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31.
The examination of specific disease mortality by five-year age groups helps identify health problems as problems of people and how they live. Traditional methods of examining data in broad classifications tend to obscure etiological factors and the importance of behaviour. Violence, a major cause of death in young adults, gives way to so-called diseases of indulgence in middle age, especially among men who have a much higher death rate than women. Male life expectancy at age 40 has increased only marginally in the past 40 years. Health-related human behaviour must be considered within an ecological framework since social, cultural and physical environmental differences as well as personal factors influence life-style. The responsibility for prevention rests more with the individual and society at large than with health workers. Probability tables, Health Hazard Appraisal (a system of personal risk assessment) and personal counselling can reinforce healthful life-styles and help correct hazardous ones. 相似文献
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The tissue inhibitor of metalloproteinases-3 (TIMP-3) gene is specifically down-regulated in neoplastic cells of the mouse JB6 progression model, suggesting a role for TIMP-3 inactivation in neoplastic progression. On the basis of 5-azacytidine reversal, the mechanism for this down-regulation appears to involve changes in the methylation state of the TIMP-3 promoter. Although total genomic methylation levels are comparable, specific differences in the methylation of the TIMP-3 promoter were observed between preneoplastic and neoplastic JB6 cells at three Hpall sites, with preneoplastic cells being less methylated. Expression of antisense methyltransferase in a neoplastic JB6 variant known to be hypermethylated in TIMP-3 resulted in reactivation of the endogenous TIMP-3 gene and restoration of hypomethylated status to the three implicated Hpall sites. Thus, hypermethylation at specific sequences in the TIMP-3 promoter appears to contribute to the silencing of the gene in neoplastic cells. 相似文献
33.
Matthews JM Qin N Colburn RW Dax SL Hawkins M McNally JJ Reany L Youngman MA Baker J Hutchinson T Liu Y Lubin ML Neeper M Brandt MR Stone DJ Flores CM 《Bioorganic & medicinal chemistry letters》2012,22(8):2922-2926
A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model. 相似文献
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Tobias Schmid Johanna S. Blees Magdalena M. Bajer Janine Wild Luca Pescatori Giuliana Cuzzucoli Crucitti Luigi Scipione Roberta Costi Curtis J. Henrich Bernhard Brüne Nancy H. Colburn Roberto Di Santo 《PloS one》2016,11(3)
The translation inhibitor and tumor suppressor Pdcd4 was reported to be lost in various tumors and put forward as prognostic marker in tumorigenesis. Decreased Pdcd4 protein stability due to PI3K-mTOR-p70S6K1 dependent phosphorylation of Pdcd4 followed by β-TrCP1-mediated ubiquitination, and proteasomal destruction of the protein was characterized as a major mechanism contributing to the loss of Pdcd4 expression in tumors. In an attempt to identify stabilizers of Pdcd4, we used a luciferase-based high-throughput compatible cellular assay to monitor phosphorylation-dependent proteasomal degradation of Pdcd4 in response to mitogen stimulation. Following a screen of approximately 2000 compounds, we identified 1,2-bis(4-chlorophenyl)disulfide as a novel Pdcd4 stabilizer. To determine an initial structure-activity relationship, we used 3 additional compounds, synthesized according to previous reports, and 2 commercially available compounds for further testing, in which either the linker between the aryls was modified (compounds 2–4) or the chlorine residues were replaced by groups with different electronic properties (compounds 5 and 6). We observed that those compounds with alterations in the sulfide linker completely lost the Pdcd4 stabilizing potential. In contrast, modifications in the chlorine residues showed only minor effects on the Pdcd4 stabilizing activity. A reporter with a mutated phospho-degron verified the specificity of the compounds for stabilizing the Pdcd4 reporter. Interestingly, the active diaryl disulfides inhibited proliferation and viability at concentrations where they stabilized Pdcd4, suggesting that Pdcd4 stabilization might contribute to the anti-proliferative properties. Finally, computational modelling indicated that the flexibility of the disulfide linker might be necessary to exert the biological functions of the compounds, as the inactive compound appeared to be energetically more restricted. 相似文献
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INTRODUCTION It has been over twenty years since the onset of the AIDS epidemic, and in spite of the tremendous progress made towards the understanding of the disease, the virus that causes the disease and the development of highly ef- fective anti-retrov… 相似文献
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Calvo RR Meegalla SK Parks DJ Parsons WH Ballentine SK Lubin ML Schneider C Colburn RW Flores CM Player MR 《Bioorganic & medicinal chemistry letters》2012,22(5):1903-1907
Thermosensitive transient receptor potential melastatin 8 (TRPM8) antagonists are considered to be potential therapeutic agents for the treatment of cold hypersensitivity. The discovery of a new class of TRPM8 antagonists that shows in vivo efficacy in the rat chronic constriction injury (CCI)-induced model of neuropathic pain is described. 相似文献
39.
Youngman MA Carson JR Lee JS Dax SL Zhang SP Colburn RW Stone DJ Codd EE Jetter MC 《Bioorganic & medicinal chemistry letters》2003,13(7):1341-1344
The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B(2) receptor antagonists are described. Several members of this series display nanomolar affinity at the B(2) receptor and show activity in an animal model of antinociception. 相似文献
40.