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771.
772.
Martin Marek Srinivasaraghavan Kannan Alexander-Thomas Hauser Marina Moraes Mour?o Stéphanie Caby Vincent Cura Diana A. Stolfa Karin Schmidtkunz Julien Lancelot Luiza Andrade Jean-Paul Renaud Guilherme Oliveira Wolfgang Sippl Manfred Jung Jean Cavarelli Raymond J. Pierce Christophe Romier 《PLoS pathogens》2013,9(9)
The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical α/β HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens. 相似文献
773.
Formation of poly-beta-hydroxybutyrate by Actinomycetes 总被引:4,自引:0,他引:4
774.
Control of human airway smooth muscle: in vitro studies 总被引:9,自引:0,他引:9
Davis C.; Kannan M. S.; Jones T. R.; Daniel E. E. 《Journal of applied physiology》1982,53(5):1080-1087
775.
776.
Joe Collis Anthony J. Connor Marcin Paczkowski Pavitra Kannan Joe Pitt-Francis Helen M. Byrne Matthew E. Hubbard 《Bulletin of mathematical biology》2017,79(4):939-974
In this work, we present a pedagogical tumour growth example, in which we apply calibration and validation techniques to an uncertain, Gompertzian model of tumour spheroid growth. The key contribution of this article is the discussion and application of these methods (that are not commonly employed in the field of cancer modelling) in the context of a simple model, whose deterministic analogue is widely known within the community. In the course of the example, we calibrate the model against experimental data that are subject to measurement errors, and then validate the resulting uncertain model predictions. We then analyse the sensitivity of the model predictions to the underlying measurement model. Finally, we propose an elementary learning approach for tuning a threshold parameter in the validation procedure in order to maximize predictive accuracy of our validated model. 相似文献
777.
The phytoplankton biomass was estimated in terms of chlorophyll in Sathiar reservoir. The chlorophyll values were high during the low water phase in the reservoir which was also the period of summer. Following the rains and increase in water depth phytoplankton biomass decreases on account of (a) dilution, (b) loss from the reservoir through the outlets and (c) settling to the bottom along with silt. The diel variations of chlorophyll showed that the peak value was reached mostly at 12 noon due to the migration of phytoplankton to the surface. 相似文献
778.
Restriction of glucosyl-free HMC-DNA mediated by RglB is alleviated inrecBC sbcA strains ofEscherichia coli K12. Mutation in the unlinkedrra gene reverses thisrecBC sbcA-mediated alleviation. The map position ofrra is 90.16 min on the standard map, and therra
+ gene product counteracts Rgl restriction. The activation of therra gene is controlled by thesbcA gene, and this regulation does not seem to require the involvement of other gene functions. 相似文献
779.
780.
Subburaj Kannan 《Theoretical biology & medical modelling》2006,3(1):22-16