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841.
Crystal structures of the catalytic subunit α of cAMP-dependent protein kinase (PKAc) with three adenosine analogue-oligoarginine conjugates (ARCs) are presented. The rationally designed ARCs include moieties that, in combination, target both the ATP- and the peptide-substrate-binding sites of PKAc, thereby taking advantage of high-affinity binding interactions offered by the ATP site while utilizing an additional mechanism for target specificity via binding to the peptide substrate site. The crystal structuresdemonstrate that, in accord with the previously reported bisubstrate character of ARCs, the inhibitors occupy both binding sites of PKAc. Further, they show new binding modes that may also apply to natural protein substrates of PKAc, which have not been revealed by previous crystallographic studies. The crystal structures described here contribute to the understanding of the substrate-binding patterns of PKAc and should also facilitate the design of inhibitors targeting PKAc and related protein kinases. 相似文献
842.
Electrophoretically homogenous isoforms of malate dehydrogenase with different quaternary structure were prepared from Rhodopseudomonas palustris strain f8pt cultured photolithoheterotrophically on malate and acetate. By selective inhibition of the tricarboxylic acid cycle or glyoxylate cycle, it was shown that the dimeric isoform of the enzyme is responsible for Krebs cycle functioning and the tetrameric isoform is involved in functioning of the glyoxylate cycle. 相似文献
843.
A novel polarographic method for the determination of coenzyme Q(10) in beta-cyclodextrin (beta-CD) and iodinate system is proposed. The stability of coenzyme Q(10) to light was improved by the formation of coenzyme Q(10)-beta-CD inclusion complex. In addition, the sensitivity for the determination of coenzyme Q(10) was enhanced by both the formation and the polarographic catalytic wave of the inclusion complex in the presence of iodinate. In 0.1 mol/L HAc-NaAc (pH 4.7)-5.0 x 10(-5) mol/L beta-CD-1.2 x 10(-3) mol/L potassium iodinate-ethanol/water (60:40, v/v) medium, coenzyme Q(10)-beta-CD inclusion complex yielded a sensitive association/parallel catalytic wave. The second-order derivative peak current of the catalytic wave was proportional to coenzyme Q(10) concentration in the range of 6.0 x 10(-8)-2.5 x 10(-7) mol/L, and the detection limit was 1.0 x 10(-8) mol/L. The proposed method has high analytical sensitivity and is allowed to determine coenzyme Q(10) under light. 相似文献
844.
845.
Kucharova K Lukacova N Pavel J Radonak J Hefferan MP Kolesar D Kolesarova M Marsala M Marsala J 《Cellular and molecular neurobiology》2006,26(7-8):1293-1308
1. Brief interruption of spinal cord blood flow resulting from transient abdominal aortic occlusion may lead to degeneration of specific spinal cord neurons and to irreversible loss of neurological function. The alteration of nitric oxide/nitric oxide synthase (NO/NOS) pool occurring after ischemic insult may play a protective or destructive role in neuronal survival of affected spinal cord segments.2. In the present study, the spatiotemporal changes of NOS following transient ischemia were evaluated by investigating neuronal NOS immunoreactivity (nNOS-IR), reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry, and calcium-dependent NOS (cNOS) conversion of [3H] l-arginine to [3H] l-citrulline.3. The greatest levels of these enzymes and activities were detected in the dorsal horn, which appeared to be most resistant to ischemia. In that area, the first significant increase in NADPHd staining and cNOS catalytic activity was found immediately after a 15-min ischemic insult.4. Increases in the ventral horn were observed later (i.e., after a 24-h reperfusion period). While the most intense increase in nNOS-IR was detected in surviving motoneurons of animals with a shorter ischemic insult (13 min), the greatest increase of cNOS catalytic activity and NADPHd staining of the endothelial cells was found after stronger insult (15 min).5. Given that the highest levels of nNOS, NADPHd, and cNOS were found in the ischemia-resistant dorsal horn, and nNOS-IR in surviving motoneurons, it is possible that NO production may play a neuroprotective role in ischemic/reperfusion injury. 相似文献
846.
Osmotic flow through asymmetric membrane: A means for controlled delivery of drugs with varying solubility 总被引:1,自引:0,他引:1
A nondisintegrating, controlled release, asymmetric membrane capsular system of flurbiprofen was developed and evaluated for
controlled release of the drug to overcome some of its side effects. Asymmetric membrane capsules were prepared using fabricated
glass mold pins by phase inversion process. The effect of different formulation variables was studied based on 23 factorial design; namely, level of osmogen, membrane thickness, and level of pore former. Effects of polymer diffusibility
and varying osmotic pressure on drug release were also studied. Membrane characterization by scanning electron microscopy
showed an outer dense region with less pores and an inner porous region for the prepared asymmetric membrane. Differential
scanning calorimetry studies showed no incompatibility between the drug and the excipients used in the study. In vitro release
studies for all the prepared formulations were done (n=6). Statistical test (Dunnett multiple comparison test) was applied for in vitro drug release atP>.05. The best formulation closely corresponded to the extra design checkpoint formulation by a similarity (f2) value of 92.94. The drug release was independent of pH but dependent on the osmotic pressure of the dissolution medium.
The release kinetics followed the Higuchi model and the mechanism of release was Fickian diffusion.
Published: July 7, 2006 相似文献
847.
微生物酶转化合成手性药物的研究进展 总被引:1,自引:0,他引:1
通过微生物酶催化不对称合成反应或拆分外消旋体合成医药手性中间体具有独特的优势。结合作者自身近年来在该技术领域的实践对相关课题作了介绍,总结了微生物酶催化不对称反应和拆分反应得到手性药物的研究进展。 相似文献
848.
Phytochromes are light-sensing macromolecules that are part of a two component phosphorelay system controlling gene expression. Photoconversion between the Pr and Pfr forms facilitates autophosphorylation of a histidine in the dimerization domain (DHp). We report the low-resolution structure of a bacteriophytochrome (Bph) in the catalytic (CA) Pr form in solution determined by small-angle X-ray scattering (SAXS). Ab initio modeling reveals, for the first time, the domain organization in a typical bacteriophytochrome, comprising an chromophore binding and phytochrome (PHY) N terminal domain followed by a C terminal histidine kinase domain. Homologous high-resolution structures of the light-sensing chromophore binding domain (CBD) and the cytoplasmic part of a histidine kinase sensor allows us to model 75% of the structure with the remainder comprising the phytochrome domain which has no 3D representative in the structural database. The SAXS data reveal a dimeric Y shaped macromolecule and the relative positions of the chromophores (biliverdin), autophosphorylating histidine residues and the ATP molecules in the kinase domain. SAXS data were collected from a sample in the autophosphorylating Pr form and reveal alternate conformational states for the kinase domain that can be modeled in an open (no-catalytic) and closed (catalytic) state. This model suggests how light-induced signal transduction can stimulate autophosphorylation followed by phosphotransfer to a response regulator (RR) in the two-component system. 相似文献
849.
Calderone V Forleo C Benvenuti M Thaller MC Rossolini GM Mangani S 《Journal of molecular biology》2006,355(4):708-721
The Escherichia coli gene aphA codes for a periplasmic acid phosphatase called AphA, belonging to class B bacterial phosphatases, which is part of the DDDD superfamily of phosphohydrolases. After our first report about its crystal structure, we have started a series of crystallographic studies aimed at understanding of the catalytic mechanism of the enzyme. Here, we report three crystal structures of the AphA enzyme in complex with the hydrolysis products of nucleoside monophosphate substrates and a fourth with a proposed intermediate analogue that appears to be covalently bound to the enzyme. Comparison with the native enzyme structure and with the available X-ray structures of different phosphatases provides clues about the enzyme chemistry and allows us to propose a catalytic mechanism for AphA, and to discuss it with respect to the mechanism of other bacterial and human phosphatases. 相似文献
850.
Many secondary metabolic peptides from bacteria and fungi are produced by non-ribosomal peptide synthetases (NRPS) where the final step of biosynthesis is often catalysed by designated thioesterase domains. Here, we report the 1.8A crystal structure of the fengycin thioesterase (FenTE) from Bacillus subtilis F29-3, which catalyses the regio- and stereoselective release and macrocyclization of the antibiotic fengycin from the NRPS template. A structure of the PMSF-inactivated FenTE domain suggests the location of the oxyanion hole and the binding site of the C-terminal residue l-Ile11 of the lipopeptide. Using a combination of docking, molecular dynamics simulations and in vitro activity assays, a model of the FenTE-fengycin complex was derived in which peptide cyclization requires strategic interactions with residues lining the active site canyon. 相似文献