全文获取类型
收费全文 | 6649篇 |
免费 | 304篇 |
国内免费 | 288篇 |
出版年
2024年 | 8篇 |
2023年 | 73篇 |
2022年 | 143篇 |
2021年 | 159篇 |
2020年 | 222篇 |
2019年 | 314篇 |
2018年 | 318篇 |
2017年 | 207篇 |
2016年 | 208篇 |
2015年 | 170篇 |
2014年 | 425篇 |
2013年 | 672篇 |
2012年 | 197篇 |
2011年 | 408篇 |
2010年 | 226篇 |
2009年 | 284篇 |
2008年 | 291篇 |
2007年 | 318篇 |
2006年 | 261篇 |
2005年 | 275篇 |
2004年 | 245篇 |
2003年 | 216篇 |
2002年 | 184篇 |
2001年 | 110篇 |
2000年 | 85篇 |
1999年 | 90篇 |
1998年 | 83篇 |
1997年 | 103篇 |
1996年 | 109篇 |
1995年 | 81篇 |
1994年 | 62篇 |
1993年 | 70篇 |
1992年 | 62篇 |
1991年 | 52篇 |
1990年 | 29篇 |
1989年 | 42篇 |
1988年 | 25篇 |
1987年 | 34篇 |
1986年 | 29篇 |
1985年 | 31篇 |
1984年 | 70篇 |
1983年 | 41篇 |
1982年 | 51篇 |
1981年 | 31篇 |
1980年 | 31篇 |
1979年 | 31篇 |
1978年 | 11篇 |
1977年 | 17篇 |
1976年 | 12篇 |
1974年 | 14篇 |
排序方式: 共有7241条查询结果,搜索用时 218 毫秒
991.
Gravielle María Clara Peña Clara Pignataro Leonardo de Plazas Sara Fiszer 《Neurochemical research》1998,23(11):1395-1401
In the present paper we describe the presence in avian CNS of an endogenous inhibitor of [3H]flunitrazepam binding. This compound was extracted from a synaptic membrane fraction isolated from chick optic lobe and brain using an exhaustive aqueous washing procedure, then purified by means of solid-phase extraction with C18 cartridges and several HPLC steps until an homogeneous peak was obtained. Its chemical structure was studied by size-exclusion chromatography of the purified material which indicated that it possesses a molecular weight below 1350. Although its inhibitory activity was lost by HCl treatment, its peptidic nature was ruled out by an amino acid and N-terminal sequence analyses. Ultraviolet absorption spectrum showed two main peaks at 230 and 280 nm. The endogenous compound was found to inhibit competitively [3H]flunitrazepam binding to its recognition site without affecting [3H]GABA binding to the same receptor complex. The behavior of the endogenous factor in an in vitro GABA shift test and GABA-dependent chloride flux experiments were similar to that of benzodiazepine receptor agonists. In conclusion, these results demonstrate the existence in avian CNS of a competitive endogenous inhibitor of benzodiazepine binding with agonistic action on benzodiazepine receptors. 相似文献
992.
993.
The orthomolecular treatment of cancer. I. The role of ascorbic acid in host resistance 总被引:4,自引:0,他引:4
Natural resistance to neoplastic disease governs the incidence of clinical cancer and influences the individual's response to standard methods of treatment. Supportive measures, specifically designed to enhance the natural resistance of the host, should diminish cancer incidence, morbidity and mortality. The various factors involved in host resistance are briefly reviewed, and it is contended that the availability of ascorbic acid plays an important role in many of these physiological processes. The potential value of ascorbic acid in the supportive treatment of cancer is a matter for urgent study at many levels. It offers the promise of general improvement in the results of cancer management, including prophylaxis in general, supportive therapy when standard methods of treatment are being used, and palliative treatment in advanced terminal cancer. 相似文献
994.
Aklima Nasrin Mahbub Hassan Ping Ye 《Biochemical and biophysical research communications》2018,495(3):2118-2124
How to effectively delivering therapeutic agents, including γ-secretase inhibitors (GSIs), into live cells, remains a significant challenge. This study assessed the effect of Notch signaling inhibition by examining levels of the Notch1 intracellular domain (N1ICD) in cultured oral cancer cells analyzed with random stitched images (2D) and 3D visualizations using confocal microscopy and quantitative gene analysis. Substantially, we have developed a novel method to assist the delivery of γ-secretase inhibitor, DAPT, into live cells in the presence of an effective minimum concentration of Triton-X100 (0.001%) without damaging cell activity and membrane integrity assessed with cell proliferation assays. The images obtained in this study showed that DAPT alone could not block the γ-secretase inhibitor despite inhibiting cell growth. Further analysis of quantitative gene expressions of Notch signaling canonical pathway to verify the effectiveness of the novel method for delivering inhibitor into live cells, displayed deregulation of Notch1, Delta-like ligand 1 (DLL1) and hairy and enhancer of split 1 (Hes1). Our data suggest that Notch1/Hes1 signaling pathway is deactivated using DAPT with a low dose of Triton-X100 in this cancer cells. And the finding also suggests that Notch1 could be engaged by DLL1 to promote differentiation in oral cancer cells. Using this approach, we demonstrate that Triton-X100 is a promising and effective permeabilization agent to deliver γ-secretase inhibitor DAPT into live oral epithelial cells. This strategy has the potential to implicate in the treatment of cancer diseases. 相似文献
995.
Umakant Ashok Bahirat Rekha Raghuveer Shenoy Rashmi Talwar Rajan Naresh Goel Kumar V.S. Nemmani 《Biochemical and biophysical research communications》2018,495(2):1608-1613
Non-Alcoholic SteatoHepatitis (NASH) is the more severe form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, hepatocyte injury with or without fibrosis. Recently, GPR119 receptor has emerged as a novel therapeutic target for the treatment of dyslipidemia and non-alcoholic steatohepatitis. In the present study, we investigated the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor on the progression of steatohepatitis in mice fed on a high trans-fat diet. In this study, monotherapy with either APD668 or linagliptin caused a reduction in the levels of ALT, AST, glucose, cholesterol and epididymal fat mass but the effect was more pronounced upon treatment with combination of both drugs.On the other hand, combined treatment of APD668 with linagliptin demonstrated a non-significant additive effect in reduction of hepatic triglyceride (?78%) and cholesterol (?56%) compared to monotherapy groups. Moreover, co-administration of APD668 and linagliptin resulted in enhanced levels of active GLP-1 with additional benefit of significant synergistic decrease in body weight gain (?19%) in mice. We speculated that the enhanced effect observed with the combination treatment could be due to either 1) direct activation of GPR119 receptors present in liver and intestine or 2) enhanced active GLP-1 levels or 3) decreased degradation of GLP-1 in-vivo through DPPIV inhibition. Therefore, these findings clearly suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of non-alcoholic steatohepatitis. 相似文献
996.
997.
Jianyun Huang Raja Dey Yufeng Wang Jean Jakoncic Igor Kurinov Xin-Yun Huang 《Journal of molecular biology》2018,430(9):1324-1335
Tumor metastasis is responsible for ~ 90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main actin-bundling protein in filopodia. Small-molecule fascin inhibitors block tumor cell migration, invasion, and metastasis. Here we present the structural basis for the mechanism of action of these small-molecule fascin inhibitors. X-ray crystal structural analysis of a complex of fascin and a fascin inhibitor shows that binding of the fascin inhibitor to the hydrophobic cleft between the domains 1 and 2 of fascin induces a ~ 35o rotation of domain 1, leading to the distortion of both the actin-binding sites 1 and 2 on fascin. Furthermore, the crystal structures of an inhibitor alone indicate that the conformations of the small-molecule inhibitors are dynamic. Mutations of the inhibitor-interacting residues decrease the sensitivity of fascin to the inhibitors. Our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors. 相似文献
998.
《Bioorganic & medicinal chemistry》2016,24(21):5340-5352
γ-Glutamyl transpeptidase (GGT, EC 2.3.2.2) that catalyzes the hydrolysis and transpeptidation of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive pharmaceutical target. We report here the evaluation of a phosphonate-based irreversible inhibitor, 2-amino-4-{[3-(carboxymethyl)phenoxy](methoyl)phosphoryl}butanoic acid (GGsTop) and its analogues as a mechanism-based inhibitor of human GGT. GGsTop is a stable compound, but inactivated the human enzyme significantly faster than the other phosphonates, and importantly did not inhibit a glutamine amidotransferase. The structure–activity relationships, X-ray crystallography with Escherichia coli GGT, sequence alignment and site-directed mutagenesis of human GGT revealed a critical electrostatic interaction between the terminal carboxylate of GGsTop and the active-site residue Lys562 of human GGT for potent inhibition. GGsTop showed no cytotoxicity toward human fibroblasts and hepatic stellate cells up to 1 mM. GGsTop serves as a non-toxic, selective and highly potent irreversible GGT inhibitor that could be used for various in vivo as well as in vitro biochemical studies. 相似文献
999.
1000.
Megumi Narukawa‐Nara Ayako Nakamura Ko Kikuzato Yusuke Kakei Akiko Sato Yuka Mitani Yumiko Yamasaki‐Kokudo Takahiro Ishii Ken‐ichiro Hayashi Tadao Asami Takehiko Ogura Shigeo Yoshida Shozo Fujioka Takashi Kamakura Tsutomu Kawatsu Masanori Tachikawa Kazuo Soeno Yukihisa Shimada 《The Plant journal : for cell and molecular biology》2016,87(3):245-257
We previously reported l ‐α‐aminooxy‐phenylpropionic acid (AOPP) to be an inhibitor of auxin biosynthesis, but its precise molecular target was not identified. In this study we found that AOPP targets TRYPTOPHAN AMINOTRANSFERASE of ARABIDOPSIS 1 (TAA1). We then synthesized 14 novel compounds derived from AOPP to study the structure–activity relationships of TAA1 inhibitors in vitro. The aminooxy and carboxy groups of the compounds were essential for inhibition of TAA1 in vitro. Docking simulation analysis revealed that the inhibitory activity of the compounds was correlated with their binding energy with TAA1. These active compounds reduced the endogenous indole‐3‐acetic acid (IAA) content upon application to Arabidopsis seedlings. Among the compounds, we selected 2‐(aminooxy)‐3‐(naphthalen‐2‐yl)propanoic acid (KOK1169/AONP) and analyzed its activities in vitro and in vivo. Arabidopsis seedlings treated with KOK1169 showed typical auxin‐deficient phenotypes, which were reversed by exogenous IAA. In vitro and in vivo experiments indicated that KOK1169 is more specific for TAA1 than other enzymes, such as phenylalanine ammonia‐lyase. We further tested 41 novel compounds with aminooxy and carboxy groups to which we added protection groups to increase their calculated hydrophobicity. Most of these compounds decreased the endogenous auxin level to a greater degree than the original compounds, and resulted in a maximum reduction of about 90% in the endogenous IAA level in Arabidopsis seedlings. We conclude that the newly developed compounds constitute a class of inhibitors of TAA1. We designated them ‘pyruvamine’. 相似文献