TCR gene recombination is the major determinant of clonotype sharing between individuals.  相似文献   
982.
The urokinase receptor urokinase-type plasminogen activator receptor (uPAR) is a surface receptor capable of not only focalizing urokinase-type plasminogen activator (uPA)-mediated fibrinolysis to the pericellular micro-environment but also promoting cell migration and chemotaxis. Consistent with this multifunctional role, uPAR binds several extracellular ligands, including uPA and vitronectin. Structural studies suggest that uPAR possesses structural flexibility. It is, however, not clear whether this flexibility is an inherent property of the uPAR structure per se or whether it is induced upon ligand binding. The crystal structure of human uPAR in its ligand-free state would clarify this issue, but such information remains unfortunately elusive. We now report the crystal structures of a stabilized, human uPAR (H47C/N259C) in its ligand-free form to 2.4 Å and in complex with amino-terminal fragment (ATF) to 3.2 Å. The structure of uPARH47C/N259C in complex with ATF resembles the wild-type uPAR·ATF complex, demonstrating that these mutations do not perturb the uPA binding properties of uPAR. The present structure of uPARH47C/N259C provides the first structural definition of uPAR in its ligand-free form, which represents one of the biologically active conformations of uPAR as defined by extensive biochemical studies. The domain boundary between uPAR DI–DII domains is more flexible than the DII–DIII domain boundary. Two important structural features are highlighted by the present uPAR structure. First, the DI–DIII domain boundary may face the cell membrane. Second, loop 130–140 of uPAR plays a dynamic role during ligand loading/unloading. Together, these studies provide new insights into uPAR structure–function relationships, emphasizing the importance of the inter-domain dynamics of this modular receptor.  相似文献   
983.
984.
985.
Xiang Y  Zheng K  Ju H  Wang S  Pei Y  Ding W  Chen Z  Wang Q  Qiu X  Zhong M  Zeng F  Ren Z  Qian C  Liu G  Kitazato K  Wang Y 《Journal of virology》2012,86(16):8440-8451
Herpes simplex virus 1 (HSV-1) invades the nervous system and causes pathological changes. In this study, we defined the remodeling of F-actin and its possible mechanisms during HSV-1 infection of neuronal cells. HSV-1 infection enhanced the formation of F-actin-based structures in the early stage of infection, which was followed by a continuous decrease in F-actin during the later stages of infection. The disruption of F-actin dynamics by chemical inhibitors significantly reduced the efficiency of viral infection and intracellular HSV-1 replication. The active form of the actin-depolymerizing factor cofilin 1 was found to increase at an early stage of infection and then to continuously decrease in a manner that corresponded to the remodeling pattern of F-actin, suggesting that cofilin 1 may be involved in the biphasic F-actin dynamics induced by HSV-1 infection. Knockdown of cofilin 1 impaired HSV-1-induced F-actin assembly during early infection and inhibited viral entry; however, overexpression of cofilin 1 did not affect F-actin assembly or viral entry during early infection but decreased intracellular viral reproduction efficiently. Our results, for the first time, demonstrated the biphasic F-actin dynamics in HSV-1 neuronal infection and confirmed the association of F-actin with the changes in the expression and activity of cofilin 1. These results may provide insight into the mechanism by which HSV-1 productively infects neuronal cells and causes pathogenesis.  相似文献   
986.
Sphingosine-1-phosphate (S1P) regulates an array of biological activities in various cell types. Many S1P-regulated functions are mediated by S1P receptor subtypes. Previous studies have shown that the S1P receptor-2 (S1P(2) receptor) is involved in senescence of endothelial cells in vitro. However, the functional outcomes of S1P(2) receptor-mediated signaling pathways in a physiological environment are currently unknown. The main aim of this study was to explore the underlying mechanisms of senescent-associated impairments in pulmonary microvascular endothelial cells (PMECs) isolated from young and aged rats in vivo. The expression of S1P receptor subtypes in PMECs was detected using RT-PCR and Western blot analyses. The chemotaxis of PMECs was measured using the transwell migration assay. The endothelial morphogenesis assay was performed in three-dimensional Matrigel. The wound-healing assay was performed using a scratch wound model on primary PMEC monolayers. We observed that the S1P(2) receptor was markedly increased and S1P-regulated responses were significantly inhibited in PMECs isolated from aged rats. Furthermore, the senescent-associated impairments were revoked by the down-regulation of the S1P(2) receptor in senescent PMECs. These results indicate that the impaired functions (such as chemotactic, wound healing, and morphogenetic responses) in senescent PMECs in vivo are mediated by the S1P(2) receptor.  相似文献   
987.
The gene for proteasome subunit alpha type-7 (PSMA7) is located in chromosomal 20q13.33, a region frequently amplified in tumor. In this study, we employed A549 human lung adenocarcinoma cells and showed that PSMA7 inhibits the proliferation, tumorigenicity and invasion of A549 cells in vitro. Moreover, both gain and loss of function studies demonstrated that PSMA7 modulates the tumorigenicity of A549 cells in a xenograft nude mice model. In conclusion, these results identify inhibitory effects associated with PSMA7 that affect the tumorigenicity of A549 cells, suggesting PSMA7 as a potential tumor biomarker.  相似文献   
988.
989.
Manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1), and catalase (CAT) provide the primary antioxidant defense system. Impaired antioxidant defense increases oxidative stress and contributes to the development of type 2 diabetes and diabetic cardiovascular disease (CVD). We preformed a case-control study in Chinese type 2 diabetes patients, to determine if the MnSOD Val16Ala (T→C), GPX1 Pro198Leu (C→T), and CAT -262C/T (C→T) functional polymorphisms contribute to the development of type 2 diabetes or diabetic CVD. Patients with type 2 diabetes (n = 168) were divided into the non-CVD group (n = 83, >10 year since diagnosis) and CVD group (n = 85, history of ischemic CVD). Genotyping was performed using PCR-restriction fragment length polymorphism (PCR-RFLP) or PCR-based direct sequencing. The genotypic distribution in the non-CVD- and CVD-group and the clinical parameters in genotypic groups were not significantly different in the three polymorphic sites, respectively. Among eight genotypic combinations, the most common TT+CC+CC genotype (59.5%) was associated with higher triglyceride levels than the TT+CT+CC genotype, the second frequent one (14.9%; 1.77 ± 0.12 vs. 1.21 ± 0.11 mmol/l, P = 0.001), and all non-TT+CC+CC genotypes (40.5%; 1.77 ± 0.12 vs. 1.43 ± 0.12 mmol/l, P = 0.048). In the CVD group, significantly elevated triglyceride levels were also observed in patients with TT+CC+CC compared to patients with TT+CT+CC (2.00 ± 0.18 vs. 1.37 ± 0.16 mmol/l, P = 0.018) or non-TT+CC+CC genotypes (2.00 ± 0.18 vs. 1.65 ± 0.19 mmol/l, P = 0.070). The common MnSOD, GPX1, and CAT TT+CC+CC genotype may contribute to hypertriglyceridemia in Chinese patients with type 2 diabetes or diabetic CVD.  相似文献   
990.
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