全文获取类型
收费全文 | 28287篇 |
免费 | 2562篇 |
国内免费 | 3889篇 |
专业分类
34738篇 |
出版年
2024年 | 107篇 |
2023年 | 447篇 |
2022年 | 951篇 |
2021年 | 1586篇 |
2020年 | 1113篇 |
2019年 | 1407篇 |
2018年 | 1280篇 |
2017年 | 965篇 |
2016年 | 1228篇 |
2015年 | 1861篇 |
2014年 | 2276篇 |
2013年 | 2372篇 |
2012年 | 2877篇 |
2011年 | 2500篇 |
2010年 | 1635篇 |
2009年 | 1528篇 |
2008年 | 1649篇 |
2007年 | 1497篇 |
2006年 | 1252篇 |
2005年 | 1119篇 |
2004年 | 889篇 |
2003年 | 810篇 |
2002年 | 658篇 |
2001年 | 441篇 |
2000年 | 355篇 |
1999年 | 367篇 |
1998年 | 253篇 |
1997年 | 200篇 |
1996年 | 191篇 |
1995年 | 152篇 |
1994年 | 133篇 |
1993年 | 92篇 |
1992年 | 96篇 |
1991年 | 86篇 |
1990年 | 70篇 |
1989年 | 62篇 |
1988年 | 54篇 |
1987年 | 35篇 |
1986年 | 34篇 |
1985年 | 44篇 |
1984年 | 13篇 |
1983年 | 15篇 |
1982年 | 12篇 |
1981年 | 11篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1977年 | 2篇 |
1969年 | 2篇 |
1965年 | 1篇 |
1950年 | 2篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
992.
Effective virtual screening relies on our ability to make accurate prediction of protein-ligand binding, which remains a great challenge. In this work, utilizing the molecular-mechanics Poisson-Boltzmann (or Generalized Born) surface area approach, we have evaluated the binding affinity of a set of 156 ligands to seven families of proteins, trypsin β, thrombin α, cyclin-dependent kinase (CDK), cAMP-dependent kinase (PKA), urokinase-type plasminogen activator, β-glucosidase A, and coagulation factor Xa. The effect of protein dielectric constant in the implicit-solvent model on the binding free energy calculation is shown to be important. The statistical correlations between the binding energy calculated from the implicit-solvent approach and experimental free energy are in the range of 0.56-0.79 across all the families. This performance is better than that of typical docking programs especially given that the latter is directly trained using known binding data whereas the molecular mechanics is based on general physical parameters. Estimation of entropic contribution remains the barrier to accurate free energy calculation. We show that the traditional rigid rotor harmonic oscillator approximation is unable to improve the binding free energy prediction. Inclusion of conformational restriction seems to be promising but requires further investigation. On the other hand, our preliminary study suggests that implicit-solvent based alchemical perturbation, which offers explicit sampling of configuration entropy, can be a viable approach to significantly improve the prediction of binding free energy. Overall, the molecular mechanics approach has the potential for medium to high-throughput computational drug discovery. 相似文献
993.
Chen Y Ip SP Ko KM Poon TC Ng EW Lai PB Mao QQ Xian YF Che CT 《Journal of proteome research》2011,10(1):299-304
To identify key proteins involved in the hepatoprotection afforded by schisandrin B (Sch B), we used a proteomic approach to screen proteins that were specifically regulated by Sch B in mouse livers and to investigate the role of the proteins in hepatoprotection. Thirteen proteins were specifically activated or suppressed by Sch B treatment. Among the 13 proteins, Raf kinase inhibitor protein (RKIP) was postulated to be the key regulator involved in the development of hepatotoxin-induced cellular damage. The results indicated that the downregulation of RKIP by antisense RKIP vector transfection led to the activation of the Raf-1/MEK/ERK signaling pathway, as evidenced by increases in the level of MEK/ERK phosphorylation and the level of nuclear factor erythroid 2-related factor 2 in the nucleus. The signaling effect produced by RKIP downregulation resembled that triggered by Sch B, wherein both treatments resulted in a decrease in the extent of carbon tetrachloride-induced apoptotic cell death in AML12 hepatocytes. Overexpression of RKIP by the sense RKIP transfection vector or the inhibition of MEK kinase by PD98059 was able to abrogate the cytoprotective effect of Sch B in the hepatocytes. The results indicate that Sch B triggers the Raf/MEK/ERK signaling pathway, presumably by downregulating RKIP, thereby protecting against carbon tetrachloride-induced cytotoxicity. 相似文献
994.
目的:探讨一次和反复力竭性运动后不同时相大鼠血清肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)与心肌损伤的变化规律。方法:通过力竭性游泳制备运动性心肌损伤模型,分别于运动后即刻和3 h6、h、12 h2、4 h4、8 h、96 h检测血清CK、CK-MB活性,并观察心肌组织形态学的动态变化。结果:大鼠一次力竭运动后0~12 h,CK和CK-MB活性明显增加,6 h达高峰;心肌炎细胞浸润灶逐渐增多,胞质嗜酸性增强,损伤高峰在12 h左右。反复力竭运动后0~12 h和48 h9、6 h CK和CK-MB活性皆明显增加,分别于运动后即刻和96 h达高峰;心肌细胞均有不同程度的损伤,48 h最严重。结论:过度运动和/或力竭性运动皆引起运动性心肌损伤,同时存在延迟性心肌损伤。 相似文献
995.
996.
997.
Background
Developing control policies for zoonotic diseases is challenging, both because of the complex spread dynamics exhibited by these diseases, and because of the need for implementing complex multi-species surveillance and control efforts using limited resources. Mathematical models, and in particular network models, of disease spread are promising as tools for control-policy design, because they can provide comprehensive quantitative representations of disease transmission.Methodology/Principal Findings
A layered dynamical network model for the transmission and control of zoonotic diseases is introduced as a tool for analyzing disease spread and designing cost-effective surveillance and control. The model development is achieved using brucellosis transmission among wildlife, cattle herds, and human sub-populations in an agricultural system as a case study. Precisely, a model that tracks infection counts in interacting animal herds of multiple species (e.g., cattle herds and groups of wildlife for brucellosis) and in human subpopulations is introduced. The model is then abstracted to a form that permits comprehensive targeted design of multiple control capabilities as well as model identification from data. Next, techniques are developed for such quantitative design of control policies (that are directed to both the animal and human populations), and for model identification from snapshot and time-course data, by drawing on recent results in the network control community.Conclusions/Significance
The modeling approach is shown to provide quantitative insight into comprehensive control policies for zoonotic diseases, and in turn to permit policy design for mitigation of these diseases. For the brucellosis-transmission example in particular, numerous insights are obtained regarding the optimal distribution of resources among available control capabilities (e.g., vaccination, surveillance and culling, pasteurization of milk) and points in the spread network (e.g., transhumance vs. sedentary herds). In addition, a preliminary identification of the network model for brucellosis is achieved using historical data, and the robustness of the obtained model is demonstrated. As a whole, our results indicate that network modeling can aid in designing control policies for zoonotic diseases. 相似文献998.
Background
Depletion of the circulating actin-binding protein, plasma gelsolin (pGSN) has been described in critically ill surgical patients. We hypothesized that the extent of pGSN reduction might correlate with different outcome of burn patients. The study was performed to evaluate the prognostic implications of pGSN levels on the development of multiple organ dysfunction syndrome (MODS) and fatal outcome in a group of severely burn patients.Methods and Findings
95 patients were included, and they were divided into three groups with different burn area: group I (n = 33), group II (n = 32) and group III (n = 30). According to whether there was development of MODS or not, patients were divided into MODS group (n = 28) and none-MODS group (n = 67); then the patients with MODS were further divided into non-survivor group (n = 17) and survivor group (n = 11). The peripheral blood samples were collected on postburn days (PBD) 1, 3, 7, 14, and 21. The levels of pGSN were determined and T cells were procured from the blood. The contents of cytokines (IL-2, IL-4 and IFN-γ) released by T cells were also measured. The related factors of prognosis were analyzed by using multivariate logistic regression analysis. The results showed that pGSN concentrations, as well as the levels of IL-2 and IFN-γ, decreased markedly on PBD 1–21, whereas, the levels of IL-4 increased markedly in all burn groups as compared with normal controls (P<0.05 or P<0.01), and there were obviously differences between group I and group III (P<0.05 or P<0.01). The similar results were found in MODS patients and the non-survivor group as compared with those without MODS and the survival group on days 3–21 postburn (P<0.05 or P<0.01). Moreover, as the pGSN levels decreased, the incidence of septic complication as well as MODS remarkably increased.Conclusions
pGSN levels appear to be an early prognostic marker in patients suffering from major burns. 相似文献999.
1000.