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Nicolas Levoin Olivier Labeeuw Stéphane Krief Thierry Calmels Olivia Poupardin-Olivier Isabelle Berrebi-Bertrand Jeanne-Marie Lecomte Jean-Charles Schwartz Marc Capet 《Bioorganic & medicinal chemistry》2013,21(15):4526-4529
Due to its involvement in major CNS functions, the histamine H3 receptor (H3R) is the subject of intensive medicinal chemistry investigation, supported by the range of modern drug discovery tools, such as receptor modeling and ligand docking. Although the receptor models described to date share a majority of common traits, they display discrete alternatives in amino-acid conformation, rendering ligand binding modes quite different. Such variations impede structure-based drug design in the H3R field. In the present study, we used a combination of medicinal chemistry, receptor-guided and ligand-based methods to elucidate the binding mode of antagonists. The approaches converged towards a ligand orientation perpendicular to the membrane plane, bridging Glu206 of the transmembrane helix 5 to acidic amino acids of the extracellular loops. This consensus will help future structure-based drug design for H3R ligands. 相似文献
23.
Constance Delaby Vincent Oustric Caroline Schmitt Francoise Muzeau Anne-Marie Robreau Philippe Letteron Eric Couchi Angel Yu Saïd Lyoumi Jean-Charles Deybach Herve Puy Zoubida Karim Carole Beaumont Bernard Grandchamp Peter Demant Laurent Gouya 《Mammalian genome》2013,24(11-12):427-438
Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders. 相似文献
24.
Lucien David Jean-Charles Gayet Henri Veschambre 《Bioscience, biotechnology, and biochemistry》2013,77(9):2693-2698
Oxydative cyclization of lapachol was attempted by feeding this compound into the culture broth of Beauveria sulfurescens and two ionophore-producing strains of Streptomyces albus and Streptomyces griseus. As a result, three compounds were obtained, lomatiol, lomatic acid and lomatiol acetate, only with B. sulfurescens and S. albus. The structures of these products were determinated by NMR and mass spectrometry. The stereochemistry is given by a comparison with butene analogs. 相似文献
25.
Feng Liu Leona Bessonova Thomas H. Taylor Argyrios Ziogas Frank L. Meyskens Jr. Hoda Anton‐Culver 《Pigment cell & melanoma research》2013,26(1):128-135
Using US SEER17 Registry data, age‐specific melanoma incidence rates were calculated and comparisons were made between males and females. Relative Risk (RR) for males and females in each age group was computed and compared with that from Nordic Cancer Registry data set and to that for non‐melanoma skin cancer (NMSC). For age groups 44 and younger, females showed higher incidence rates, with a peak difference at age 20–24 (RR = 2.01, 95% CI = 1.21–3.33). Males exhibited higher incidence rates after age 44. The same bimodal gender difference was confirmed by the Nordic Cancer Registry data set, but it was not observed for NMSC, which is known to be strongly associated with cumulative exposure to solar UV radiation. We conclude that exposure to solar ultraviolet (UV) radiation is the major causative factor for melanoma at older age (>44 yr), but that other factors may play a role in early onset melanomas, particularly in females. 相似文献
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Sheng-Da Zhang Claire-Lise Santini Wei-Jia Zhang Valérie Barbe Sophie Mangenot Charlotte Guyomar Marc Garel Hai-Tao Chen Xue-Gong Li Qun-Jian Yin Yuan Zhao Jean Armengaud Jean-Charles Gaillard Séverine Martini Nathalie Pradel Claude Vidaud François Alberto Claudine Médigue Christian Tamburini Long-Fei Wu 《Extremophiles : life under extreme conditions》2016,20(3):301-310
Bacteria of the genus Photobacterium thrive worldwide in oceans and show substantial eco-physiological diversity including free-living, symbiotic and piezophilic life styles. Genomic characteristics underlying this variability across species are poorly understood. Here we carried out genomic and physiological analysis of Photobacterium phosphoreum strain ANT-2200, the first deep-sea luminous bacterium of which the genome has been sequenced. Using optical mapping we updated the genomic data and reassembled it into two chromosomes and a large plasmid. Genomic analysis revealed a versatile energy metabolic potential and physiological analysis confirmed its growth capacity by deriving energy from fermentation of glucose or maltose, by respiration with formate as electron donor and trimethlyamine N-oxide (TMAO), nitrate or fumarate as electron acceptors, or by chemo-organo-heterotrophic growth in rich media. Despite that it was isolated at a site with saturated dissolved oxygen, the ANT-2200 strain possesses four gene clusters coding for typical anaerobic enzymes, the TMAO reductases. Elevated hydrostatic pressure enhances the TMAO reductase activity, mainly due to the increase of isoenzyme TorA1. The high copy number of the TMAO reductase isoenzymes and pressure-enhanced activity might imply a strategy developed by bacteria to adapt to deep-sea habitats where the instant TMAO availability may increase with depth. 相似文献
28.
FXR-deficiency confers increased susceptibility to torpor 总被引:1,自引:0,他引:1
Cariou B Bouchaert E Abdelkarim M Dumont J Caron S Fruchart JC Burcelin R Kuipers F Staels B 《FEBS letters》2007,581(27):5191-5198
The role of the nuclear receptor FXR in adaptive thermogenesis was investigated using FXR-deficient mice. Despite elevated serum bile acid concentrations and increased mRNA expression profiles of thermogenic genes in brown adipose tissue, FXR-deficiency did not alter energy expenditure under basal conditions. However, FXR-deficiency accelerated the fasting-induced entry into torpor in a leptin-dependent manner. FXR-deficient mice were also extremely cold-intolerant. These altered responses may be linked to a more rapid decrease in plasma concentrations of metabolic fuels (glucose, triglycerides) thus impairing uncoupling protein 1-driven thermogenesis. These results identify FXR as a modulator of energy homeostasis. 相似文献
29.
Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis 总被引:1,自引:0,他引:1 下载免费PDF全文
Crawford NP Qian X Ziogas A Papageorge AG Boersma BJ Walker RC Lukes L Rowe WL Zhang J Ambs S Lowy DR Anton-Culver H Hunter KW 《PLoS genetics》2007,3(11):e214
A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis. 相似文献
30.
Genome sequence of Babesia bovis and comparative analysis of apicomplexan hemoprotozoa 总被引:1,自引:0,他引:1
Brayton KA Lau AO Herndon DR Hannick L Kappmeyer LS Berens SJ Bidwell SL Brown WC Crabtree J Fadrosh D Feldblum T Forberger HA Haas BJ Howell JM Khouri H Koo H Mann DJ Norimine J Paulsen IT Radune D Ren Q Smith RK Suarez CE White O Wortman JR Knowles DP McElwain TF Nene VM 《PLoS pathogens》2007,3(10):1401-1413