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91.
Tony Ngo Timothy J. Nicholas Junli Chen Angela M. Finch Renate Griffith 《Journal of computer-aided molecular design》2013,27(4):305-319
The α1-adrenoceptors (α1-ARs), in particular the α1A-AR subtype, are current therapeutic targets of choice for the treatment of urogenital conditions, such as benign prostatic hyperplasia (BPH). Due to the similarity between the transmembrane domains of the α1-AR subtypes, and the serotonin receptor subtype 1A (5-HT1A-R), currently used α1-AR subtype-selective drugs to treat BPH display considerable off-target affinity for the 5-HT1A-R, leading to side effects. We describe the construction and validation of pharmacophores for 5-HT1A-R agonists and antagonists. Through the structural diversity of the training sets used in their development, these pharmacophores define the properties of a compound needed to bind to 5-HT1A receptors. Using these and previously published pharmacophores in virtual screening and profiling, we have identified unique chemical compounds (hits) that fit the requirements to bind to our target, the α1A-AR, selectively over the off-target, the 5-HT1A-R. Selected hits have been obtained and their affinities for α1A-AR, α1B-AR and 5-HT1A-R determined in radioligand binding assays, using membrane preparations which contain human receptors expressed individually. Three of the tested hits demonstrate statistically significant selectivity for α1A-AR over 5-HT1A-R. All seven tested hits bind to α1A-AR, with two compounds displaying K i values below 1 μM, and a further two K i values of around 10 μM. The insights and knowledge gained through the development of the new 5-HT1A-R pharmacophores will greatly aid in the design and synthesis of derivatives of our lead compound, and allow the generation of more efficacious and selective ligands. 相似文献
92.
The Arctic Ocean and sea ice form a feedback system that plays an important role in the global climate. The complexity of highly parameterized global circulation (climate) models makes it very difficult to assess feedback processes in climate without the concurrent use of simple models where the physics is understood. We introduce a two-dimensional energy-based regular network model to investigate feedback processes in an Arctic ice-ocean layer. The model includes the nonlinear aspect of the ice-water phase transition, a nonlinear diffusive energy transport within a heterogeneous ice-ocean lattice, and spatiotemporal atmospheric and oceanic forcing at the surfaces. First results for a horizontally homogeneous ice-ocean layer show bistability and related hysteresis between perennial ice and perennial open water for varying atmospheric heat influx. Seasonal ice cover exists as a transient phenomenon. We also find that ocean heat fluxes are more efficient than atmospheric heat fluxes to melt Arctic sea ice. 相似文献
93.
Stereoselective Fluorination Alters the Geometry of a Cyclic Peptide: Exploration of Backbone‐Fluorinated Analogues of Unguisin A
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Dr. Xiang‐Guo Hu Dr. Donald S. Thomas Prof. Renate Griffith Dr. Luke Hunter 《Angewandte Chemie (International ed. in English)》2014,53(24):6176-6179
New methods for enhancing the efficiency of peptide cyclization, and for fine‐tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogues of the natural cyclic heptapeptide unguisin A have been efficiently synthesized. The analogues are found to adopt dramatically different secondary structures, controlled by the fluorine stereochemistry. 相似文献
94.
95.
Recently the replica limit n = 0 of the U(n) and U(n)/SO(n) models have attracted interest since they describe the Anderson localization behaviour in the band-centre of a two-sublattice model. For n ≠ 0 the theories can be decomposed into one with symmetry U(1) and one for SU(n) and U(n)/SO(n). This does not no longer hold for n = 0. We show how the beta-functions and zeta-functions for operators without derivatives can be obtained in this limit from those of SU(n) and U(n)/SO(n) and draw consequences for these functions in this limit. 相似文献
96.
Abstract— Aqueous solutions of 3-carbethoxypsoralen (3-CPs) induce lysis of egg lecithin liposomes and whole human erythrocytes in the dark. Near-UV irradiation of 3-CPs sensitizes the inactivation of lysozyme attributed to the production of reactive radical intermediates. The implications of these findings for the use of 3-CPs as a sensitizer in PUVA therapy of psoriasis are discussed. 相似文献
97.
98.
Friedrich MG Kirste VU Zhu J Gennis RB Knoll W Naumann RL 《The journal of physical chemistry. B》2008,112(10):3193-3201
A systematic study of the influence of the packing density of proteins on their activity is performed with cytochrome c oxidase (CcO) from R. sphaeroides as an example. The protein was incorporated into a protein-tethered bilayer lipid membrane and CcO was genetically engineered with a histidine-tag, attached to Subunit II, and then tethered by an interaction with functionalized thiol compounds bound to a gold electrode. The packing density was varied by diluting the functionalized thiol with a nonfunctionalized thiol that does not bind to the enzyme. After attaching the CcO to the gold surface, a lipid bilayer was formed to incorporate the tethered proteins. The reconstituted protein-lipid bilayer was characterized by surface enhanced infrared reflection absorption spectroscopy (SEIRAS), electrochemical impedance spectroscopy, surface plasmon resonance, and atomic force microscopy. The activity of the proteins within the reconstituted bilayer was probed by direct electrochemical electron injection and was shown to be very sensitive to the packing density of protein molecules. At low surface density of CcO, the bilayer did not effectively form, and protein aggregates were observed, whereas at very high surface density, very little lipid is able to intrude between the closely packed proteins. In both of these cases, redox activity, measured by the efficiency to accept electrons, is low. Redox activity of the enzyme is preserved in the biomimetic structure but only at a moderate surface coverage in which a continuous lipid bilayer is present and the proteins are not forced to aggregate. Electrostatic and other interaction forces between protein molecules are held responsible for these effects. 相似文献
99.
Ganzevles RA Fokkink R van Vliet T Cohen Stuart MA de Jongh HH 《Journal of colloid and interface science》2008,317(1):137-147
Based on earlier reported surface rheological behaviour two factors appeared to be important for the functional behaviour of mixed protein/polysaccharide adsorbed layers at air/water interfaces: (1) protein/polysaccharide mixing ratio and (2) formation history of the layers. In this study complexes of beta-lactoglobulin (positively charged at pH 4.5) and low methoxyl pectin (negatively charged) were formed at two mixing ratios, resulting in negatively charged and nearly neutral complexes. Neutron reflection showed that adsorption of negative complexes leads to more diffuse layers at the air/water interface than adsorption of neutral complexes. Besides (simultaneous) adsorption of protein/polysaccharide complexes, a mixed layer can also be formed by adsorption of (protein/)polysaccharide (complexes) to a pre-formed protein layer (sequential adsorption). Despite similar bulk concentrations, adsorbed layer density profiles of simultaneously and sequentially formed layers were persistently different, as illustrated by neutron reflection analysis. Time resolved fluorescence anisotropy showed that the mobility of protein molecules at an air/water interface is hampered by the presence of pectin. This hampered mobility of protein through a complex layer could account for differences observed in density profiles of simultaneously and sequentially formed layers. These insights substantiated the previously proposed organisations of the different adsorbed layers based on surface rheological data. 相似文献
100.
Christine Willemann Reiner Waibel Reinhard Troschütz Renate Grünert Patrick Bednarski 《Journal of heterocyclic chemistry》2008,45(5):1517-1519