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   5086篇
  免费   493篇
  国内免费   181篇
  2024年   8篇
  2023年   131篇
  2022年   138篇
  2021年   192篇
  2020年   236篇
  2019年   287篇
  2018年   265篇
  2017年   201篇
  2016年   238篇
  2015年   250篇
  2014年   368篇
  2013年   517篇
  2012年   206篇
  2011年   221篇
  2010年   161篇
  2009年   197篇
  2008年   196篇
  2007年   210篇
  2006年   193篇
  2005年   147篇
  2004年   152篇
  2003年   131篇
  2002年   132篇
  2001年   87篇
  2000年   62篇
  1999年   58篇
  1998年   74篇
  1997年   46篇
  1996年   29篇
  1995年   53篇
  1994年   53篇
  1993年   45篇
  1992年   33篇
  1991年   34篇
  1990年   34篇
  1989年   32篇
  1988年   38篇
  1987年   34篇
  1986年   22篇
  1985年   45篇
  1984年   58篇
  1983年   40篇
  1982年   29篇
  1981年   26篇
  1980年   19篇
  1979年   9篇
  1978年   9篇
  1977年   7篇
  1976年   4篇
  1973年   2篇
排序方式: 共有5760条查询结果,搜索用时 15 毫秒
1.
Key players in translational regulation such as ribosomes might represent powerful, but hitherto largely unexplored, targets to eliminate drug-refractory cancer stem cells (CSCs). A recent study by the Lisanti group has documented how puromycin, an old antibiotic derived from Streptomyces alboniger that inhibits ribosomal protein translation, can efficiently suppress CSC states in tumorspheres and monolayer cultures. We have used a closely related approach based on Biolog Phenotype Microarrays (PM), which contain tens of lyophilized antimicrobial drugs, to assess the chemosensitivity profiles of breast cancer cell lines enriched for stem cell-like properties. Antibiotics directly targeting active sites of the ribosome including emetine, puromycin and cycloheximide, inhibitors of ribosome biogenesis such as dactinomycin, ribotoxic stress agents such as daunorubicin, and indirect inhibitors of protein synthesis such as acriflavine, had the largest cytotoxic impact against claudin-low and basal-like breast cancer cells. Thus, biologically aggressive, treatment-resistant breast cancer subtypes enriched for stem cell-like properties exhibit exacerbated chemosensitivities to anti-protozoal and anti-bacterial antibiotics targeting protein synthesis. These results suggest that old/existing microbicides might be repurposed not only as new cancer therapeutics, but also might provide the tools and molecular understanding needed to develop second-generation inhibitors of ribosomal translation to eradicate CSC traits in tumor tissues.  相似文献   
2.
Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi’s [J. Med. Chem. 2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem. 2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem. 2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450’s 2C9 and 2C19. Lowering the log D by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects.  相似文献   
3.
A new drug delivery approach, apoptotic-induced drug delivery (AIDD), is presented that is based on apoptosis as a mechanism to trigger delivery of drugs from carrier cells. It was investigated whether apoptotic drug-loaded carrier cells could deliver drugs to tumour cells by various mechanisms, including drug release through a more permeable apoptotic cell membrane, and by phagocytosis of drug-loaded apoptotic cells by tumour cells. The feasibility of this novel concept was evaluated in an in vitro carrier cell model that consisted of S49 mouse lymphoma cells that apoptose upon exposure to dexamethasone (DX). Membrane permeability was evaluated by measurement of release of a fluorescent dye (calcein-AM, C-AM) from C-AM-loaded S49 cells. Phagocytotsis of fluorescent PKH-26-labeled S49 cells was determined in co-culture studies with rat glioma (RG-2) cells using fluorescence microscopy and flow cytometry. Cytotoxicity of RG-2 cells due to temozolomide (TMZ)-loaded S49 cells was evaluated by a colony formation assay following co-culture of these cells for up to 8h. Calcein release from S49 cells was enhanced by approximately 30% at 48h following treatment with DX compared to control S49 cells. Based on both flow cytometric and microscopic analyses, RG2 phagocytized apoptotic S49 cells to a four- to sevenfold greater extent than control S49 cells at co-incubation times from 4–48h. The TMZ-loaded apoptotic S49 cells caused the largest degree of toxicity, about 50% cell kill, whereas TMZ-loaded control S49 caused 30% cell kill. The preliminary data suggest that AIDD should be further explored. This revised version was published online in June 2006 with corrections to the Cover Date.  相似文献   
4.
The structures of three complexes of human fructose-1,6-bisphosphatase (FB) with the allosteric inhibitor AMP and two AMP analogues have been determined and all fully refined. The data used for structure determination were collected at cryogenic temperature (110 K), and with the use of synchrotron radiation. The structures reveal a common mode of binding for AMP and formycine monophosphate (FMP). 5-Amino-4-carboxamido-1 beta-D-5-phosphate-ribofuranosyl-1H-imidazole (AICAR-P) shows an unexpected mode of binding to FB, different from that of the other two ligands. The imidazole ring of AICAR-P is rotated 180 degrees compared to the AMP and FMP bases. This rotation results in a slightly different hydrogen bonding pattern and minor changes in the water structure in the binding pocket. Common features of binding are seen for the ribose and phosphate moieties of all three compounds. Although binding in a different mode, AICAR-P is still capable of making all the important interactions with the residues building the allosteric binding pocket. The IC50 values of AMP, FMP, and AICAR-P were determined to be 1.7, 1.4, and 20.9 microM, respectively. Thus, the approximately 10 times lower potency of AICAR-P is difficult to explain solely from the variations observed in the binding pocket. Only one water molecule in the allosteric binding pocket was found to be conserved in all four subunits in all three structures. This water molecule coordinates to a phosphate oxygen atom and the N7 atom of the AMP molecule, and to similarly situated atoms in the FMP and AICAR-P complexes. This implies an important role of the conserved water molecule in binding of the ligand.  相似文献   
5.
Parkinson's disease (PD) is a movement disorder caused by the progressive loss of dopaminergic neurons. Natural antioxidants and plant extracts with neuroprotective properties offer a promising new therapeutic approach for PD patients, but a suitable large‐scale screening system is required for their discovery and preclinical analysis. Here we used the red flour beetle (Tribolium castaneum ) as a whole‐animal screening system for the detection and characterization of neuroprotective substances. Paraquat was added to the diet of adult beetles to induce PD‐like symptoms, which were quantified using a novel positive geotaxis behavioral assay. These paraquat‐induced behavioral changes were reduced in beetles fed on diets supplemented with l‐ dihydroxyphenylalanine, ascorbic acid, curcumin, hempseed flour, or the Chinese herb gou‐teng. T. castaneum is, therefore, a valuable model for the screening of neuroprotective substances in chemical libraries and plant extracts and could be developed as a model for the preclinical testing of therapeutic candidates for the treatment of neurodegenerative diseases, such as PD.  相似文献   
6.
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.  相似文献   
7.
The surfactant proteins (SPs), SP-B and SP-C, are important components of pulmonary surfactant involved in the reduction of alveolar surface tension. Quantification of SP-B and SP-C in surfactant drugs is informative for their quality control and the evaluation of their biological activity. Western blot analysis enabled the quantification of SP-B, but not SP-C, in surfactant drugs. Here, we report a new procedure involving chemical treatments and LC-MS to analyze SP-C peptides. The procedure enabled qualitative analysis of SP-C from different species with discrimination of the palmitoylation status and the artificial modifications that occur during handling and/or storage. In addition, the method can be used to estimate the total amount of SP-C in pulmonary surfactant drugs. The strategy described here might serve as a prototype to establish analytical methods for peptides that are extremely hydrophobic and behave like lipids. The new method provides an easy measurement of SP-C from various biological samples, which will help the characterization of various experimental animal models and the quality control of surfactant drugs, as well as diagnostics of human samples.  相似文献   
8.
9.
In the present work, we show that we obtained nanometric structures made of water, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), cholesterol (Chol), and a mixture of ethoxylated and non-ethoxylated sorbitan fatty acid esters (Tween 20, Span 20, Tween 80, and Span 80) by mixing all of them near the cloud point temperature (cp) of the ethoxylated surfactant. The influence that the constituents had on the size of the particle was determined by a pseudo-ternary phase diagram of water/Tween–Span/DPPC–Chol; the colloidal particles obtained were studied by differential scanning calorimetry, confocal fluorescence microscopy, scanning electron microscopy, and atomic force microscopy. These studies were made for all the systems with at least 23 d of colloidal stability. The most stable system was obtained with the Tween 80–Span 80 pair, behaving as a typical suspension for 48 d; this system was made of water, Tween 80–Span 80 (80:20), DPPC–Chol (95:5) in a corresponding molar ratio of 48:37:100:10. The colloidal particles obtained were a kind of emulsion and liposome structures. The second stable system was obtained with the same mixture, but in a molar ratio of 8:6:9:0, its structure was also a kind of emulsion particles. In both systems and in other less stable ones, the “emulsion particle” was completely new, it structurally corresponds to a nucleus of mixed micelles surrounded by at least one bilayer of DPPC.  相似文献   
10.
介绍了我国的卫生机构状况、药品市场终端规模,以及我国公立医院终端化学药和中成药各大类药品市场份额状况,并分别对 我国公立医院终端化学药和中成药各大类重点品种的销售额 Top10 进行了分析。  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