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   1013篇
  免费   83篇
  2023年   4篇
  2022年   16篇
  2021年   29篇
  2020年   14篇
  2019年   19篇
  2018年   27篇
  2017年   18篇
  2016年   36篇
  2015年   51篇
  2014年   60篇
  2013年   69篇
  2012年   99篇
  2011年   99篇
  2010年   62篇
  2009年   45篇
  2008年   58篇
  2007年   72篇
  2006年   62篇
  2005年   49篇
  2004年   36篇
  2003年   35篇
  2002年   33篇
  2001年   5篇
  2000年   11篇
  1999年   4篇
  1998年   3篇
  1997年   8篇
  1995年   4篇
  1994年   2篇
  1993年   3篇
  1992年   2篇
  1991年   3篇
  1990年   3篇
  1989年   4篇
  1988年   4篇
  1987年   3篇
  1986年   5篇
  1985年   3篇
  1984年   3篇
  1983年   2篇
  1982年   5篇
  1981年   3篇
  1980年   2篇
  1974年   2篇
  1973年   2篇
  1970年   2篇
  1964年   2篇
  1936年   2篇
  1932年   1篇
  1931年   1篇
排序方式: 共有1096条查询结果,搜索用时 328 毫秒
71.
A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.  相似文献   
72.
Several simple scoring methods were examined for 2 series of beta-secretase (BACE-1) inhibitors to identify a docking/scoring protocol which could be used to design BACE-1 inhibitors in a drug discovery program. Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors.  相似文献   
73.
Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)-MS can report on conformational behavior of specific states. We used IM-MS to study a conformationally labile protein (α1-antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z-variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild-type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z α1-antitrypsin polymerogenicity. We show the ability of IM-MS to track such disease-relevant conformational behavior in detail by studying the effects of peptide binding on α1-antitrypsin conformation and dynamics. IM-MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native α1-antitrypsin. Our findings are confirmed with high-resolution X-ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue-specific level. IM-MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest.PDB Code(s): 4PYW  相似文献   
74.
Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 (1) and the more rigid indazole constraint of MK-6186 (2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI’s.  相似文献   
75.
A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.  相似文献   
76.
Advances in technologies associated with mass spectrometry-based proteomic techniques have added a new dimension to the field of biomedical research. Most of the existing research on human gestation has focused on the application of these high-throughput methodologies in the study of amniotic fluid. In cases of fetal aneuploidies, the use of proteomic platforms has contributed to the identification of relevant protein biomarkers that could potentially change early diagnosis and treatment. The current article focuses on studies of normal amniotic fluid using proteomic technologies and describes alterations noted in the amniotic fluid proteome in the presence of fetal aneuploidies.  相似文献   
77.
Adult pancreatic β cells can replicate during growth and after injury to maintain glucose homeostasis. Here, we report that β cells deficient in Dnmt1, an enzyme that propagates DNA methylation patterns during cell division, were converted to α cells. We identified the lineage determination gene aristaless-related homeobox (Arx), as methylated and repressed in β cells, and hypomethylated and expressed in α cells and Dnmt1-deficient β cells. We show that the methylated region of the Arx locus in β cells was bound by methyl-binding protein MeCP2, which recruited PRMT6, an enzyme that methylates histone H3R2 resulting in repression of Arx. This suggests that propagation of DNA methylation during cell division also ensures recruitment of enzymatic machinery capable of modifying and transmitting histone marks. Our results reveal that propagation of DNA methylation during cell division is essential for repression of α cell lineage determination genes to maintain pancreatic β cell identity.  相似文献   
78.
Vaccinomics aims to integrate variability information from multiple levels of the biological hierarchy from genome to proteome to metabolome, and ways in which these biological parts interact with each other and the environment. Vaccinomics holds significant promise as a new public health tool in designing safer and more effective vaccines for both developed and developing countries. Vaccinomics tests that are envisioned to be used in tandem with vaccine-based health interventions could permit an informed forecast of individual and subpopulation variations in immune responses to vaccines, reduce adverse effects, and contribute to a foundation for rational and directed use of vaccines. A proactive, multidisciplinary engagement with vaccinomics is now timely and much needed in order to develop regulations that best ensure the protection of the public and promote the transition of vaccinomics innovations from discovery to real-life public health applications. This article examines and compares the regulatory oversight of vaccinomics tests in Canada, the United States, and Europe. Recent trends in these jurisdictions suggest that regulatory agencies view personalized genomics/omics medicine, such as vaccinomics, as a desirable goal. At the same time, proposals to increase oversight could impact progress in the field and affect the availability of vaccinomics tests in public health practice and the diagnostic test market. The comparative analysis of vaccinomics in three jurisdictions presented in this article highlights both the convergence and divergence of regulatory oversight. In a rapidly emerging field such as vaccinomics that is pivotal for global public health, achieving better harmonization of policies may be an advantageous target, while ensuring that symmetry exists between the goals of public safety and promoting public health innovation. We suggest it is now timely to proactively initiate a constructive dialogue among all stakeholders (publics, policymakers, researchers, private sector, governments) to foster the development of appropriately targeted regulatory policies in this field.  相似文献   
79.
Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for their continued proliferation and survival. Myc and HIF-1 are believed to promote such a metabolic switch by, in part, upregulating gene expression of pyruvate dehydrogenase (PDH) kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial PDH and consequently pyruvate dehydrogenase complex (PDC). Here we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of the matrix in some cancer cells and PDHK1 is commonly tyrosine phosphorylated in human cancers by diverse oncogenic tyrosine kinases localized to different mitochondrial compartments. Expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate and reduced tumor growth in xenograft nude mice. Together, tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth.  相似文献   
80.
Human osteosarcoma cell lines were recently shown to express and secrete the small leucine rich proteoglycan (SLRP) lumican, with the ability to regulate the growth and motility of these cells. In this study, lumican-deficient Saos 2 cells were demonstrated to have increased adhesive capability onto fibronectin (FN) (p≤0.01). Upon neutralization of endogenous transforming growth factor β2 (TGF-β2) activity, no difference in the ability of lumican siRNA-transfected and scramble siRNA-transfected Saos 2 cells to adhere onto FN was detected (p=NS). Exogenous TGF-β2 was shown to stimulate Saos 2 cell adhesion to FN (p≤0.01). These results therefore, suggest that the inverse correlation existing between lumican expression and Saos 2 cell adhesion is dependent on active TGF-β2 signaling. Furthermore, the significant increase in Smad 2 activation present in lumican-deficient cells (p≤0.01) was annulled in the presence of the anti-TGF-β2 peptide, demonstrating that lumican is an upstream regulator of the TGF-β2/Smad 2 signaling cascade. Crucial to FN-dependent adhesion, β1 integrin expression and pFAK activation were likewise identified as downstream TGF-β2 effectors regulated by lumican expression. In conclusion, this study demonstrates a novel out-in signaling circuit in human osteosarcoma cells: secreted to extracellular matrix lumican is an endogenous inhibitor of TGF-β2 activity, resulting in downstream effector modulation including pSmad 2, integrin β1 and pFAK to regulate osteosarcoma adhesion.  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