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71.
A model of structure and catalysis for ketoreductase domains in modular polyketide synthases 总被引:7,自引:0,他引:7
Reid R Piagentini M Rodriguez E Ashley G Viswanathan N Carney J Santi DV Hutchinson CR McDaniel R 《Biochemistry》2003,42(1):72-79
A putative catalytic triad consisting of tyrosine, serine, and lysine residues was identified in the ketoreductase (KR) domains of modular polyketide synthases (PKSs) based on homology modeling to the short chain dehydrogenase/reductase (SDR) superfamily of enzymes. This was tested by constructing point mutations for each of these three amino acid residues in the KR domain of module 6 of the 6-deoxyerythronolide B synthase (DEBS) and determining the effect on ketoreduction. Experiments conducted in vitro with the truncated DEBS Module 6+TE (M6+TE) enzyme purified from Escherichia coli indicated that any of three mutations, Tyr --> Phe, Ser --> Ala, and Lys --> Glu, abolish KR activity in formation of the triketide lactone product from a diketide substrate. The same mutations were also introduced in module 6 of the full DEBS gene set and expressed in Streptomyces lividans for in vivo analysis. In this case, the Tyr --> Phe mutation appeared to completely eliminate KR6 activity, leading to the 3-keto derivative of 6-deoxyerythronolide B, whereas the other two mutations, Ser --> Ala and Lys --> Glu, result in a mixture of both reduced and unreduced compounds at the C-3 position. The results support a model analogous to SDRs in which the conserved tyrosine serves as a proton donating catalytic residue. In contrast to deletion of the entire KR6 domain of DEBS, which causes a loss in substrate specificity of the adjacent acyltransferase (AT) domain in module 6, these mutations do not affect the AT6 specificity and offer a potentially superior approach to KR inactivation for engineered biosynthesis of novel polyketides. The homology modeling studies also led to identification of amino acid residues predictive of the stereochemical nature of KR domains. Finally, a method is described for the rapid purification of engineered PKS modules that consists of a biotin recognition sequence C-terminal to the thioesterase domain and adsorption of the biotinylated module from crude extracts to immobilized streptavidin. Immobilized M6+TE obtained by this method was over 95% pure and as catalytically effective as M6+TE in solution. 相似文献
72.
Hutchinson TM Bakulin AV Rakhmanov AS Martin RB Steele CR Arnaud SB 《Journal of medical primatology》2001,30(6):313-321
To determine the effects of the relative inactivity and unloading on the strength of the tibias of monkeys, Macaca mulatta, we used a non-invasive test to measure bending stiffness, or EI (Nm2), a mechanical property. The technique was validated by comparisons of in vivo measurements with standard measures of EI in the same bones post-mortem (r2 = 0.95, P < 0.0001). Inter-test precision was 4.28+/-1.4%. Normative data in 24 monkeys, 3.0+/-0.7 years and 3.6+/-0.6 kg, revealed EI to be 16% higher in the right than left tibia (4.4+/-1.6 vs. 3.7+/-1.6 Nm2, P < 0.05). Five monkeys, restrained in chairs for 14 days, showed decreases in EI. There were no changes in EI in two chaired monkeys that lost weight during a 2-week space flight. The factors that account for both the decreases in bone mechanical properties after chair restraint at 1 g and lack of change after microgravity remain to be identified. Metabolic factors associated with body weight changes are suggested by our results. 相似文献
73.
Nair SV Burandt M Hutchinson A Raison RL Raftos DA 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2001,129(1):11-24
Previous studies have identified proteins from tunicates (invertebrate members of the Phylum Chordata) that have physicochemical and functional properties similar to those of the inflammatory cytokine, interleukin 1 (IL-1). Here we characterize one of those proteins from the tunicate, Styela plicata, that can stimulate tunicate and mammalian cell proliferation, activate phagocytosis, increase interleukin 2 (IL-2) secretion by mammalian peripheral blood mononuclear cells and enhance IL-2 receptor (IL-2R) expression by mammalian EL-4.IL-2 cells. Partial amino acid sequence data showed that the S. plicata protein resembles three C-type lectins (TC14, TC14-1 and TC14-2) from a closely related tunicate species, Polyandrocarpa misakiensis. Its similarity to carbohydrate recognition domains (CRDs) from P. misakiensis lectins suggests that the S. plicata protein modulates the activities of mammalian immunocompetent cells by interacting with carbohydrate moieties of glycosylated cell surface receptors. 相似文献
74.
In this article, we develop a new reconstruction of the pelvic and hindlimb muscles of the large theropod dinosaur Tyrannosaurus rex. Our new reconstruction relies primarily on direct examination of both extant and fossil turtles, lepidosaurs, and archosaurs. These observations are placed into a phylogenetic context and data from extant taxa are used to constrain inferences concerning the soft-tissue structures in T. rex. Using this extant phylogenetic bracket, we are able to offer well-supported inferences concerning most of the hindlimb musculature in this taxon. We also refrain from making any inferences for certain muscles where the resulting optimizations are ambiguous. This reconstruction differs from several previous attempts and we evaluate these discrepancies. In addition to providing a new and more detailed understanding of the hindlimb morphology of T. rex--the largest known terrestrial biped--this reconstruction also helps to clarify the sequence of character-state change along the line to extant birds. 相似文献
75.
Brashear KM Hunt CA Kucer BT Duggan ME Hartman GD Rodan GA Rodan SB Leu CT Prueksaritanont T Fernandez-Metzler C Barrish A Homnick CF Hutchinson JH Coleman PJ 《Bioorganic & medicinal chemistry letters》2002,12(23):3483-3486
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements. 相似文献
76.
Coleman PJ Askew BC Hutchinson JH Whitman DB Perkins JJ Hartman GD Rodan GA Leu CT Prueksaritanont T Fernandez-Metzler C Merkle KM Lynch R Lynch JJ Rodan SB Duggan ME 《Bioorganic & medicinal chemistry letters》2002,12(17):2463-2465
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors. 相似文献
77.
78.
Alexander RP Warrellow GJ Eaton MA Boyd EC Head JC Porter JR Brown JA Reuberson JT Hutchinson B Turner P Boyce B Barnes D Mason B Cannell A Taylor RJ Zomaya A Millican A Leonard J Morphy R Wales M Perry M Allen RA Gozzard N Hughes B Higgs G 《Bioorganic & medicinal chemistry letters》2002,12(11):1451-1456
The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described. Structure-activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC(50) 4nM). CDP840 is non-emetic in the ferret at 30mgkg(-1) (po), active in models of inflammation and reverses ozone-induced bronchial hyperreactivity in the guinea pig. 相似文献
79.
Hutchinson TP Gudlaugsdottir S 《Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology》2002,24(2):121-124
OBJECTIVE: To construct a statistical model for the agreements and disagreements between two observers on darkness of staining. STUDY DESIGN: Data from an earlier observer-agreement study by van Diest et al were reanalyzed. RESULTS: A model in which the random variation in error is permitted to depend upon the true darkness of staining wasfound tofit the data much better than does one in which the random variation is constant. CONCLUSION: For the dataset analyzed, error tends to be greater (that is, correlation between observers tends to be less) when staining is darker. 相似文献
80.
Aojula HS Offerman S Aojula RR Hutchinson AP Nicklin S Clarke DJ 《Biochimica et biophysica acta》2002,1564(1):73-81
Potent cytolytic peptides with specific tethering and cloaking sites have been synthesised and used to release payload from liposomes in a quantitative manner. A functionally located cloaking site has been modified specifically by simple conjugation without adversely affecting the cytolytic properties of the peptide. The cytolytic activity of modified peptides was then efficiently (>98%) cloaked and uncloaked by ligand-protein or hapten-antibody interactions. The principle of a dual response peptide has been demonstrated using an avidin-cloaked pH-sensitive peptide. Biospecific cloaking/uncloaking provided a new sensitive (approximately 12 pmol) homogeneous diagnostic and also appears potentially suited to bioresponsively targeted release of antimicrobial, anticancer and other drugs now delivered using liposomes. 相似文献