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

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

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

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?

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

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

Exome Sequencing Identifies Mitochondrial Alanyl-tRNA Synthetase Mutations in Infantile Mitochondrial Cardiomyopathy

Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure

OXPHOS gene expression and control in mitochondrial disorders.

Contains fulltext : 81397.pdf (publisher's version ) (Closed access)The cellular consequences of deficiencies of the mitochondrial OXPHOS system include a variety of direct and secondary changes in metabolite homeostasis, such as ROS, Ca(2+), ADP/ATP, and NAD/NADH. The adaptive responses to these changes include the transcriptional responses of nuclear and mitochondrial genes that are mediated by these metabolites, control of the mitochondria permeability transition pore, and a great variety of secondary signalling elements. Among the transcriptional responses reported over more than a decade using material harboring mtDNA mutations, deletions, or depletions, nuclear and mitochondrial DNA OXPHOS genes have mostly been up-regulated. However, it is evident from the limited data in a variety of disease models that expression responses are highly diverse and inconsistent. In this article, the mechanisms and controlling elements of these transcriptional responses are reviewed. In addition, the elements that need to be evaluated, in order to gain an improved perspective of the manner in which OXPHOS genes respond and impact on mitochondrial disease expression, are highlighted