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Julio Casta?o Cristina Morera Borja Sesé Stephanie Boue Carles Bonet-Costa Merce Martí Alicia Roque Albert Jordan Maria J. Barrero 《PloS one》2016,11(2)
The successful use of specialized cells in regenerative medicine requires an optimization in the differentiation protocols that are currently used. Understanding the molecular events that take place during the differentiation of human pluripotent cells is essential for the improvement of these protocols and the generation of high quality differentiated cells. In an effort to understand the molecular mechanisms that govern differentiation we identify the methyltransferase SETD7 as highly induced during the differentiation of human embryonic stem cells and differentially expressed between induced pluripotent cells and somatic cells. Knock-down of SETD7 causes differentiation defects in human embryonic stem cell including delay in both the silencing of pluripotency-related genes and the induction of differentiation genes. We show that SETD7 methylates linker histone H1 in vitro causing conformational changes in H1. These effects correlate with a decrease in the recruitment of H1 to the pluripotency genes OCT4 and NANOG during differentiation in the SETD7 knock down that might affect the proper silencing of these genes during differentiation. 相似文献
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Mar Hernandez-Guillamon Stephanie Mawhirt Silvia Fossati Steven Blais Mireia Pares Anna Penalba Merce Boada Pierre-Olivier Couraud Thomas A. Neubert Joan Montaner Jorge Ghiso Agueda Rostagno 《The Journal of biological chemistry》2010,285(35):27144-27158
Patients carrying mutations within the amyloid-β (Aβ) sequence develop severe early-onset cerebral amyloid angiopathy with some of the related variants manifesting primarily with hemorrhagic phenotypes. Matrix metalloproteases (MMPs) are typically associated with blood brain barrier disruption and hemorrhagic transformations after ischemic stroke. However, their contribution to cerebral amyloid angiopathy-related hemorrhage remains unclear. Human brain endothelial cells challenged with Aβ synthetic homologues containing mutations known to be associated in vivo with hemorrhagic manifestations (AβE22Q and AβL34V) showed enhanced production and activation of MMP-2, evaluated via Multiplex MMP antibody arrays, gel zymography, and Western blot, which in turn proteolytically cleaved in situ the Aβ peptides. Immunoprecipitation followed by mass spectrometry analysis highlighted the generation of specific C-terminal proteolytic fragments, in particular the accumulation of Aβ-(1–16), a result validated in vitro with recombinant MMP-2 and quantitatively evaluated using deuterium-labeled internal standards. Silencing MMP-2 gene expression resulted in reduced Aβ degradation and enhanced apoptosis. Secretion and activation of MMP-2 as well as susceptibility of the Aβ peptides to MMP-2 degradation were dependent on the peptide conformation, with fibrillar elements of AβE22Q exhibiting negligible effects. Our results indicate that MMP-2 release and activation differentially degrades Aβ species, delaying their toxicity for endothelial cells. However, taking into consideration MMP ability to degrade basement membrane components, these protective effects might also undesirably compromise blood brain barrier integrity and precipitate a hemorrhagic phenotype. 相似文献
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Casagrande F Ratera M Schenk AD Chami M Valencia E Lopez JM Torrents D Engel A Palacin M Fotiadis D 《The Journal of biological chemistry》2008,283(48):33240-33248
The L-arginine/agmatine antiporter AdiC is a key component of the arginine-dependent extreme acid resistance system of Escherichia coli. Phylogenetic analysis indicated that AdiC belongs to the amino acid/polyamine/organocation (APC) transporter superfamily having sequence identities of 15-17% to eukaryotic and human APC transporters. For functional and structural characterization, we cloned, overexpressed, and purified wild-type AdiC and the point mutant AdiC-W293L, which is unable to bind and consequently transport L-arginine. Purified detergent-solubilized AdiC particles were dimeric. Reconstitution experiments yielded two-dimensional crystals of AdiC-W293L diffracting beyond 6 angstroms resolution from which we determined the projection structure at 6.5 angstroms resolution. The projection map showed 10-12 density peaks per monomer and suggested mainly tilted helices with the exception of one distinct perpendicular membrane spanning alpha-helix. Comparison of AdiC-W293L with the projection map of the oxalate/formate antiporter from Oxalobacter formigenes, a member from the major facilitator superfamily, indicated different structures. Thus, two-dimensional crystals of AdiC-W293L yielded the first detailed view of a transport protein from the APC superfamily at sub-nanometer resolution. 相似文献
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Marta Estrader Carmen Diaz Joan Ribas Xavier Solans Merce Font-Bardía 《Inorganica chimica acta》2008,361(14-15):3963-3969
The synthesis, crystallographic analysis and magnetic studies of six new copper(II) complexes of formulae [Cu(μ-ala)(im)(H2O)]n(ClO4)n (1), [Cu(μ-ala)(pz)(μ-ClO4)] (2), [Cu(μ-phe)(im)(H2O)]n(ClO4)n (3), [Cu(μ-gly)(H2O)(ClO4)]n (4), [Cu(μ-gly)(pz)(ClO4)]n(5) and [Cu(μ-pro)(pz)(ClO4)]n (6) have been carried out (ala = alanine; phe = phenylalanine; gly = glycine; pro = proline; im = imidazole; pz = pyrazole). In all cases, the deprotonated aminoacid ligand acts as chelate through the N(amine) and one O(carboxylato), whereas the second O atom of the same carboxylato acts as a bridge to the neighbouring copper(II) ion. The coordination of copper(II) ions is square-pyramidal in all complexes but 2 (elongated Oh). All complexes (1–6) are uniform chains with syn–anti (equatorial–equatorial) coordination mode of the carboxylato bridging ligand, exhibiting intrachain ferromagnetic interactions. 相似文献
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Nino Künzli Michael Jerrett Raquel Garcia-Esteban Xavier Basaga?a Bernardo Beckermann Frank Gilliland Merce Medina John Peters Howard N. Hodis Wendy J. Mack 《PloS one》2010,5(2)
Background
Cross-sectional studies suggest an association between exposure to ambient air pollution and atherosclerosis. We investigated the association between outdoor air quality and progression of subclinical atherosclerosis (common carotid artery intima-media thickness, CIMT).Methodology/Principal Findings
We examined data from five double-blind randomized trials that assessed effects of various treatments on the change in CIMT. The trials were conducted in the Los Angeles area. Spatial models and land-use data were used to estimate the home outdoor mean concentration of particulate matter up to 2.5 micrometer in diameter (PM2.5), and to classify residence by proximity to traffic-related pollution (within 100 m of highways). PM2.5 and traffic proximity were positively associated with CIMT progression. Adjusted coefficients were larger than crude associations, not sensitive to modelling specifications, and statistically significant for highway proximity while of borderline significance for PM2.5 (P = 0.08). Annual CIMT progression among those living within 100 m of a highway was accelerated (5.5 micrometers/yr [95%CI: 0.13–10.79; p = 0.04]) or more than twice the population mean progression. For PM2.5, coefficients were positive as well, reaching statistical significance in the socially disadvantaged; in subjects reporting lipid lowering treatment at baseline; among participants receiving on-trial treatments; and among the pool of four out of the five trials.Conclusion
Consistent with cross-sectional findings and animal studies, this is the first study to report an association between exposure to air pollution and the progression of atherosclerosis – indicated with CIMT change – in humans. Ostensibly, our results suggest that air pollution may contribute to the acceleration of cardiovascular disease development – the main causes of morbidity and mortality in many countries. However, the heterogeneity of the volunteering populations across the five trials, the limited sample size within trials and other relevant subgroups, and the fact that some key findings reached statistical significance in subgroups rather than the sample precludes generalizations to the general population. 相似文献7.
García-Fruitós E Vázquez E Díez-Gil C Corchero JL Seras-Franzoso J Ratera I Veciana J Villaverde A 《Trends in biotechnology》2012,30(2):65-70
Many protein species produced in recombinant bacteria aggregate as insoluble protein clusters named inclusion bodies (IBs). IBs are discarded from further processing or are eventually used as a pure protein source for in vitro refolding. Although usually considered as waste byproducts of protein production, recent insights into the physiology of recombinant bacteria and the molecular architecture of IBs have revealed that these protein particles are unexpected functional materials. In this Opinion article, we present the relevant mechanical properties of IBs and discuss the ways in which they can be explored as biocompatible nanostructured materials, mainly, but not exclusively, in biocatalysis and tissue engineering. 相似文献
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Hiroshi Sembongi Merce Miranda Gil-Soo Han Stylianos Fakas Neil Grimsey Joan Vendrell George M. Carman Symeon Siniossoglou 《The Journal of biological chemistry》2013,288(48):34502-34513
Lipins are evolutionarily conserved Mg2+-dependent phosphatidate phosphatase (PAP) enzymes with essential roles in lipid biosynthesis. Mammals express three paralogues: lipins 1, 2, and 3. Loss of lipin 1 in mice inhibits adipogenesis at an early stage of differentiation and results in a lipodystrophic phenotype. The role of lipins at later stages of adipogenesis, when cells initiate the formation of lipid droplets, is less well characterized. We found that depletion of lipin 1, after the initiation of differentiation in 3T3-L1 cells but before the loading of lipid droplets with triacylglycerol, results in a reciprocal increase of lipin 2, but not lipin 3. We generated 3T3-L1 cells where total lipin protein and PAP activity levels are down-regulated by the combined depletion of lipins 1 and 2 at day 4 of differentiation. These cells still accumulated triacylglycerol but displayed a striking fragmentation of lipid droplets without significantly affecting their total volume per cell. This was due to the lack of the PAP activity of lipin 1 in adipocytes after day 4 of differentiation, whereas depletion of lipin 2 led to an increase of lipid droplet volume per cell. We propose that in addition to their roles during early adipogenesis, lipins also have a role in lipid droplet biogenesis. 相似文献
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