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101.
Escherichia coli O104:H4 was identified as an emerging pathogen during the spring and summer of 2011 and was responsible for a widespread outbreak that resulted in the deaths of 50 people and sickened over 4075. Traditional phenotypic and genotypic assays, such as serotyping, pulsed field gel electrophoresis (PFGE), and multilocus sequence typing (MLST), permit identification and classification of bacterial pathogens, but cannot accurately resolve relationships among genotypically similar but pathotypically different isolates. To understand the evolutionary origins of E. coli O104:H4, we sequenced two strains isolated in Ontario, Canada. One was epidemiologically linked to the 2011 outbreak, and the second, unrelated isolate, was obtained in 2010. MLST analysis indicated that both isolates are of the same sequence type (ST678), but whole-genome sequencing revealed differences in chromosomal and plasmid content. Through comprehensive phylogenetic analysis of five O104:H4 ST678 genomes, we identified 167 genes in three gene clusters that have undergone homologous recombination with distantly related E. coli strains. These recombination events have resulted in unexpectedly high sequence diversity within the same sequence type. Failure to recognize or adjust for homologous recombination can result in phylogenetic incongruence. Understanding the extent of homologous recombination among different strains of the same sequence type may explain the pathotypic differences between the ON2010 and ON2011 strains and help shed new light on the emergence of this new pathogen. 相似文献
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Kendall JD O'Connor PD Marshall AJ Frédérick R Marshall ES Lill CL Lee WJ Kolekar S Chao M Malik A Yu S Chaussade C Buchanan C Rewcastle GW Baguley BC Flanagan JU Jamieson SM Denny WA Shepherd PR 《Bioorganic & medicinal chemistry》2012,20(1):69-85
We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model. 相似文献
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The aging of tissue-specific stem cell and progenitor cell compartments is believed to be central to the decline of tissue and organ integrity and function in the elderly. Here, we examine evidence linking stem cell dysfunction to the pathophysiological conditions accompanying aging, focusing on the mechanisms underlying stem cell decline and their contribution to disease pathogenesis. 相似文献
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Victoria Ng Patrick Tang Frances Jamieson Steven J. Drews Shirley Brown Donald E. Low Caroline C. Johnson David N. Fisman 《EcoHealth》2008,5(4):482-490
Legionella species are increasingly recognized as a cause of both healthcare- and community-acquired pneumonia (so-called “Legionnaire’s
disease”). These pathogens are ubiquitous in the environment, but environmental factors in the occurrence of sporadic legionellosis
remain poorly understood. We analyzed all legionellosis cases identified in the Greater Toronto Area of Ontario from 1978
to 2006, and evaluated seasonal and environmental patterns in legionellosis case occurrence by using both negative binomial
models and case-crossover analysis. A total of 837 cases were reported during the study period. After adjusting for seasonal
effects, changes in the local watershed, rather than weather, were the strongest contributors to legionellosis risk. A 3.6-fold
increase (95% confidence interval (CI), 2.4–5.3) in odds of disease was identified with decreasing watershed levels approximately
4 weeks before case-occurrence. We also found a 33% increase (95% CI, 8–64%) in odds of disease with decreasing lake temperature
during the same period and a 34% increase (95% CI, 14–57%) with increasing humidity 5 weeks before case-occurrence. We conclude
that local watershed ecology influences the risk of legionellosis, notwithstanding the availability of advanced water treatment
capacity in Toronto. Enhancement of risk might occur through direct contamination of water sources or via introduction of
micronutrients or commensal organisms into residential and hospital water supplies. These observations suggest testable hypotheses
for future empiric studies. 相似文献
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