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   20767篇
  免费   2253篇
  国内免费   1452篇
  2024年   13篇
  2023年   394篇
  2022年   501篇
  2021年   689篇
  2020年   668篇
  2019年   927篇
  2018年   871篇
  2017年   557篇
  2016年   612篇
  2015年   779篇
  2014年   1403篇
  2013年   1517篇
  2012年   1005篇
  2011年   1380篇
  2010年   1019篇
  2009年   1099篇
  2008年   1093篇
  2007年   1225篇
  2006年   1064篇
  2005年   934篇
  2004年   787篇
  2003年   662篇
  2002年   639篇
  2001年   409篇
  2000年   392篇
  1999年   342篇
  1998年   348篇
  1997年   262篇
  1996年   265篇
  1995年   313篇
  1994年   254篇
  1993年   221篇
  1992年   200篇
  1991年   192篇
  1990年   162篇
  1989年   132篇
  1988年   126篇
  1987年   105篇
  1986年   72篇
  1985年   113篇
  1984年   164篇
  1983年   121篇
  1982年   148篇
  1981年   65篇
  1980年   55篇
  1979年   55篇
  1978年   41篇
  1977年   21篇
  1976年   13篇
  1974年   13篇
排序方式: 共有10000条查询结果,搜索用时 93 毫秒
1.
Past studies have suggested that a key feature of the mechanism of heparin allosteric activation of the anticoagulant serpin, antithrombin, is the release of the reactive center loop P14 residue from a native state stabilizing interaction with the hydrophobic core. However, more recent studies have indicated that this structural change plays a secondary role in the activation mechanism. To clarify this role, we expressed and characterized 15 antithrombin P14 variants. The variants exhibited basal reactivities with factors Xa and IXa, heparin affinities and thermal stabilities that were dramatically altered from wild type, consistent with the P14 mutations perturbing native state stability and shifting an allosteric equilibrium between native and activated states. Rapid kinetic studies confirmed that limiting rate constants for heparin allosteric activation of the mutants were altered in conjunction with the observed shifts of the allosteric equilibrium. However, correlations of the P14 mutations'' effects on parameters reflecting the allosteric activation state of the serpin were inconsistent with a two-state model of allosteric activation and suggested multiple activated states. Together, these findings support a minimal three-state model of allosteric activation in which the P14 mutations perturb equilibria involving distinct native, intermediate, and fully activated states wherein the P14 residue retains an interaction with the hydrophobic core in the intermediate state but is released from the core in the fully activated state, and the bulk of allosteric activation has occurred in the intermediate.  相似文献   
2.
We evaluated the status of Clonorchis sinensis infection and potential risk factors among residents of riverside areas (Geumgang) in Muju-gun, Jeollabuk-do (Province), Korea. From January to February 2010, a total of 349 (171 males, 178 females) stool samples were collected and examined by the formalin-ether concentration technique. Also, village residents were interviewed using questionnaires to obtain information about C. sinensis infection-related risk factors. Overall egg-positive rate of C. sinensis was 13.2%. Egg-positive rates were significantly higher in males, farmers, and residents who had lived there more than 20 years, and in residents who had eaten raw freshwater fish than in opposite groups, respectively. However, there was no significant difference between age groups, education levels, cigarette smoking, alcohol drinking, health status, past history of infection, and experience of clonorchiasis medication and examination. Logistic regression analysis was performed to determine risk factors for clonorchiasis. On univariate analysis, the odds ratios for males, farmers, those who had lived there more than 20 years, and who had eaten raw freshwater fish were 2.41, 4.44, 3.16, and 4.88 times higher than those of the opposites, respectively. On multivariate analysis, the odds ratio of residents who had eaten raw freshwater fish was 3.2-fold higher than that of those who had not. These results indicate that residents living in Muju-gun, along the Geum River, Korea, have relatively high C. sinensis egg-positive rates, and the habit of eating raw freshwater fish was the major factor for the maintenance of clonorchiasis.  相似文献   
3.
目的:探讨经阴道超声与宫腔镜检查诊断子宫内膜病变的临床价值,为临床诊断子宫内膜病变提供理论依据。方法:选取2011年3月-2014年3月间我院收治的158例疑似子宫内膜病变患者,分别采用经阴道超声和宫腔镜进行检查,并以病理诊断结果为"金标准",比较两种检查方法的诊断价值。结果:病理检查结果中,143例患者被确诊为子宫内膜病变,其中子宫内膜增生23例(16.08%),子宫内膜息肉31例(21.68%),子宫粘膜下肌瘤24例(16.78%),子宫内膜癌19例(13.29%),慢性非特异性子宫内膜炎46例(32.17%)。宫腔镜对子宫内膜病变诊断的准确率为94.41%,高于阴道超声的81.12%,差异有统计学意义(P0.05),其中阴道超声和宫腔镜对子宫粘膜下肌瘤、子宫内膜癌诊断的准确率比较差异无统计学意义(P0.05),阴道超声对子宫内膜增生、子宫内膜息肉及慢性非特异性子宫内膜炎的诊断准确率均较宫腔镜降低,差异有统计学意义(P0.05)。阴道超声对子宫内膜病变诊断的特异度较宫腔镜更低(P0.05),但两者灵敏度、AUC比较差异无统计学意义(P0.05)。结论:经阴道超声诊断子宫内膜病变简单、有效,而宫腔镜诊断子宫内膜病变具有准确率以及特异度较高的特点。  相似文献   
4.
近年来研究认为在创伤失血性休克的发生发展及液体复苏、缺血再关注过程中均伴随着炎症因子的变化,现将与炎症因子密切相关基因环氧化酶-2(COX-2)、核因子κB(NF-κB)、诱导型一氧化氮合酶(iNOS)、高迁移率族蛋白1(HMGB1)、低氧诱导因子1α(HIF1α)、血红素氧合酶-1(HO-1)、寒冷诱导的RNA结合蛋白(CIRBP)在创伤失血性休克中的作用机制方面的研究及进展作一综述,为创伤失血性休克临床救治提供思路。  相似文献   
5.
6.
The P-Rex (phosphatidylinositol (3,4,5)-trisphosphate (PIP3)-dependent Rac exchanger) family (P-Rex1 and P-Rex2) of the Rho guanine nucleotide exchange factors (Rho GEFs) activate Rac GTPases to regulate cell migration, invasion, and metastasis in several human cancers. The family is unique among Rho GEFs, as their activity is regulated by the synergistic binding of PIP3 and Gβγ at the plasma membrane. However, the molecular mechanism of this family of multi-domain proteins remains unclear. We report the 1.95 Å crystal structure of the catalytic P-Rex1 DH-PH tandem domain in complex with its cognate GTPase, Rac1 (Ras-related C3 botulinum toxin substrate-1). Mutations in the P-Rex1·Rac1 interface revealed a critical role for this complex in signaling downstream of receptor tyrosine kinases and G protein-coupled receptors. The structural data indicated that the PIP3/Gβγ binding sites are on the opposite surface and markedly removed from the Rac1 interface, supporting a model whereby P-Rex1 binding to PIP3 and/or Gβγ releases inhibitory C-terminal domains to expose the Rac1 binding site.  相似文献   
7.
8.
Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.  相似文献   
9.
ADP-ribosylation factor (Arf) 1 is thought to affect the morphologies of organelles, such as the Golgi apparatus, and regulate protein trafficking pathways. Mice have six Arf isoforms. In knockdown experiments with HeLa cells, no single Arf isoform among Arf1–5 is required for organelle morphologies or any membrane trafficking step. This suggests that the cooperation of two or more Arfs is a general feature. Although many cell biological and biochemical analyses have proven the importance of Arf1, the physiological roles of Arf1 in mice remain unknown. To investigate the activity of Arf1 in vivo, we established Arf1-deficient mice. Arf−/− blastocysts were identified at the expected Mendelian ratio. The appearance of these blastocysts was indistinguishable from that of wild-type and Arf+/− blastocysts, and they grew normally in an in vitro culture system. However, Arf−/− embryos were degenerated at E5.5, and none survived to E12.5, suggesting that they died soon after implantation. These data establish for the first time that the Arf1 gene is indispensable for mouse embryonic development after implantation.  相似文献   
10.
Pleiotrophin (Ptn) plays an important role in bone growth through regulating osteoblasts’ functions. The underlying signaling mechanisms are not fully understood. In the current study, we found that Ptn induced heparin-binding epidermal growth factor (HB-EGF) release to trans-activate EGF-receptor (EGFR) in both primary osteoblasts and osteoblast-like MC3T3-E1 cells. Meanwhile, Ptn activated Akt and Erk signalings in cultured osteoblasts. The EGFR inhibitor AG1478 as well as the monoclonal antibody against HB-EGF (anti-HB-EGF) significantly inhibited Ptn-induced EGFR activation and Akt and Erk phosphorylations in MC3T3-E1 cells and primary osteoblasts. Further, EGFR siRNA depletion or dominant negative mutation suppressed also Akt and Erk activation in MC3T3-E1 cells. Finally, we observed that Ptn increased alkaline phosphatase (ALP) activity and inhibited dexamethasone (Dex)-induced cell death in both MC3T3-E1 cells and primary osteoblasts, such effects were alleviated by AG1478 or anti-HB-EGF. Together, these results suggest that Ptn-induced Akt/Erk activation and some of its pleiotropic functions are mediated by EGFR trans-activation in cultured osteoblasts.  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