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71.
Montagnoli A Valsasina B Croci V Menichincheri M Rainoldi S Marchesi V Tibolla M Tenca P Brotherton D Albanese C Patton V Alzani R Ciavolella A Sola F Molinari A Volpi D Avanzi N Fiorentini F Cattoni M Healy S Ballinari D Pesenti E Isacchi A Moll J Bensimon A Vanotti E Santocanale C 《Nature chemical biology》2008,4(6):357-365
Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics. 相似文献
72.
Luis Fernando da Costa Medina Cassiana Macagnan Viau Dinara Jaqueline Moura Jenifer Saffi Valter Stefani Adriano Brandelli Joo Antonio Pêgas Henriques 《Mutation Research - Genetic Toxicology and Environmental Mutagenesis》2008,650(2):140-149
There are few studies on the biological activity of aminohydroxy derivates of 1,4-naphthoquinone (1,4-NQ) on prokaryotic and eukaryotic cells. We determined the mutagenic activity of 5-amino-8-hydroxy-1,4-naphthoquinone (ANQ) and 5-amino-2,8-dihydroxy-1,4-naphthoquinone (ANQ-OH) as compared to the unsubstituted 1,4-NQ in Salmonella/microsome assay. Potential mutagenic and recombinogenic effects and cytotoxicity were analyzed in haploid and diploid cultures of the yeast Saccharomyces cerevisiae. In Salmonella/microsome assay, 1,4-NQ was not mutagenic, whereas aminohydroxynaphthoquinones were weakly mutagenic in TA98 and TA102 strains. In haploid yeast in stationary growth phase (STAT), mutagenic response was only observed for the hom3 locus at the highest dose. In diploid yeast, aminohydroxynaphthoquinones did not induce any recombinogenic events, but 1,4-NQ was shown to be a recombinogenic agent. These results suggest that aminohydroxynaphthoquinones are weak mutagenic agents only in prokaryotic cells. The cytotoxicity of 1,4-NQ in yeast stationary cells was more significant in diploid cells as compared to that observed in haploid cells. However, ANQ and ANQOH were slightly cytotoxic in all treatments. Genotoxicity of these naphthoquinone compounds was also determined in V79 Chinese hamster lung fibroblast cells using standard Comet, as well as modified Comet assay with the bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (ENDOIII). Both 1,4-NQ and ANQ induced pronounced DNA damage in the standard Comet assay. The genotoxic effect of ANQ-OH was observed only at the highest dose. In presence of metabolic activation all substances showed genotoxic effects on V79 cells. Post-treatment of V79 cells with ENDOIII and FPG proteins did not have a significant effect on ANQ-OH-induced oxidative DNA damage as compared to standard alkaline Comet assay. However, all naphthoquinones were genotoxic in V79 cells in the presence of metabolic activation and post-treatment with enzymes, indicating that all compounds induced oxidative DNA damage in V79 cells. Our data suggest that aminohydroxynaphthoquinone pro-oxidant activity, together with their capability of DNA intercalation, have an important role in mutagenic and genotoxic activities. 相似文献
73.
Juan Manuel Chao de la Barca Nuan-Ting Huang Haihan Jiao Lydie Tessier Cédric Gadras Gilles Simard Riccardo Natoli Guillaume Tcherkez Pascal Reynier Krisztina Valter 《Metabolomics : Official journal of the Metabolomic Society》2017,13(3):22
Introduction
Light is the primary stimulus for vision, but may also cause damage to the retina. Pre-exposing the retina to sub-lethal amount of light (or preconditioning) improves chances for retinal cells to survive acute damaging light stress.Objectives
This study aims at exploring the changes in retinal metabolome after mild light stress and identifying mechanisms that may be involved in preconditioning.Methods
Retinas from 12 rats exposed to mild light stress (1000 lux?×?for 12 h) and 12 controls were collected one and seven days after light stress (LS). One retina was used for targeted metabolomics analysis using the Biocrates p180 kit while the fellow retina was used for histological and immunohistochemistry analysis.Results
Immunohistochemistry confirmed that in this experiment, a mild LS with retinal immune response and minimal photoreceptor loss occurred. Compared to controls, LS induced an increased concentration in phosphatidylcholines. The concentration in some amino acids and biogenic amines, particularly those related to the nitric oxide pathway (like asymmetric dimethylarginine (ADMA), arginine and citrulline) also increased 1 day after LS. 7 days after LS, the concentration in two sphingomyelins and phenylethylamine was found to be higher. We further found that in controls, retina metabolome was different between males and females: male retinas had an increased concentration in tyrosine, acetyl-ornithine, phosphatidylcholines and (acyl)-carnitines.Conclusions
Besides retinal sexual metabolic dimorphism, this study shows that preconditioning is mostly associated with re-organisation of lipid metabolism and changes in amino acid composition, likely reflecting the involvement of arginine-dependent NO signalling.74.
Jean R. S. Vitule Angelo A. Agostinho Valter M. Azevedo-Santos Vanessa S. Daga William R. T. Darwall Daniel B. Fitzgerald Fabrício A. Frehse David J. Hoeinghaus Dilermando P. Lima-Junior André L. B. Magalhães Mário L. Orsi André A. Padial Fernando M. Pelicice Miguel PetrereJr. Paulo S. Pompeu Kirk O. Winemiller 《Biodiversity and Conservation》2017,26(3):757-762
Here we extend a discussion initiated by Toussaint et al. (Sci Rep 6:22125, 2016) concerning the relationship between global patterns of freshwater fish functional diversity (FD) and its vulnerability to human impacts. Based on a set of morphological traits, they concluded that Neotropical freshwater fishes have highest FD, but low vulnerability given high levels of functional redundancy. This conclusion implies that conservation efforts for freshwater fishes should emphasize temperate regions. This perspective is risky, because Toussaint et al.’s study seriously underestimates the full scope of FD, including important ecosystem services provided by fishes in the tropics. We briefly discuss some additional and well-documented aspects of tropical freshwater fish FD and conclude that tropical fish FD is highly vulnerable. 相似文献
75.
Donatella Gentili Massimo Zucchetti Valter Torri Cristiana Sessa Jolanda Jong et al. 《Cancer immunology, immunotherapy : CII》1991,34(1):70-70
Meeting announcement
7th NCI-EORTC symposium on New Drugs in cancer therapy 相似文献76.
Wallace MA Liou LL Martins J Clement MH Bailey S Longo VD Valentine JS Gralla EB 《The Journal of biological chemistry》2004,279(31):32055-32062
Among the phenotypes of Saccharomyces cerevisiae mutants lacking CuZn-superoxide dismutase (Sod1p) is an aerobic lysine auxotrophy; in the current work we show an additional leaky auxotrophy for leucine. The lysine and leucine biosynthetic pathways each contain a 4Fe-4S cluster enzyme homologous to aconitase and likely to be superoxide-sensitive, homoaconitase (Lys4p) and isopropylmalate dehydratase (Leu1p), respectively. We present evidence that direct aerobic inactivation of these enzymes in sod1 Delta yeast results in the auxotrophies. Located in the cytosol and intermembrane space of the mitochondria, Sod1p likely provides direct protection of the cytosolic enzyme Leu1p. Surprisingly, Lys4p does not share a compartment with Sod1p but is located in the mitochondrial matrix. The activity of a second matrix protein, the tricarboxylic acid cycle enzyme aconitase, was similarly lowered in sod1 Delta mutants. We measured only slight changes in total mitochondrial iron and found no detectable difference in mitochondrial "free" (EPR-detectable) iron making it unlikely that a gross defect in mitochondrial iron metabolism is the cause of the decreased enzyme activities. Thus, we conclude that when Sod1p is absent a lysine auxotrophy is induced because Lys4p is inactivated in the matrix by superoxide that originates in the intermembrane space and diffuses across the inner membrane. 相似文献
77.
Valter M. Azevedo-Santos James R. Garcia-Ayala Philip M. Fearnside Francisco A. Esteves Fernando M. Pelicice William F. Laurance Ricardo C. Benine 《Biodiversity and Conservation》2016,25(13):2831-2834
Oil exploitation poses a significant threat to freshwater biodiversity, and future plans to develop petroleum leases in the Amazon Basin should be seem with caution. A series of oil spills have significantly affected biodiversity and human activities in some Amazonian basins, indicating that disturbances by petroleum activities will increase in the region, particularly in upper basins and river headwaters. Measures are needed to reduce the risk of spills and to minimize their impacts. More fundamentally, changes in decision making are needed that give proper weight to these impacts. 相似文献
78.
Arduino Arduini Giovanna Mancinelli Maurizio Belfiglio Jerome DeJulia Valter Damonti Stefano Storto Giorgio Federici 《Neurochemical research》1989,14(1):55-61
The treatment of Lewis rat peritoneal macrophages with p1-nitrophenyl p-guanidinobenzoate (NPGB) inhibited the superoxide anion production stimulated with phorbol myristate acetate (PMA). The addition of NPGB at the time of maximum superoxide generation was still able to block the superoxide release. It appears from these findings that NPGB may block either the activation process of the membrane bound NAD(P)H oxidase or directly on the active enzyme. Other protease inhibitors such as, epsilon-amino caproic acid (EACA), pepstatin, trans aminomethyl cyclohexane carboxylic acid (AMCA), aprotinin, and leupeptin did not inhibit the superoxide release. The superoxide anion release by the xanthine-xanthine oxidase system was not inhibited by NPGB. This finding indicates that NPGB does not itself react with superoxide. It has been also demonstrated that NPGB is a good reactant toward sulfhydryl group. The relevance of these finding to experimental allergic encephalomyelitis (EAE) is discussed. 相似文献
79.
Christoph Krafft Daniela Codrich Gloria Pelizzo Valter Sergo 《Journal of biophotonics》2008,1(2):154-169
Colon tissue constitutes a valid model for the comparative analysis of soft tissue by Raman and Fourier transform infrared (FTIR) imaging because it contains four major tissue types such as muscle tissue, connective tissue, epithelium and nerve cells. Raman microscopic images were recorded in the mapping mode using 785 nm laser excitation and a step size of 10 μm from three regions within a thin section that encompassed mucus, mucosa, submucosa, and longitudinal and circular muscle layers. FTIR microscopic images that were composed of 4, 8 and 9 individual images of 4096 spectra each were recorded from the same regions using a FTIR spectrometer coupled to a microscope with a focal plane array detector. Furthermore, Raman microscopic images were recorded at a step size of 2.5 μm from three ganglia that belong to the myenteric plexus. The results are discussed with respect to lateral resolution, spectral resolution, acquisition time and sensitivity of both modalities. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) 相似文献
80.
Silvana Balzan Renata Del Carratore Giuseppina Nicolini Francesca Forini Valter Lubrano Marcella Simili Pier Alberto Benedetti Giorgio Iervasi 《Cell biochemistry and function》2009,27(5):259-263
Thyroid stimulating hormone (TSH) binds to a specific TSH receptor (TSHR) which activates adenylate cyclase and increases cAMP levels in thyroidal cells. Recent studies have reported the presence of TSH receptor in several extra‐thyroidal cell types, including erythrocytes. We have previously suggested that TSH is able to influence the erythrocyte Na/K‐ATPase ouabain binding properties through a receptor mediated mechanism. The direct interaction of TSH receptor with the Na/K‐pump and a functional role of TSHR in erythrocytes was not demonstrated. The interaction of TSH receptor with Na/K‐pump and a TSHR functional role are not yet demonstrated in erythrocytes. In this study, we examined the interaction between the two receptors after TSH treatment using immunofluorescence coupled to confocal microscopy and a co‐immunoprecipitation technique. The cAMP dependent signalling after TSH treatment was measured to verify TSHR functionality. We found that TSH receptor and Na/K‐ATPase are localized on the membranes of both erythrocytes and erythrocyte ghosts; TSH receptor responds to TSH treatment by increasing intracellular cAMP levels from two to tenfold. In ghost membranes TSH treatment enhances up to three fold co‐localization of TSHR with Na/K‐ATPase and co‐immunoprecipitation confirms their direct physical interaction. In conclusion our results are compatible with the existence, in erythrocytes, of a functional TSHR that interacts with Na/K‐ATPase after TSH treatment, thus suggesting a novel cell signalling pathway, potentially active in local circulatory control. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献