45 research outputs found

    Can Lower Mantle Slab-like Seismic Anomalies be Explained by Thermal Coupling Between the Upper and Lower Mantles?

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    Below subduction zones, high resolution seismic tomographic models resolve fast anomalies that often extend into the deep lower mantle. These anomalies are generally interpreted as slabs penetrating through the 660-km seismic discontinuity, evidence in support of whole-mantle convection. However, thermal coupling between two ow systems separated by an impermeable interface might provide an al ternative explanation of the tomographic results. We have tested this hypothesis within the context of an axisymmet ric model of mantle convection in which an impermeable boundary is imposed at a depth of 660 km. When an increase in viscosity alone is imposed across the impermeable interface, our results demonstrate the dominant role of mechanical coupling between shells, producing lower mantle upwellings (downwellings) below upper mantle downwellings (upwellings). However, we find that the effect of mechanical coupling can be significantly weakened if a narrow low viscosity zone exists beneath the 660-km discontinuity. In such a case, both thermally induced `slabs' in the lower mantle and thermally activated plumes that rise from the upper/lower mantle boundary are observed even though mass transfer between the shells does not exist

    Sudden cardiac death due to deficiency of the mitochondrial inorganic pyrophosphatase PPA2

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    We have used whole exome sequencing to identify biallelic missense mutations in the nuclearencoded mitochondrial inorganic pyrophosphatase (PPA2) in ten individuals from four unrelated pedigrees that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis and cardiac arrhythmia and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutated PPA2 containing mitochondria from fibroblasts showed the activity of inorganic pyrophosphatase significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations, and suggest that PPA2 is a new cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized

    Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

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    The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.This work was funded by ERC starting grant Relieve IMDs (L.V., N.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.H., F.S.), the Evelyn trust (N.H.) and the EU Fp7 grant TissuGEN (M.CDB.). FS has been supported by an Addenbrooke’s Charitable Trust Clinical Research Training Fellowship and a joint MRC-Sparks Clinical Research Training Fellowship.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nbt.327

    The 3-methylglutaconic acidurias: what’s new?

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    The heterogeneous group of 3-methylglutaconic aciduria (3-MGA-uria) syndromes includes several inborn errors of metabolism biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. Five distinct types have been recognized: 3-methylglutaconic aciduria type I is an inborn error of leucine catabolism; the additional four types all affect mitochondrial function through different pathomechanisms. We provide an overview of the expanding clinical spectrum of the 3-MGA-uria types and provide the newest insights into the underlying pathomechanisms. A diagnostic approach to the patient with 3-MGA-uria is presented, and we search for the connection between urinary 3-MGA excretion and mitochondrial dysfunction

    Crise de abastecimento de água em São Paulo e falta de planejamento estratégico

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    Embora a crise no abastecimento de água na Região Metropolitana de São Paulo (RMSP) tenha se manifestado de maneira mais intensa no verão de 2013-2014, ela revela um problema crônico que vem afetando toda a Região nos últimos dez anos. Esse problema foi gerado pela falta de um planejamento estratégico que considere questões climatológicas que podem indicar, com meses de antecedência, problemas de recomposição dos níveis dos mananciais, permitindo que ações sejam empreendidas com razoável antecedência, reduzindo os impactos para a população. Este estudo mostra como é possível utilizar informações climáticas na gestão estratégica do sistema de abastecimento da RMSP.Though the crisis in the water supplying system in the Metropolitan Region of São Paulo (RMSP) was more intensively felt in the 2013-2014 summer, it reveals a chronic problem that has been affecting the whole RMSP for the past ten years. This problem is originated from the lack of a strategic planning that takes into consideration climate issues that could, months before, foresee problems to restore the levels of water resources, allowing measures to be implemented within a reasonable anticipation, therefore reducing the impacts on the population. This study shows how it is possible to use climate information in the strategic management of the water supply in the RMSP

    First report of Geosmithia langdonii and Geosmithia spp. isolated from a decaying elm (Ulmus minor) in Geneva, Switzerland

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    The mortality of a young elm Ulmus minor in 2014 in Geneva prompted a search for the microorganisms potentially involved. Symptoms included foliar chlorosis and wilting followed by defoliation of branches. Wood symptoms included a brown streaking of sap wood and brown stains in trunk and branches. The comparison of the resulting ITS rDNA sequences to the NCBI Nucleotide database allowed to identify 10 different organisms. The genus Geosmithia represented 48% of the isolates belonging to three species: Geosmithia langdonii (7 isolates) and 2 unknown morphologically and genetically different Geosmithia sp. 1 and sp. 2 (4 isolates). Geosmithia species are very little known ascomycetes, which have been recently shown to be opportunistic pathogens on broadleaved trees and conifers, living as saprobes in galleries of many bark beetle species. In the case described here, Geosmithia langdonii, and the unknown Geosmithia species were found in symptomatic wood while bark beetle galleries were found in close regions of the symptomatic wood. Geosmithia langdonii was the major fungus retrieved from the symptomatic wood and could have contributed, along with other identified fungal species, to a pathogenic complex producing symptoms similar to the ones of the Dutch Elm Disease and led to the dieback of this elm tree. Geosmithia langdonii and 2 yet unknown Geosmithia species (sp. 1 and sp. 2), different from any other reported Geosmithia species are reported from an elm tree in Switzerland for the first time
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