全文获取类型
收费全文 | 1740篇 |
免费 | 110篇 |
国内免费 | 1篇 |
出版年
2023年 | 6篇 |
2022年 | 23篇 |
2021年 | 26篇 |
2020年 | 26篇 |
2019年 | 41篇 |
2018年 | 47篇 |
2017年 | 40篇 |
2016年 | 51篇 |
2015年 | 79篇 |
2014年 | 78篇 |
2013年 | 112篇 |
2012年 | 125篇 |
2011年 | 118篇 |
2010年 | 79篇 |
2009年 | 63篇 |
2008年 | 94篇 |
2007年 | 124篇 |
2006年 | 109篇 |
2005年 | 109篇 |
2004年 | 85篇 |
2003年 | 72篇 |
2002年 | 68篇 |
2001年 | 20篇 |
2000年 | 14篇 |
1999年 | 24篇 |
1998年 | 26篇 |
1997年 | 16篇 |
1996年 | 16篇 |
1995年 | 17篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 6篇 |
1988年 | 8篇 |
1987年 | 4篇 |
1986年 | 5篇 |
1985年 | 8篇 |
1983年 | 7篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1979年 | 6篇 |
1977年 | 4篇 |
1976年 | 3篇 |
1975年 | 4篇 |
1974年 | 3篇 |
1969年 | 3篇 |
1967年 | 3篇 |
排序方式: 共有1851条查询结果,搜索用时 15 毫秒
51.
52.
53.
A new molecular dynamics method for calculating free energy profiles for rare events is presented. The new method is based on the creation of an adiabatic separation between the reaction coordinate subspace and the remaining degrees of freedom within a molecular dynamics run. This is achieved by associating with the reaction coordinate(s) a high temperature and large mass, thereby allowing the activated process to occur while permitting the remaining degrees of freedom to respond adiabatically. In this limit, by applying a formal multiple time scale Liouville operator factorization, it can be rigorously shown that the free energy profiles are obtained directly from the probability distribution of the reaction coordinate subspace and, therefore, require no postprocessing of the output data. The new method is applied to a variety of model problems and its performance tested against free energy calculations using the "bluemoon ensemble" approach. The comparison shows that free energy profiles can be calculated with greater ease and efficiency using the new method. 相似文献
54.
55.
Application of Hazard Analysis and Critical Control Points (HACCP) to the Cultivation Line of Mushroom and Other Cultivated Edible Fungi 总被引:1,自引:0,他引:1
José E. Pardo Vinícius Reis de Figueirêdo Manuel Álvarez-Ortí Diego C. Zied Jesús A. Peñaranda Eustáquio Souza Dias Arturo Pardo-Giménez 《Indian journal of microbiology》2013,53(3):359-369
The Hazard analysis and critical control points (HACCP) is a preventive system which seeks to ensure food safety and security. It allows product protection and correction of errors, improves the costs derived from quality defects and reduces the final overcontrol. In this paper, the system is applied to the line of cultivation of mushrooms and other edible cultivated fungi. From all stages of the process, only the reception of covering materials (stage 1) and compost (stage 3), the pre-fruiting and induction (step 6) and the harvest (stage 7) have been considered as critical control point (CCP). The main hazards found were the presence of unauthorized phytosanitary products or above the permitted dose (stages 6 and 7), and the presence of pathogenic bacteria (stages 1 and 3) and/or heavy metals (stage 3). The implementation of this knowledge will allow the self-control of their productions based on the system HACCP to any plant dedicated to mushroom or other edible fungi cultivation. 相似文献
56.
57.
Sajiv K. Nair Jean J. Matthews Stephan J. Cripps Hengmiao Cheng Jacqui E. Hoffman Christopher Smith Stanley Kupchinsky Michael Siu Wendy D. Taylor Yong Wang Theodore O. Johnson Klaus R. Dress Martin P. Edwards Sue Zhou Natilie A. Hosea Amy LaPaglia Ping Kang Arturo Castro Deepak Dalvie 《Bioorganic & medicinal chemistry letters》2013,23(8):2344-2348
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure–activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay. 相似文献
58.
Maricarmen Hernández‐Rodríguez José Correa‐Basurto Claudia G. Benitez‐Cardoza Aldo Arturo Resendiz‐Albor Martha C. Rosales‐Hernández 《Protein science : a publication of the Protein Society》2013,22(10):1320-1335
The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1–42) is the most important pathophysiological event associated with Alzheimer''s disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α-helix to a β-sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+ and various drugs used for AD treatment, such as galanthamine (Reminyl®), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu2+ and galanthamine prevent the formation of Aβ1–42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1–42 acquires a characteristic U-shape before the α-helix to β-sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ1−42 in the presence of Cu2+ or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1−42 from adopting the U-characteristic conformation that allows the amino acids to transition to a β-sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu2+ and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils. 相似文献
59.
Arturo Roca-Rivada Cecilia Castelao Lucía L. Senin María O. Landrove Javier Baltar Ana Belén Crujeiras Luisa María Seoane Felipe F. Casanueva María Pardo 《PloS one》2013,8(4)
Exercise provides clear beneficial effects for the prevention of numerous diseases. However, many of the molecular events responsible for the curative and protective role of exercise remain elusive. The recent discovery of FNDC5/irisin protein that is liberated by muscle tissue in response to exercise might be an important finding with regard to this unsolved mechanism. The most striking aspect of this myokine is its alleged capacity to drive brown-fat development of white fat and thermogenesis. However, the nature and secretion form of this new protein is controversial. The present study reveals that rat skeletal muscle secretes a 25 kDa form of FNDC5, while the 12 kDa/irisin theoretical peptide was not detected. More importantly, this study is the first to reveal that white adipose tissue (WAT) also secretes FNDC5; hence, it may also behave as an adipokine. Our data using rat adipose tissue explants secretomes proves that visceral adipose tissue (VAT), and especially subcutaneous adipose tissue (SAT), express and secrete FNDC5. We also show that short-term periods of endurance exercise training induced FNDC5 secretion by SAT and VAT. Moreover, we observed that WAT significantly reduced FNDC5 secretion in fasting animals. Interestingly, WAT of obese animals over-secreted this hormone, which might suggest a type of resistance. Because 72% of circulating FNDC5/irisin was previously attributed to muscle secretion, our findings suggest a muscle-adipose tissue crosstalk through a regulatory feedback mechanism. 相似文献
60.
Many cancers are aneuploid. However, the precise role that chromosomal instability plays in the development of cancer and in the response of tumours to treatment is still hotly debated. Here, to explore this question from a theoretical standpoint we have developed an agent-based model of tissue homeostasis in which to test the likely effects of whole chromosome mis-segregation during cancer development. In stochastic simulations, chromosome mis-segregation events at cell division lead to the generation of a diverse population of aneuploid clones that over time exhibit hyperplastic growth. Significantly, the course of cancer evolution depends on genetic linkage, as the structure of chromosomes lost or gained through mis-segregation events and the level of genetic instability function in tandem to determine the trajectory of cancer evolution. As a result, simulated cancers differ in their level of genetic stability and in their growth rates. We used this system to investigate the consequences of these differences in tumour heterogeneity for anti-cancer therapies based on surgery and anti-mitotic drugs that selectively target proliferating cells. As expected, simulated treatments induce a transient delay in tumour growth, and reveal a significant difference in the efficacy of different therapy regimes in treating genetically stable and unstable tumours. These data support clinical observations in which a poor prognosis is correlated with a high level of chromosome mis-segregation. However, stochastic simulations run in parallel also exhibit a wide range of behaviours, and the response of individual simulations (equivalent to single tumours) to anti-cancer therapy prove extremely variable. The model therefore highlights the difficulties of predicting the outcome of a given anti-cancer treatment, even in cases in which it is possible to determine the genotype of the entire set of cells within the developing tumour. 相似文献