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61.
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am Ende CW Knudson SE Liu N Childs J Sullivan TJ Boyne M Xu H Gegina Y Knudson DL Johnson F Peloquin CA Slayden RA Tonge PJ 《Bioorganic & medicinal chemistry letters》2008,18(10):3029-3033
Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values. 相似文献
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Response to treatment in hereditary metabolic disease: 1993 survey and 10-year comparison. 总被引:1,自引:1,他引:0
Knowledge about cause, pathogenesis, and manifestations of hereditary metabolic diseases puts them among the best known of all human diseases. On the other hand, outcomes of treatment are cause for uncertainty and concern. In 1985, Hayes et al. analyzed efficacy of treatment up to 1983 in 65 of these diseases selected randomly from the McKusick catalogs. Disease scores were calculated for seven parameters: longevity; reproductive capability; somatic and cognitive development; and handicaps affecting schooling, work, and cosmetic appearance. Scores of the untreated and treated phenotypes were then compared. We have now measured progress over the past decade by calculating scores on the same 65 diseases from data in several hundred new reports published since 1983. All seven parameters in the 1993 survey reflect improved efficacy of treatment in the 10-year interval. However, the percent of diseases for which all manifestations of the disease were removed by treatment has not changed (12% in 1983; 12% in 1993). The group in which manifestations were untouched by treatment has become smaller (48% in 1983; 31% in 1993), and the group partially ameliorated by treatment had increased reciprocally (40% in 1983; 57% in 1993). Progress in the treatment of hereditary metabolic disease is thus better than it was, but it is still only a partial success. The advances are attributable to greater success with organ and tissue transplantation, better pharmacotherapy, and better support systems. Restoration of normal homeostasis, the key to successful treatment, remains an elusive challenge and is a logical, major focus for research in human genetics. 相似文献
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Ultrafast excited-state dynamics in the green fluorescent protein variant S65T/H148D. 1. Mutagenesis and structural studies 总被引:1,自引:0,他引:1
Shu X Kallio K Shi X Abbyad P Kanchanawong P Childs W Boxer SG Remington SJ 《Biochemistry》2007,46(43):12005-12013
Wild type green fluorescent protein (wt-GFP) and the variant S65T/H148D each exhibit two absorption bands, A and B, which are associated with the protonated and deprotonated chromophores, respectively. Excitation of either band leads to green emission. In wt-GFP, excitation of band A ( approximately 395 nm) leads to green emission with a rise time of 10-15 ps, due to excited-state proton transfer (ESPT) from the chromophore hydroxyl group to an acceptor. This process produces an anionic excited-state intermediate I* that subsequently emits a green photon. In the variant S65T/H148D, the A band absorbance maximum is red-shifted to approximately 415 nm, and as detailed in the accompanying papers, when the A band is excited, green fluorescence appears with a rise time shorter than the instrument time resolution ( approximately 170 fs). On the basis of the steady-state spectroscopy and high-resolution crystal structures of several variants described herein, it is proposed that in S65T/H148D, the red shift of absorption band A and the ultrafast appearance of green fluorescence upon excitation of band A are due to a very short (相似文献
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70.
Keith F. Childs Xue-Han Ning Steven F. Bolling 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1996,678(2):181
A new simple, simultaneous matrix HPLC methodology was developed to facilitate better peak separability and resolution for the determination of levels of myocardial tissue nucleotides, nucleosides and oxidative metabolites. The components of interests were ATP, AMP, ADP, IMP, hypoxanthine, xanthine, adenosine, inosine, NAD, and NADH, which are used to establish myocardial cellular energy status and effectiveness of cardioprotection. Their detection was achieved using a 4-μm spherical bead, 300 × 3.9 mm I.D. Nova-Pak C18 column in a 12% methanol mobile phase solvent selection, ion-pairing reagents 1.47 mM TBAP (tetrabutylammonium phosphate) and 73.5 mM KH2PO4, at a pH of 4.0. The extraction method was modified for rapid determination to ensure diminished acid labile NADH effects. Comparisons of peak retention (k), resolution (Rs) of solvents of varying concentrations and pH adjustments facilitated this method. This isocratic single run determination allows for simple, simultaneous rapid quantification and identification of alterations in high-energy phosphates, nucleoside degradation products and NAD/NADH levels associated with myocardial ischemia, with excellent reliability. 相似文献