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81.
John G. Mina Jackie A. Mosely Hayder Z. Ali Hosam Shams-Eldin Ralph T. Schwarz Patrick G. Steel Paul W. Denny 《The international journal of biochemistry & cell biology》2010,42(9):1553-1561
Sphingolipids are key components of eukaryotic membranes, particularly the plasma membrane. The biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals, which produce sphingomyelin, organisms such as the pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) as the primary phosphosphingolipid. The key step involves the reaction of ceramide and phosphatidylinositol catalysed by IPC synthase, an essential enzyme with no mammalian equivalent encoded by the AUR1 gene in yeast and recently identified functional orthologues in the pathogenic kinetoplastid protozoa. As such this enzyme represents a promising target for novel anti-fungal and anti-protozoal drugs. Given the paucity of effective treatments for kinetoplastid diseases such as leishmaniasis, there is a need to characterize the protozoan enzyme. To this end a fluorescent-based cell-free assay protocol in a 96-well plate format has been established for the Leishmania major IPC synthase. Using this system the kinetic parameters of the enzyme have been determined as obeying the double displacement model with apparent Vmax = 2.31 pmol min?1 U?1. Furthermore, inhibitory substrate analogues have been identified. Importantly this assay is amenable to development for use in high-throughput screening applications for lead inhibitors and as such may prove to be a pivotal tool in drug discovery. 相似文献
82.
Genotoxicity of non-covalent interactions: DNA intercalators 总被引:1,自引:0,他引:1
This review provides an update on the mutagenicity of intercalating chemicals, as carried out over the last 17 years. The most extensively studied DNA intercalating agents are acridine and its derivatives, that bind reversibly but non-covalently to DNA. These are frameshift mutagens, especially in bacteria and bacteriophage, but do not otherwise show a wide range of mutagenic properties. Di-acridines or di-quinolines may be either mono- or bis-intercalators, depending upon the length of the alkyl chain separating the chromophores. Those which monointercalate appear as either weak frameshift mutagens in bacteria, or as non-mutagens. However, some of the bisintercalators act as "petite" mutagens in Saccharomyces cerevisiae, suggesting that they may be more likely to target mitochondrial as compared with nuclear DNA. Some of the new methodologies for detecting intercalation suggest this may be a property of a wider range of chemicals than previously recognised. For example, quite a number of flavonoids appear to intercalate into DNA. However, their mutagenic properties may be dominated by the fact that many of them are also able to inhibit topoisomerase II enzymes, and this property implies that they will be potent recombinogens and clastogens. DNA intercalation may serve to position other, chemically reactive molecules, in specific ways on the DNA, leading to a distinctive (and wider) range of mutagenic properties, and possible carcinogenic potential. 相似文献
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Skin pigmentation is a human phenotype that varies greatly among human populations and it has long been speculated that this
variation is adaptive. We therefore expect the genes that contribute to these large differences in phenotype to show large
allele frequency differences among populations and to possibly harbor signatures of positive selection. To identify the loci
that likely contribute to among-population human skin pigmentation differences, we measured allele frequency differentiation
among Europeans, Chinese and Africans for 24 human pigmentation genes from 2 publicly available, large scale SNP data sets.
Several skin pigmentation genes show unusually large allele frequency differences among these populations. To determine whether
these allele frequency differences might be due to selection, we employed a within-population test based on long-range haplotype
structure and identified several outliers that have not been previously identified as putatively adaptive. Most notably, we
identify the DCT gene as a candidate for recent positive selection in the Chinese. Moreover, our analyses suggest that it is likely that different
genes are responsible for the lighter skin pigmentation found in different non-African populations.
Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. 相似文献
85.
Harris RB Mitchell TD Kelso EW Flatt WP 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(1):R106-R115
Loss of body fat in leptin-treated animals has been attributed to reduced energy intake, increased thermogenesis, and preferential fatty acid oxidation. Leptin does not decrease food intake or body fat in leptin-resistant high-fat (HF)-fed mice, possibly due to a failure of leptin to activate hypothalamic receptors. We measured energy expenditure of male C57BL/6 mice adapted to low-fat (LF) or HF diet and infused them for 13 days with PBS or 10 mug leptin/day from an intraperitoneal mini-osmotic pump to test whether leptin resistance prevented leptin-induced increases in energy expenditure and fatty acid oxidation. There was no effect of low-dose leptin infusions on either of these measures in LF-fed or HF-fed mice, even though LF-fed mice lost body fat. Experiment 2 tested leptin responsiveness in LF-fed and HF-fed mice housed at different temperatures (18 degrees C, 23 degrees C, 27 degrees C), assuming that the cold would increase and the hot environment would inhibit food intake and thermogenesis, which could potentially interfere with leptin action. LF-fed mice housed at 23 degrees C were the only mice that lost body fat during leptin infusion, suggesting that an ability to modify energy expenditure is essential to the maintenance of leptin responsiveness. HF-fed mice in cold or warm environments did not respond to leptin. HF-fed mice in the hot environment were fatter than other HF-fed mice, and, surprisingly, leptin caused a further increase in body fat, demonstrating that the mice were not totally leptin resistant and that partial leptin resistance in a hot environment favors positive energy balance and fat deposition. 相似文献
86.
Kendall JD Rewcastle GW Frederick R Mawson C Denny WA Marshall ES Baguley BC Chaussade C Jackson SP Shepherd PR 《Bioorganic & medicinal chemistry》2007,15(24):7677-7687
A series of 2-methyl-5-nitrobenzenesulfonohydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110α isoform over p110β and p110δ, and also demonstrates good in vitro activity in a cell proliferation assay. Molecular modelling provides a rationalisation for the observed SAR. 相似文献
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C.I. Morse J. Smith A. Denny J. Tweedale N.D. Searle 《Journal of musculoskeletal & neuronal interactions》2015,15(2):154-160