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51.
In recent years, an increasing number of small molecules and short peptides have been identified that interfere with aggregation and/or oligomerization of the Alzheimer β-amyloid peptide (Aβ). Many of them possess aromatic moieties, suggesting a dominant role for those in interacting with Aβ along various stages of the aggregation process. In this study, we attempt to elucidate whether interactions of such aromatic inhibitors with monomeric Aβ(12-28) point to a common mechanism of action by performing atomistic molecular dynamics simulations at equilibrium. Our results suggest that, independently of the presence of inhibitors, monomeric Aβ(12-28) populates a partially collapsed ensemble that is largely devoid of canonical secondary structure at 300 K and neutral pH. The small molecules have different affinities for Aβ(12-28) that can be partially rationalized by the balance of aromatic and charged moieties constituting the molecules. There are no predominant binding modes, although aggregation inhibitors preferentially interact with the N-terminal portion of the fragment (residues 13-20). Analysis of the free energy landscape of Aβ(12-28) reveals differences highlighted by altered populations of a looplike conformer in the presence of inhibitors. We conclude that intrinsic disorder of Aβ persists at the level of binding small molecules and that inhibitors can significantly alter properties of monomeric Aβ via multiple routes of differing specificity. 相似文献
52.
Martin Karplus Amedeo Caflisch Andrej Săli Eugene Shakhnovich 《Molecular Engineering》1995,5(1-3):55-70
Simulations to study protein unfolding and folding were performed. The unfolding simulations make use of molecular dynamics and treat an atomic model of barnase in aqueous solvent. The cooperative nature of the unfolding transition and the important role of water are described. The folding simulations are based on a bead model of the protein on a cubic lattice. It is shown for the 27-mer model that a large energy gap between the lowest energy (native) state and the excited states is a necessary and sufficient condition for fast folding. 相似文献
53.
Carlo Guarnieri Giovanni Melandri Ilaria Caldarera Mauro Scheda Amedeo Ligabue Sandro Guizzardi Angelo Branzi 《Cell biochemistry and function》1990,8(3):157-162
Circulating neutrophils isolated from patients 3–4 h after a myocardial infarction produced less $ {\rm O}\frac{ \cdot }{{\rm 2}} $ compared with controls, when stimulated with phorbol myrystate acetate or formyl-methionine-leucine-phenylalanine. Three days after the infraction the $ {\rm O}\frac{ \cdot }{{\rm 2}} $ generation elicited by both stimuli further decreased markedly. Seven and 15 days after infarction the $ {\rm O}\frac{ \cdot }{{\rm 2}} $ stimulated production was only slightly lower than or similar to the control values. The neutrophils of infarcted patients showed an augmented latency period before $ {\rm O}\frac{ \cdot }{{\rm 2}} $ production compared with controls in response to exogenous stimuli, particularly three days after infarction. Electron microscopy revealed that the neutrophils isolated from the infarcted patients displayed signs of cell exhaustion with few alterations of the plasma membranes when stimulated with phorbol ester. In contrast, control neutrophils displayed alterations of the plasma membranes characteristic of active neutrophils. The results of this study indicate that the circulating neutrophils appear exhausted and functionally inhibited immediately after myocardial infarction. 相似文献
54.
Seeber M Cecchini M Rao F Settanni G Caflisch A 《Bioinformatics (Oxford, England)》2007,23(19):2625-2627
Wordom is a versatile program for manipulation of molecular dynamics trajectories and efficient analysis of simulations. Original tools in Wordom include a procedure to evaluate significance of sampling for principal component analysis as well as modules for clustering multiple conformations and evaluation of order parameters for folding and aggregation. The program was developed with special emphasis on user-friendliness, effortless addition of new modules and efficient handling of large sets of trajectories. 相似文献
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58.
Growth and nutrient absorption of two submerged aquatic macrophytes in mesocosms, for reinsertion in a eutrophicated shallow lake 总被引:5,自引:0,他引:5
Aquatic macrophytes play a central role in preserving the ecological equilibrium of shallow lakes and in the restoration of
eutrophic lakes that have switched to phytoplankton-dominated turbid water. Massaciuccoli Lake, a shallow lake located along
the Tuscan coast in Italy, has shown a constant and progressive simplification of the submerged plant community, for anthropogenic
reasons, leading, in recent years, to turbid water. The growth and nutrient absorption capability of two macrophyte species,
Myriophyllum verticillatum L. and Elodea canadensis Michaux, in the lake was investigated, with the prospect of a future lake restoration programme centred on their replacement.
Mesocosm experiments were conducted to monitor the plant growth and nutrient (NO2−, NO3−, NH4+, Ntot, PO43−, Ptot) content in the plant dry matter and water at the beginning and at the end of the trial. Bacterial activity was analysed
in the water in order to verify the possible nutrient absorption contribution by organisms other than plants. Both M. verticillatum and E. canadensis showed satisfactory growth and nutrient reduction in the water body. Moreover, their different growth patterns suggested
that optimal replacement can be performed with their introduction in two steps, starting with M. verticillatum, which shows the best capacity to colonise the aquatic environment, due to its tendency towards lengthening. 相似文献
59.
Christophe Bodenreider David Beer Thomas H. Keller Sebastian Sonntag Daying Wen LiJian Yap Yin Hoe Yau Susana Geifman Shochat Danzhi Huang Ting Zhou Amedeo Caflisch Xun-Cheng Su Kiyoshi Ozawa Gottfried Otting Subhash G. Vasudevan Julien Lescar Siew Pheng Lim 《Analytical biochemistry》2009,395(2):195-204
In drug discovery, the occurrence of false positives is a major hurdle in the search for lead compounds that can be developed into drugs. A small-molecular-weight compound that inhibits dengue virus protease at low micromolar levels was identified in a screening campaign. Binding to the enzyme was confirmed by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). However, a structure–activity relationship study that ensued did not yield more potent leads. To further characterize the parental compound and its analogues, we developed a high-speed, low-cost, quantitative fluorescence quenching assay. We observed that specific analogues quenched dengue protease fluorescence and showed variation in IC50 values. In contrast, nonspecifically binding compounds did not quench its fluorescence and showed similar IC50 values with steep dose–response curves. We validated the assay using single Trp-to-Ala protease mutants and the competitive protease inhibitor aprotinin. Specific compounds detected in the binding assay were further analyzed by competitive ITC, NMR, and surface plasmon resonance, and the assay’s utility in comparison with these biophysical methods is discussed. The sensitivity of this assay makes it highly useful for hit finding and validation in drug discovery. Furthermore, the technique can be readily adapted for studying other protein–ligand interactions. 相似文献
60.
Fibrillar protein aggregates (amyloids) are involved in several common pathologies, e.g., Alzheimer's disease and type II diabetes. Accumulating evidence suggests that toxicity in amyloid-related diseases originates from the deposition of protein aggregates on the cell membrane, which results in bilayer disruption and cell leakage. The molecular mechanism of damage to the membrane, however, is still obscure. To shed light on it we have performed coarse-grained molecular dynamics simulations of fibril-forming amphipathic peptides in the presence of lipid vesicles. The simulation results show that highly amyloidogenic peptides fibrillate on the surface of the vesicle, damaging the bilayer and promoting leakage. In contrast, the ordered aggregation of peptides with low amyloidogenicity is hindered by the vesicles. Remarkably, leakage from the vesicle is caused by growing aggregates, but not mature fibrils. The simulation results provide a basis for understanding the range of aggregation behavior that is observed in experiments with fibril-forming (poly)peptides. 相似文献