全文获取类型
收费全文 | 5999篇 |
免费 | 765篇 |
国内免费 | 181篇 |
出版年
2024年 | 3篇 |
2023年 | 154篇 |
2022年 | 121篇 |
2021年 | 212篇 |
2020年 | 280篇 |
2019年 | 376篇 |
2018年 | 301篇 |
2017年 | 335篇 |
2016年 | 324篇 |
2015年 | 285篇 |
2014年 | 307篇 |
2013年 | 550篇 |
2012年 | 210篇 |
2011年 | 331篇 |
2010年 | 220篇 |
2009年 | 354篇 |
2008年 | 373篇 |
2007年 | 326篇 |
2006年 | 297篇 |
2005年 | 203篇 |
2004年 | 244篇 |
2003年 | 175篇 |
2002年 | 126篇 |
2001年 | 123篇 |
2000年 | 88篇 |
1999年 | 77篇 |
1998年 | 91篇 |
1997年 | 67篇 |
1996年 | 63篇 |
1995年 | 59篇 |
1994年 | 46篇 |
1993年 | 62篇 |
1992年 | 51篇 |
1991年 | 22篇 |
1990年 | 13篇 |
1989年 | 7篇 |
1988年 | 7篇 |
1987年 | 7篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 7篇 |
1981年 | 6篇 |
1980年 | 1篇 |
1979年 | 7篇 |
1978年 | 4篇 |
1972年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有6945条查询结果,搜索用时 15 毫秒
961.
Xiaofeng Ji 《Journal of biomolecular structure & dynamics》2018,36(9):2268-2278
The pore domain of human voltage-dependent cardiac sodium channel Nav1.5 (hNav1.5) is the crucial binding targets for anti-arrhythmics drugs and some local anesthetic drugs but its three-dimensional structure is still lacking. This has affected the detailed studies of the binding features and mechanism of these drugs. In this paper, we present a structural model for open-state pore domain of hNav1.5 built using single template ROSETTA-membrane homology modeling with the crystal structure of NavMs. The assembled structural models are evaluated by rosettaMP energy and locations of binding sites. The modeled structures of the pore domain of hNav1.5 in open state will be helpful to explore molecular mechanism of a state-dependent drug binding and help designing new drugs. 相似文献
962.
Mehmet Erman Erdemli Ramin Ekhteiari Salmas Serdar Durdagi Hasan Akgul Mehmet Demirkol Zeynep Aksungur 《Journal of biomolecular structure & dynamics》2018,36(4):993-1008
In the present study, the changes that occur in rat liver tissue as a result of the use of grape seed extract (GSE) and low level laser therapy (LLLT) in intraoral wound (IW) healing are analyzed using biochemical parameters. Diode laser application groups received 8 J/cm2 dose LLLT once a day for 4 days (810 nm wavelength, continuous mode, 0.25 W, 9 s). As a result of the biological parameter analysis, it was determined that the oxidative damage caused by the IWs and recovery period on 7th and 14th days could be substantially removed with GSE applications that have antioxidant capacity especially in rat liver tissue. In addition, the active compound of grape seed, catechin is studied in the active site of glycogen synthase kinase 3 (GSK3) target using molecular modeling approaches. Post-processing molecular dynamics (MD) results for catechin is compared with a standard GSK3 inhibitor. MD simulations assisted for better understanding of inhibition mechanism and the crucial amino acids contributing in the ligand binding. These results along with a through free energy analysis of ligands using sophisticated simulations methods are quite striking and it suggests a greater future role for simulation in deciphering complex patterns of molecular mechanism in combination with methods for understanding drug-receptor interactions. 相似文献
963.
Varsha Bhavnani Swarnendu Kaviraj Priyabrata Panigrahi C.G. Suresh SuneelShekar Yapara 《Journal of biomolecular structure & dynamics》2018,36(11):2845-2861
The eIF2α kinase activity of the heme-regulated inhibitor (HRI) is regulated by heme which makes it a unique member of the family of eIF2α kinases. Since heme concentrations create an equilibrium for the kinase to be active/inactive, it becomes important to study the heme binding effects upon the kinase and understanding its mechanism of functionality. In the present study, we report the thermostability achieved by the catalytic kinase domain of HRI (HRI.CKD) upon ligand (heme) binding. Our CD data demonstrates that the HRI.CKD retains its secondary structure at higher temperatures when it is in ligand bound state. HRI.CKD when incubated with hemin loses its monomeric state and attains a higher order oligomeric form resulting in its stability. The HRI.CKD fails to refold into its native conformation upon mutation of H377A/H381A, thereby confirming the necessity of these His residues for correct folding, stability, and activity of the kinase. Though our in silico study demonstrated these His being the ligand binding sites in the kinase insert region, the spectra-based study did not show significant difference in heme affinity for the wild type and His mutant HRI.CKD. 相似文献
964.
《Proteins》2018,86(5):524-535
Extensive research performed on Toll‐like receptor (TLR) signaling has identified residues in the Toll/interleukin‐1 receptor (TIR) domains that are essential for its proper functioning. Among these residues, those in BB loop are particularly significant as single amino acid mutations in this region can cause drastic changes in downstream signaling. However, while the effect of these mutations on the function is well studied (like the P681H mutation in TLR2, the A795P mutation in TLR3, and the P714H mutation in TLR4), their influence on the dynamics and inter‐residue networks is not well understood. The effects of local perturbations induced by these mutations could propagate throughout the TIR domain, influencing interactions with other TIR domain‐containing proteins. The identification of these subtle changes in inter‐residue interactions can provide new insights and structural rationale for how single‐point mutations cause drastic changes in TIR–TIR interactions. We employed molecular dynamics simulations and protein structure network (PSN) analyses to investigate the structural transitions with special emphasis on TLR2 and TLR3. Our results reveal that phosphorylation of the Tyr 759 residue in the TIR domain of TLR3 introduces rigidity to its BB loop. Subtle differences in the intra BB loop hydrogen bonding network between TLR3 and TLR2 are also observed. The PSN analyses indicate that the TIR domain is highly connected and pinpoints key differences in the inter‐residue interactions between the wild‐type and mutant TIR domains, suggesting that TIR domain structure is prone to allosteric effects, consistent with the current view of the influence of allostery on TLR signaling. 相似文献
965.
Amanda E. I. Proudfoot Manuel C. Peitsch Christine A. Power Bernard Allet Jean-Jacques Mermod Kevin Bacon Timothy N. C. Wells 《Journal of Protein Chemistry》1997,16(1):37-49
Connective tissue-activating peptide III (CTAP-III) and neutrophil-activating peptide-2 (NAP-2) are both derived from a common precursor, platelet basic protein (PBP), which is stored in the -granules of platelets and released upon their activation. CTAP-III is an 85-residue peptide which is converted to NAP-2 by enzymic removal of the 15 amino-terminal residues. Both peptides play a role in the early stages of wound healing and inflammation through different activities. We have cloned the cDNA for PBP and expressed constructs coding for the CTAP-III and NAP-2 polypeptides in Escherichia coli. We have purified and renatured these recombinant proteins. The integrity of the recombinant proteins has been ascertained by in vitro bioassays. CTAP-III causes 51% histamine release from the basophilic cell lin KU812 at 10–7 M, whereas NAP-2 only causes 28% release at the same concentration. In assays on human neutrophils, NAP-2 had an EC
50 of 2×10–8 M in chemotaxis, an EC
50 of 3×10–8 M for shape change, and could displace IL-8 from neutrophils with a K
d of 7.5×10–9 M. CTAP-III had no activity in these assays. The disulfide bonds have been identified by peptide mapping and sequence analysis, and are in the positions predicted by homology to interleukin-8 and platelet factor 4. Measurement of the molecular mass at physiologic concentrations by gel permeation chromatography has shown that CTAP-III forms predominantly tetramers and dimers, whereas NAP-2 is only dimetric. SDS/PAGE analysis of samples cross-linked with disuccinimidyl suberate support these topologies. We postulate a mechanism for tetramer formation based on the interaction of the amino-terminal extension in CTAP-III involving a helix–helix interaction that could stabilize the association of two CTAP-III dimers. 相似文献
966.
Dead-End Based Modeling Tools to Explore the Sequence Space That Is Compatible with a Given Scaffold
The dead-end elimination algorithm has proven to be a powerful tool in protein homology modeling since it allows one to determine rapidly the global minimum-energy conformation (GMEC) of an arbitrarily large collection of side chains, given fixed backbone coordinates. After introducing briefly the necessary background, we focus on logic arguments that increase the efficacy of the dead-end elimination process. Second, we present new theoretical considerations on the use of the dead-end elimination method as a tool to identify sequences that are compatible with a given scaffold structure. Third, we initiate a search for properties derived from the computed GMEC structure to predict whether a given sequence can be well packed in the core of a protein. Three properties will be considered: the nonbonded energy, the accessible surface area, and the extent by which the GMEC side-chain conformations deviate from a locally optimal conformation. 相似文献
967.
968.
Sylvie Baltora-Rosset Danielle Marty François-Yves Dupradeau Emmanuel Pauthe Véronique Larreta-Garde Gilles Gacel Jean-Pierre Monti 《International journal of peptide research and therapeutics》1997,4(4-6):391-395
Summary The conformations of thermolysin synthetic substrates in H2O/D2O (9/1) and glycerol-d
5 (5 M) are investigated using two-dimensional nuclear magnetic resonance spectroscopy and molecular modeling. The structures
obtained from molecular modeling and NMR studies are compared. Comparisons of these structures with bound inhibitor in the
active site of thermolysin are also discussed. 相似文献
969.
A model was constructed to estimate cancer risks associated with PM10‐bound polycydic aromatic hydrocarbons (PAHs) from Kuwait oil lakes. The design of the risk model was based on a conceptual “chain of events”; leading from levels of PAH compounds in oil lakes, erosion of oil dust and input into the atmosphere, to contaminant concentration in air, to actual human exposure in residential areas. Uncertainties in the “chain of events”; model were addressed using Monte Carlo techniques. To identify the exposure duration of concern [duration beyond which risk becomes unacceptable (i.e. Risk > 10‐6)], four exposure durations were tested 10, 20, 40, 70 years. 40 years was identified to be the exposure duration of concern based on the 95th percen‐tile of the risk distribution. As a result, the acceptability of risk was specified in terms of a single constraint on the 95th percentile of the risk distribution evaluated after 40 years of exposure: 0 < Risk (40 y)0.95 ≤ 10‐6. Based on this constraint, it was estimated that a removal rate of 217, 793.27 m3/year to be an adequate action for risk management. The northern oil lakes were identified as the lakes of most concern when inhalation exposures are considered. 相似文献
970.
This paper proposes a computer-based method for providing product designers with real-time environmental impact assessment. In this concurrent modeling approach, environmental experts build life-cycle models, define their interfaces, and publish them as distributed objects on the Internet. Traditional designers integrating these objects into their design models have access to the impact assessment methods provided by the environmental expert. In this paradigm, the focus shifts from providing techniques that let non-expert designers perform life-cycle impact assessments to tools that facilitate timely communication and information transfer between designers and appropriate environmental experts. Establishing real-time communication between the product design models and the environmental life-cycle models is the primary focus of this paper. Methods for establishing and maintaining the interaction between life-cycle and product design models are described. A beverage container design example illustrates how this collaborative approach can use environmental and traditional design goals to determine effective tradeoffs between design alternatives. 相似文献