全文获取类型
收费全文 | 533篇 |
免费 | 27篇 |
国内免费 | 4篇 |
专业分类
564篇 |
出版年
2024年 | 1篇 |
2023年 | 4篇 |
2022年 | 7篇 |
2021年 | 29篇 |
2020年 | 8篇 |
2019年 | 20篇 |
2018年 | 20篇 |
2017年 | 14篇 |
2016年 | 13篇 |
2015年 | 24篇 |
2014年 | 31篇 |
2013年 | 36篇 |
2012年 | 30篇 |
2011年 | 48篇 |
2010年 | 26篇 |
2009年 | 14篇 |
2008年 | 43篇 |
2007年 | 32篇 |
2006年 | 33篇 |
2005年 | 29篇 |
2004年 | 20篇 |
2003年 | 19篇 |
2002年 | 23篇 |
2001年 | 4篇 |
1999年 | 3篇 |
1998年 | 8篇 |
1997年 | 7篇 |
1996年 | 3篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1989年 | 1篇 |
1986年 | 1篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1977年 | 1篇 |
1975年 | 1篇 |
排序方式: 共有564条查询结果,搜索用时 23 毫秒
101.
102.
Ziv Gan-Or Naima BouslamNazha Birouk Alexandra LissoubaDaniel B. Chambers Julie VérièpeAlaura Androschuk Sandra B. LaurentDaniel Rochefort Dan SpiegelmanAlexandre Dionne-Laporte Anna SzutoMeijiang Liao Denise A. FiglewiczAhmed Bouhouche Ali BenomarMohamed Yahyaoui Reda OuazzaniGrace Yoon Nicolas DupréOksana Suchowersky Francois V. BolducJ. Alex Parker Patrick A. DionPierre Drapeau Guy A. RouleauBouchra Ouled Amar Bencheikh 《American journal of human genetics》2016,98(6):1271
103.
104.
105.
Patrick Masson Nicole Bec Marie-Thérèse Froment Florian Nachon Claude Balny Oksana Lockridge Lawrence M Schopfer 《European journal of biochemistry》2004,271(10):1980-1990
The rate-limiting step for hydrolysis of the positively charged oxoester benzoylcholine (BzCh) by human butyrylcholinesterase (BuChE) is deacylation (k(3)), whereas it is acylation (k(2)) for hydrolysis of the homologous thioester benzoylthiocholine (BzSCh). Steady-state hydrolysis of BzCh and BzSCh by wild-type BuChE and its peripheral anionic site mutant D70G was investigated at different hydrostatic pressures, which allowed determination of volume changes associated with substrate binding, and the activation volumes for the chemical steps. A differential nonlinear pressure-dependence of the catalytic parameters for hydrolysis of both substrates by both enzymes was shown. Nonlinearity of the plots may be explained in terms of compressibility changes or rate-limiting changes. To distinguish between these two possibilities, enzyme phosphorylation by diisopropylfluorophosphate (DFP) in the presence of substrate (BzSCh) under pressure was studied. There was no pressure dependence of volume changes for DFP binding or for phosphorylation of either wild-type or D70G. Analysis of the pressure dependence for steady-state hydrolysis of substrates, and for phosphorylation by DFP provided evidence that no enzyme compressibility changes occurred during the catalyzed reactions. Thus, the nonlinear pressure dependence of substrate hydrolysis reflects changes in the rate-limiting step with pressure. Change in rate-determining step occurred at a pressure of 100 MPa for hydrolysis of BzCh by wild-type and at 75 MPa for D70G. For hydrolysis of BzSCh the change occurred at higher pressures because k(2) < k(3) at atmospheric pressure for this substrate. Elementary volume change contributions upon initial binding, productive binding, acylation and deacylation were calculated from the pressure differentiation of kinetic constants. This analysis shed light on the molecular events taking place along the hydrolysis pathways of BzCh and BzSCh by wild-type BuChE and the D70G mutant. In addition, volume change differences between wild-type and D70G provided new evidence that residue D70 in the peripheral site controls hydration of the active site gorge and the dynamics of the water molecule network during catalysis. Finally, a steady-state kinetic study of the oxyanion hole mutant (G117H) showed that substitution of the ethereal sulfur for oxygen in the substrate alters the final adjustment of substrate in the active site and stabilization of the acylation transition state. 相似文献
106.
Alena Gbelov Zuzana Valovi
ov Gabriela Ba
ov Juraj Lbaj Blanka Binkov Jan Topinka Oksana Sevastyanova Radim J. rm Ivan Kalina Viera Habalov Todor A. Popov Teodor Panev Peter B. Farmer 《Mutation research》2007,620(1-2):103
Sensitivity and correlations among three endpoints were evaluated to assess the genotoxic potential of organic complex mixtures in vitro. This study was focused on DNA adduct formation, DNA single strand break induction and tumour suppressor p53 protein up-regulation produced by extractable organic matter (EOM) absorbed on respirable particulate matter PM10 (particulate matter < 10 μm) collected in three European cities (Prague, Sofia, Košice) during winter and summer period. To compare the sensitivity of particular endpoints for in vitro measurement of complex mixture genotoxicity, the metabolically competent human hepatoma cell line Hep G2 was treated with equivalent EOM concentration of 50 μg/ml. Cell exposure to EOMs resulted in significant DNA adduct formation and DNA strand break induction, however, a lack of protein p53 up-regulation over the steady-state level was found. While the maximum of DNA strand breaks was determined after 2 h cell exposure to EOMs, 24 h treatment interval was optimal for DNA adduct determination.No substantial location- and season-related differences in EOM genotoxicity were detected using DNA strand break assessment. In agreement with these results no significant variation in DNA adduct levels were found in relation to the locality and season except for the monitoring site in Prague. The Prague EOM sample collected during summer period produced nearly three-fold lower DNA adduct level in comparison to the winter EOM sample.Comparable results were obtained when the ambient air genotoxicity, based on the concentration of carcinogenic PAHs in cubic meter of air (ng c-PAHs/m3), was elicited using either DNA adduct or strand break determination. In general, at least six-fold higher genotoxicity of the winter air in comparison to the summer air was estimated by each particular endpoint. Moreover, the genotoxic potential of winter air revealed by DNA adduct assessment and DNA strand break measurement increased in the same order: Košice Prague < Sofia.Based on these data we suppose that two endpoints DNA breakage and DNA adduction are sensitive in vitro biomarkers for estimation of genotoxic activity of organic complex mixture associated with airborne particles. On the other hand, the measurement of protein p53 up-regulation manifested some limitations; therefore it cannot be used as a reliable endpoint for in vitro genotoxicity assessment. 相似文献
107.
Ionization, lipophilicity, and molecular modeling to investigate permeability and other biological properties of amlodipine 总被引:2,自引:0,他引:2
Caron G Ermondi G Damiano A Novaroli L Tsinman O Ruell JA Avdeef A 《Bioorganic & medicinal chemistry》2004,12(23):6107-6118
This paper uses a recent approach toward drug discovery, in which in silico tools and experimental data are combined together to study the structural features of amlodipine and their relevance in the peculiar pharmacodynamic and pharmacokinetic profiles of this long acting calcium antagonist. Results reveal for amlodipine two families of conformers (folded and extended) but also demonstrate that protonation is the predominant factor governing amlodipine intermolecular interactions among which ionic forces play a major role. 相似文献
108.
109.
110.
The Middle Asian tortoise Testudo horsfieldii is one of the most radioresistant animals, with Lethal Dose (LD) 50/30 around 500 Gy. Extracts were prepared from different organs of the tortoise, and their biological activity was evaluated. Crude extract from the spleen was found to significantly increase survival of mice treated with lethal doses of radiation. In an iterative process, the active extract was purified by chromatography, and the fractions were screened for biological activity. Various vital parameters were monitored: peripheral blood leukocytes, spleen colonies, mitosis in the bone marrow, and survival after 30 days. The process concluded with the isolation, characterization, and synthesis of the tetrapeptide FTGN, which accelerated repopulation of the irradiated bone marrow at very low concentrations both in vivo and ex vivo. A fluorescently labeled derivative of the peptide was found to selectively associate to CD34+ stem cells, suggesting that the peptide mediates their proliferation and allows fast repopulation of hematopoietic lineages. Interestingly, the peptide protected animals from alopecia. The studies in experimental animals suggest that treatment with FTGN can potentially benefit patients who suffer bone marrow damage due to radiotherapy or chemotherapy and patients undergoing autologous or allogenic bone marrow transplantation. 相似文献