全文获取类型
收费全文 | 662篇 |
免费 | 95篇 |
专业分类
757篇 |
出版年
2023年 | 4篇 |
2022年 | 6篇 |
2021年 | 23篇 |
2020年 | 8篇 |
2019年 | 15篇 |
2018年 | 15篇 |
2017年 | 14篇 |
2016年 | 14篇 |
2015年 | 26篇 |
2014年 | 34篇 |
2013年 | 26篇 |
2012年 | 51篇 |
2011年 | 74篇 |
2010年 | 37篇 |
2009年 | 28篇 |
2008年 | 41篇 |
2007年 | 34篇 |
2006年 | 36篇 |
2005年 | 30篇 |
2004年 | 32篇 |
2003年 | 26篇 |
2002年 | 27篇 |
2001年 | 5篇 |
2000年 | 13篇 |
1999年 | 10篇 |
1997年 | 9篇 |
1996年 | 4篇 |
1994年 | 4篇 |
1992年 | 4篇 |
1990年 | 14篇 |
1989年 | 3篇 |
1988年 | 9篇 |
1987年 | 3篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1984年 | 6篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 5篇 |
1979年 | 8篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1973年 | 5篇 |
1972年 | 2篇 |
1971年 | 4篇 |
1970年 | 3篇 |
排序方式: 共有757条查询结果,搜索用时 15 毫秒
11.
23Na NMR relaxation rate measurements show that Na+ binds specifically to phosphatidylserine vesicles and is displaced partially from the binding site by K+ and Ca2+ but to a considerably less extent by tetraethylammonium ion. The data indicate that tetraethylammonium ion affects the binding of Na+ only slightly, by affecting the surface potential through its presence in the double layer, without competing for a phosphatidylserine binding site. Values for the intrinsic binding constant for the Na+-phosphatidylserine complex that would be consistent with the competition experiments (and the dependence of the relaxation rate on concentration of free Na+) fall in the range 0.4--1.2 M-1 with a better fit towards the higher values. We conclude that in the absence of competing cations in solution an appreciable fraction of the phosphatidylserine sites could be associated with bound Na+ at 0.1 M Na+ concentration. 相似文献
12.
A theoretical model to study the effect of convection and leaky junctions on macromolecule transport in artery walls 总被引:1,自引:0,他引:1
A mathematical model is presented herein to determine the effect of convection on macromolecular transport across an artery wall due to transmural or osmotic pressure differences. The model is based on an extension of the leaky junction-cell turnover model of Weinbaum et al. (1985) to take into account a combined transport mechanism of convection and diffusion and also to provide the leaky junctions in the model with a finite resistance, thus allowing the results to be extended to intercellular clefts with a retarding extracellular matrix or to macromolecules whose dimensions are nearly the same as the junctional width. The results from this improved model show that the effect of pressure on transarterial macromolecular transport is important especially for cell turnover rates greater than 1% and that significant changes in the equilibrium balance of the cholesterol carrying LDL molecules in the arterial wall can occur due to a very small fraction of leaky junctions. At very high turnover rates (large fraction of leaky junctions) the effect of convection on macromolecular transport becomes dramatic and explains the very large increases in uptake observed experimentally after artificially inducing extensive endothelial damage. 相似文献
13.
Robert Kurland Carolyn Newton Shlomo Nir Demetrios Papahadjopoulos 《生物化学与生物物理学报:生物膜》1979,551(1):137-147
23Na NMR relaxation rate measurements show that Na+ binds specificially to phosphatidylserine vesicles and is displaced partially from the binding site by K+ and Ca2+ but to a considerably less extent by tetraethylammonium ion. The data indicate that tetraethylammonium ion affects the binding of Na+ only slightly, by affecting the surface potential through its presence in the double layer, without competing for a phosphatidylserine binding site. Values for the intrinsic binding constant for the Na+-phosphatidylserine complex that would be consistent with the competition experiments (and the dependence of the relaxation rate on concentration of free Na+) fall in the range 0.4–1.2 M?1 with a better fit towards the higher values. We conclude that in the absence of competing cations in solution an appreciable fraction of the phosphatidylserine sites could be associated with bound Na+ at 0.1 M Na+ concentration. 相似文献
14.
Matteo Pappalardo Nir Shachaf Livia Basile Danilo Milardi Mouhammed Zeidan Jamal Raiyn Salvatore Guccione Anwar Rayan 《PloS one》2014,9(10)
The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼4000 chemicals highly indexed as H4R antagonists'' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner. 相似文献
15.
16.
Nir Hecht Caroline L Monteil Guy Perrire Marina Vishkautzan Eyal Gur 《Molecular biology and evolution》2021,38(3):761
The understanding of how proteins evolve to perform novel functions has long been sought by biologists. In this regard, two homologous bacterial enzymes, PafA and Dop, pose an insightful case study, as both rely on similar mechanistic properties, yet catalyze different reactions. PafA conjugates a small protein tag to target proteins, whereas Dop removes the tag by hydrolysis. Given that both enzymes present a similar fold and high sequence similarity, we sought to identify the differences in the amino acid sequence and folding responsible for each distinct activity. We tackled this question using analysis of sequence–function relationships, and identified a set of uniquely conserved residues in each enzyme. Reciprocal mutagenesis of the hydrolase, Dop, completely abolished the native activity, at the same time yielding a catalytically active ligase. Based on the available Dop and PafA crystal structures, this change of activity required a conformational change of a critical loop at the vicinity of the active site. We identified the conserved positions essential for stabilization of the alternative loop conformation, and tracked alternative mutational pathways that lead to a change in activity. Remarkably, all these pathways were combined in the evolution of PafA and Dop, despite their redundant effect on activity. Overall, we identified the residues and structural elements in PafA and Dop responsible for their activity differences. This analysis delineated, in molecular terms, the changes required for the emergence of a new catalytic function from a preexisting one. 相似文献
17.
18.
19.
Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD–associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits. 相似文献
20.
Nir Eynon Emiliya S. Nasibulina Lauren K. Banting Pawel Cieszczyk Agnieszka Maciejewska-Karlowska Marek Sawczuk Elvira A. Bondareva Roza R. Shagimardanova Maytal Raz Yael Sharon Alun G. Williams Ildus I. Ahmetov Alejandro Lucia Ruth Birk 《PloS one》2013,8(4)