全文获取类型
收费全文 | 334篇 |
免费 | 28篇 |
专业分类
362篇 |
出版年
2024年 | 1篇 |
2023年 | 2篇 |
2022年 | 8篇 |
2021年 | 10篇 |
2020年 | 11篇 |
2019年 | 19篇 |
2018年 | 7篇 |
2017年 | 6篇 |
2016年 | 12篇 |
2015年 | 15篇 |
2014年 | 28篇 |
2013年 | 23篇 |
2012年 | 32篇 |
2011年 | 27篇 |
2010年 | 14篇 |
2009年 | 15篇 |
2008年 | 23篇 |
2007年 | 20篇 |
2006年 | 16篇 |
2005年 | 15篇 |
2004年 | 15篇 |
2003年 | 10篇 |
2002年 | 9篇 |
2001年 | 3篇 |
2000年 | 6篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1995年 | 2篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1990年 | 1篇 |
排序方式: 共有362条查询结果,搜索用时 15 毫秒
51.
Dvorsky R Blumenstein L Vetter IR Ahmadian MR 《The Journal of biological chemistry》2004,279(8):7098-7104
The Rho-ROCK pathway modulates the phosphorylation level of a variety of important signaling proteins and is thereby involved in miscellaneous cellular processes including cell migration, neurite outgrowth, and smooth muscle contraction. The observation of the involvement of the Rho-ROCK pathway in tumor invasion and in diseases such as hypertension and bronchial asthma makes it an interesting target for drug development. We herein present the crystal structure of the complex between active RhoA and the Rho-binding domain of ROCKI. The Rho-binding domain structure forms a parallel alpha-helical coiled-coil dimer and, in contrast to the published Rho-protein kinase N structure, binds exclusively to the switch I and II regions of the guanosine 5'-(beta,gamma-imido)triphosphate-bound RhoA. The switch regions of two different RhoA molecules form a predominantly hydrophobic patch, which is complementarily bound by two identical short helices of 13 residues (amino acids 998-1010). The identified ROCK-binding site of RhoA strikingly supports the assumption of a common consensus-binding site for effector recognition. 相似文献
52.
Instrumental learning involves both variation and selection: variation of what the animal does, and selection by reward from among the variation. Four experiments with rats suggested a rule about how variation is controlled by recent events. Experiment 1 used the peak procedure. Measurements of bar-press durations showed a sharp increase in mean duration after the time that food was sometimes given. The increase was triggered by the omission of expected food. Our first explanation of the increase was that it was a frustration effect. Experiment 2 tested this explanation with a procedure in which the first response of a trial usually produced food, ending the trial. In Experiment 2, unlike Experiment 1, omission of expected food did not produce a large increase in bar-press duration, which cast doubt on the frustration explanation. Experiments 3 and 4 tested an alternative explanation: a decrease in expectation of reward increases variation. Both used two signals associated with different probabilities of reward. Bar presses were more variable in duration during the signal with the lower probability of reward, supporting this alternative. These experiments show how variation can be studied with ordinary equipment and responses. 相似文献
53.
54.
55.
Mansourian M Madadkar-Sobhani A Mahnam K Fassihi A Saghaie L 《Journal of molecular modeling》2012,18(9):4309-4324
Selective A(2B) receptor antagonists and agonists may play a role in important pathologies such as gastrointestinal, neurological (i.e., Alzheimer disease and dementia) and hypersensitive disorders (i.e., asthma), diabetes, atherosclerosis, restenosis and cancer. Hence, it is regarded as a good target for the development of clinically useful agents. In this study, the effects of lipid bilayer, N-acetylglucosamine and S-palmitoyl on the dynamic behavior of A(2B)AR model is explored. Homology modeling, molecular docking and molecular dynamics simulations were performed to explore structural features of A(2B)AR in the presence of lipid bilayer. Twenty ns MD simulation was performed on the constructed model inserted in a hydrated lipid bilayer to examine stability of the best model. OSIP339391 as the most potent antagonist was docked in the active site of the model. Another MD simulation was performed on the ligand-protein complex to explore effects of the bilayer on this complex. A similar procedure was performed for the modified protein with N-acetylglucosamine and S-palmitoyl moieties in its structure. Phe173 and Glu174 located in EL2 were determined to be involved in ligand-receptor interactions through π-π stacking and hydrogen bonding. Asn254 was crucial to form hydrogen-bonding. The reliability of the model was assessed through docking using both commercial and synthetic antagonists and an r(2) of 0.70 was achieved. Our results show that molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B)AR in its native environment is a possible approach and this model can be used for designing potent and selective A(2B)AR antagonists. 相似文献
56.
Human CCRL1 belongs to the family of silent chemokine receptors. This transmembrane protein plays a role in blunting function of chemokines through binding to them. This will attenuate immune responses. Interaction between CCRL1 and CCL21 determines this immune extinction. Thus inhibiting the action of this atypical chemokine seems to stimulate immune responses especially in the case of suppressed and immune deficient conditions. In this study we predicted 3D structure of CCRL1 using comparative modeling and Hiddebn Markov Model algorithm. Final predicted model optimized by Modeller v9.8 and minimized regarding energy level using UCSF chimera candidate version1.5.3. ClasPro webserver was used to find interacting residues between CCRL1 and CCL21. Interacting residues were used as target for chemical inhibitors by simulated docking study. For finding potential inhibitors, library of KEGG compounds screened and 97 obtained chemicals docked against interacting residues between CCRL1- CCL21 and MolDock was used as docking scoring function. Results indicated that Hexadecanal is a potential inhibitor of CCRL1- CCL21 interaction. Inhibition of this interaction will increase intercellular level of CCl21 and interaction between CCL21 and CCR7 causes immune potentiaiton. 相似文献
57.
Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA) 总被引:2,自引:0,他引:2
Duncan RE Sarkadi-Nagy E Jaworski K Ahmadian M Sul HS 《The Journal of biological chemistry》2008,283(37):25428-25436
Phospholipases A(2) (PLA(2)s) catalyze hydrolysis of fatty acids from the sn-2 position of phospholipids. Here we report the identification and characterization of a membrane-associated intracellular calcium-dependent, adipose-specific PLA(2) that we named AdPLA (adipose-specific phospholipase A(2)). We found that AdPLA was highly expressed specifically in white adipose tissue and was induced during preadipocyte differentiation into adipocytes. Clearance of AdPLA by immunoprecipitation significantly decreased PLA activity in white adipose tissue lysates but had no effect on liver lysates, where expression was hardly detectable. In characterizing AdPLA, we employed radiochemical assays with TLC analysis of the enzyme activity of lysates from COS-7 cells overexpressing AdPLA. For kinetic studies, we produced purified recombinant AdPLA for use in a lipoxidase-coupled spectrophotometric assay. AdPLA generated free fatty acid and lysophospholipid from phosphatidylcholine with a preference for hydrolysis at the sn-2 position. Although we found low but detectable lysophospholipase activity, AdPLA showed no significant activity against a variety of other lipid substrates. Calcium was found to activate AdPLA but was not essential for activity. Studies with known phospholipase inhibitors, including bromoenolactone, methyl arachidonyl fluorophosphate, AACOCF(3), 7,7-dimethyl-5,8-eicosadienoic acid, and thioetheramide, supported that AdPLA is a phospholipase. Mutational studies showed that His-23 and Cys-113 are critical for activity of AdPLA and suggested that AdPLA is likely a His/Cys PLA(2). Overall, although AdPLA is similar to other histidine phospholipases in pH and calcium dependence, AdPLA showed different characteristics in many regards, including predicted catalytic mechanism. AdPLA may therefore represent the first member of a new group of PLA(2)s, group XVI. 相似文献
58.
The aims of the current study were to investigate the oxidant and antioxidant status of liver tissue challenged by doxorubicin and to examine the possible protective effects of aerobic exercise on doxorubicin-induced oxidative stress. Seventy-two rats were divided into three age groups (Young, Adult, and Elderly) with three treatment subgroups consisting of eight rats per age group: doxorubicin, aerobic exercise?+?doxorubicin, and aerobic exercise?+?saline. The experimental groups performed regular treadmill running for 3 weeks. Doxorubicin was administered by i.p. injection at a dosage of 20?mg kg?1 while the aerobic exercise?+?saline group received saline of a comparable volume. Heat shock protein 70, malondialdehyde, glutathione peroxidase, and protein carbonyl were determined from the liver homogenates following the intervention period. Treatment with doxorubicin induced hepatotoxicity in all groups with lower values of oxidative stress in young compared with the older groups. The inclusion of aerobic exercise training significantly increased heat shock protein 70 and antioxidant enzyme levels (glutathione peroxidase) whereas it decreased oxidative stress biomarkers (malondialdehyde and protein carbonyl) for all age groups. These results suggest that aerobic exercise training may be a potential, non-drug strategy to modulate doxorubicin-induced hepatotoxicity through its positive impact on antioxidant levels and oxidative stress biomarkers. 相似文献
59.
60.