Mitochondria, Bioenergetics and Excitotoxicity: New Therapeutic Targets in Perinatal Brain Injury

Injury to the fragile immature brain is implicated in the manifestation of long-term neurological disorders, including childhood disability such as cerebral palsy, learning disability and behavioral disorders. Advancements in perinatal practice and improved care mean the majority of infants suffering from perinatal brain injury will survive, with many subtle clinical symptoms going undiagnosed until later in life. Hypoxic-ischemia is the dominant cause of perinatal brain injury, and constitutes a significant socioeconomic burden to both developed and developing countries. Therapeutic hypothermia is the sole validated clinical intervention to perinatal asphyxia; however it is not always neuroprotective and its utility is limited to developed countries. There is an urgent need to better understand the molecular pathways underlying hypoxic-ischemic injury to identify new therapeutic targets in such a small but critical therapeutic window. Mitochondria are highly implicated following ischemic injury due to their roles as the powerhouse and main energy generators of the cell, as well as cell death processes. While the link between impaired mitochondrial bioenergetics and secondary energy failure following loss of high-energy phosphates is well established after hypoxia-ischemia (HI), there is emerging evidence that the roles of mitochondria in disease extend far beyond this. Indeed, mitochondrial turnover, including processes such as mitochondrial biogenesis, fusion, fission and mitophagy, affect recovery of neurons after injury and mitochondria are involved in the regulation of the innate immune response to inflammation. This review article will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after hypoxic-ischemic injury, as a means of identifying new avenues for clinical intervention

Subduction controls the distribution and fragmentation of Earth’s tectonic plates

International audienceThe theory of plate tectonics describes how the surface of the Earth is split into an organized jigsaw of seven large plates 1 of similar sizes and a population of smaller plates, whose areas follow a fractal distribution 2,3. The reconstruction of global tectonics during the past 200 My 4 suggests that this layout is probably a long-term feature of our planet, but the forces governing it are unknown. Previous studies 3,5,6 , primarily based on statistical properties of plate distributions, were unable to resolve how the size of plates is determined by lithosphere properties and/or underlying mantle convection. Here, we demonstrate that the plate layout of the Earth is produced by a dynamic feedback between mantle convection and the strength of the lithosphere. Using 3D spherical models of mantle convection with plate-like behaviour that match the plate size-frequency distribution observed for Earth, we show that subduction geometry drives the tectonic fragmentation that generates plates. The spacing between slabs controls the layout of large plates, and the stresses caused by the bending of trenches, break plates into smaller fragments. Our results explain why the fast evolution in small back-arc plates 7,8 reflects the dramatic changes in plate motions during times of major reorganizations. Our study opens the way to use convection simulations with plate-like behaviour to unravel how global tectonics and mantle convection are dynamically connected

Immunity Traits in Pigs: Substantial Genetic Variation and Limited Covariation

BACKGROUND: Increasing robustness via improvement of resistance to pathogens is a major selection objective in livestock breeding. As resistance traits are difficult or impossible to measure directly, potential indirect criteria are measures of immune traits (ITs). Our underlying hypothesis is that levels of ITs with no focus on specific pathogens define an individual's immunocompetence and thus predict response to pathogens in general. Since variation in ITs depends on genetic, environmental and probably epigenetic factors, our aim was to estimate the relative importance of genetics. In this report, we present a large genetic survey of innate and adaptive ITs in pig families bred in the same environment. METHODOLOGY/PRINCIPAL FINDINGS: Fifty four ITs were studied on 443 Large White pigs vaccinated against Mycoplasma hyopneumoniae and analyzed by combining a principal component analysis (PCA) and genetic parameter estimation. ITs include specific and non specific antibodies, seric inflammatory proteins, cell subsets by hemogram and flow cytometry, ex vivo production of cytokines (IFNα, TNFα, IL6, IL8, IL12, IFNγ, IL2, IL4, IL10), phagocytosis and lymphocyte proliferation. While six ITs had heritabilities that were weak or not significantly different from zero, 18 and 30 ITs had moderate (0.1<h2≤0.4) or high (h2>0.4) heritability values, respectively. Phenotypic and genetic correlations between ITs were weak except for a few traits that mostly include cell subsets. PCA revealed no cluster of innate or adaptive ITs. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that variation in many innate and adaptive ITs is genetically controlled in swine, as already reported for a smaller number of traits by other laboratories. A limited redundancy of the traits was also observed confirming the high degree of complementarity between innate and adaptive ITs. Our data provide a genetic framework for choosing ITs to be included as selection criteria in multitrait selection programmes that aim to improve both production and health traits

Analyse tectonique de la surface des modèles de convection mantellique

Plate tectonics theory describes first order surface motions at the surface of the Earth. Although it is agreed upon that convection in the mantle drives the plates, the relationships between deep dynamics and surface tectonics are still largely unknown. Until recently, mantle convection models could not produce surface tectonics that could be compared to that of the Earth. New global models are able to form large-scale ascending and descending mantle currents, as well as narrow regions of localized deformation at the surface where convergence and divergence occur. These models selfconsistently generate an expansion of the oceanic floor similar to that of the last 200 million years on Earth, and continental drift similar to what can be reconstructed with palaeomagnetism. This Ph.D. thesis constitutes one of the first attempts to use self-organised, spherical convection models in order to better understand surface tectonics. Here, the tectonics produced by the models is finely charaterized through the study of plate boundaries, their organisation and their velocities. The goal is to be able to compare qualitatively and quantitatively the results of convection computations with surface motions, as reconstructed using the rules of plate tectonics and field observations. Plate boundaries emerging from the models were first traced and analyzed by hand so as to understand the physics that govern the typical organization of the tectonics plates on Earth. It is characterised by seven large plates and several smaller ones, following a statistical distribution that suggests that two distinct physical processes control the plates’ layout. We have determined the processes responsible for this distribution while varying the strength of the lithosphere (the yield stress). In our models, the stronger the lithosphere, the greater the total subduction length and their curvature, and the fewer the small plates. By studying surface fragmentation with triple junctions, we showed that the formation of small plates is associated with oceanic trench curvature. Large plates, however, are controlled by the long wavelengths of the convection cells. These two processes involve two different reorganisation times, controlled either by the accretion and the subduction of the large plates (about 100 Myrs), or by trench motions for the smaller plates. In order to improve the efficiency of our analysis, we have developed automated methods to study the surface and the interior of the models. The first technique is about detecting the tectonic plates automatically at the surface of the models. It is called ADOPT. It is a tool based on image segmentation technique to detect the watersheds. The surface fields of the convection models are converted into a relief field, either directly or using a distance method. This automatic detection allows to obtain plates polygons similar to the hand analysis. Another technique of detection has been developed to study mantle plumes. These analyzes were used to determine the driving forces behind the plates layout, to quantify the timing of reorganizations and to evaluate the implication of the models rheology on the surface distribution. These new analytical tools and the constant evolution of the quality of mantle convection models allow us to improve our understanding of the link between mantle dynamics and surface tectonics, but also to target necessary improvements in the convection models usedLa théorie de la tectonique des plaques permet de décrire les mouvements de premier ordre qui opèrent à la surface de la Terre. S'il est acquis que la convection dans le manteau terrestre en est le moteur, les liens entre les phénomènes profonds et les caractéristiques tectoniques de la surface restent largement méconnus. Jusqu'à très récemment, les modèles de convection du manteau terrestre ne produisaient pas de tectonique de surface pouvant être comparée à celle de la Terre. Récemment, des modèles globaux de convection qui reproduisent une tectonique de surface comparable à la Terre au premier ordre ont été mis au point. Ces modèles produisent des courants mantelliques ascendants et descendants de grande échelle et des déformations localisées en surface dans les zones de divergence et les zones de convergence. Ils génèrent une expansion des fonds océaniques de manière auto-cohérente proche de celle reconstruite pour les 200 derniers millions d'années de l'histoire de la Terre et une dérive de continents similaire à celle observée grâce au paléomagnétisme. Cette thèse s'inscrit parmi les premières tentatives d'utilisation de modèles de convection sphériques auto-organisés à des fins de compréhension de la tectonique de surface. La tectonique produite dans ce type de modèles de convection sera caractérisée finement à travers l'étude des limites de plaques, de leur agencement et de leurs vitesses de déplacement. L'objectif est de pouvoir comparer qualitativement et quantitativement les résultats des calculs de convection avec les reconstructions des mouvements de la surface terrestre grâce à la tectonique des plaques et aux observations de terrain. Dans cette optique, les limites tectoniques ont été définies à la main dans un premier temps afin de comprendre la physique qui gouverne l'agencement caractéristique des plaques tectoniques terrestres. En effet, celle-ci est composée de sept grandes plaques et plusieurs petites dont la répartition statistique indique deux processus de mise en place distincts. Nous avons déterminé les processus responsables de la mise en place de l'agencement caractéristique des plaques tectoniques en surface en faisant varier la résistance de la lithosphère. Plus la lithosphère est résistante, plus la longueur totale et la courbure des zones de subduction diminue à la surface des modèles. Cela s'accompagne également d'une diminution du nombre de petites plaques. En étudiant la fragmentation au niveau des jonctions triples, nous avons montré que les petites plaques étaient associées aux géométries courbées des fosses océaniques. En revanche, les grandes plaques sont contrôlées par les grandes longueurs d'onde de la convection mantellique. Ces deux processus impliquent deux temps de réorganisation, c'est-à-dire l'apparition et la disparition d'une plaque plongeante dans le manteau terrestre (environ 100 millions d'années) pour les grandes plaques, alors que l'échelle de temps de réorganisation des petites plaques dépend des mouvements des fosses et est ainsi plus rapide d'un ordre de grandeur. Afin d'effectuer des analyses quantitatives rapides, des méthodes d'analyse automatique de la surface et de l'intérieur des modèles ont été développées. La première technique concerne la détection automatique des plaques tectoniques à la surface des modèles (ADOPT). ADOPT est un outil de détection basé sur une technique de segmentation d'images utilisée pour détecter des bassins versants. Les champs à la surface des modèles sont transformés en reliefs, soit directement, soit après un processus de filtrage. Cette détection permet d'obtenir des polygones de plaques comparable aux analyses réalisées à la main. Une autre technique de détection a été mise au point pour étudier les panaches mantelliques [etc...

Tectonic analysis of mantle convection models

La théorie de la tectonique des plaques permet de décrire les mouvements de premier ordre qui opèrent à la surface de la Terre. S'il est acquis que la convection dans le manteau terrestre en est le moteur, les liens entre les phénomènes profonds et les caractéristiques tectoniques de la surface restent largement méconnus. Jusqu'à très récemment, les modèles de convection du manteau terrestre ne produisaient pas de tectonique de surface pouvant être comparée à celle de la Terre. Récemment, des modèles globaux de convection qui reproduisent une tectonique de surface comparable à la Terre au premier ordre ont été mis au point. Ces modèles produisent des courants mantelliques ascendants et descendants de grande échelle et des déformations localisées en surface dans les zones de divergence et les zones de convergence. Ils génèrent une expansion des fonds océaniques de manière auto-cohérente proche de celle reconstruite pour les 200 derniers millions d'années de l'histoire de la Terre et une dérive de continents similaire à celle observée grâce au paléomagnétisme. Cette thèse s'inscrit parmi les premières tentatives d'utilisation de modèles de convection sphériques auto-organisés à des fins de compréhension de la tectonique de surface. La tectonique produite dans ce type de modèles de convection sera caractérisée finement à travers l'étude des limites de plaques, de leur agencement et de leurs vitesses de déplacement. L'objectif est de pouvoir comparer qualitativement et quantitativement les résultats des calculs de convection avec les reconstructions des mouvements de la surface terrestre grâce à la tectonique des plaques et aux observations de terrain. Dans cette optique, les limites tectoniques ont été définies à la main dans un premier temps afin de comprendre la physique qui gouverne l'agencement caractéristique des plaques tectoniques terrestres. En effet, celle-ci est composée de sept grandes plaques et plusieurs petites dont la répartition statistique indique deux processus de mise en place distincts. Nous avons déterminé les processus responsables de la mise en place de l'agencement caractéristique des plaques tectoniques en surface en faisant varier la résistance de la lithosphère. Plus la lithosphère est résistante, plus la longueur totale et la courbure des zones de subduction diminue à la surface des modèles. Cela s'accompagne également d'une diminution du nombre de petites plaques. En étudiant la fragmentation au niveau des jonctions triples, nous avons montré que les petites plaques étaient associées aux géométries courbées des fosses océaniques. En revanche, les grandes plaques sont contrôlées par les grandes longueurs d'onde de la convection mantellique. Ces deux processus impliquent deux temps de réorganisation, c'est-à-dire l'apparition et la disparition d'une plaque plongeante dans le manteau terrestre (environ 100 millions d'années) pour les grandes plaques, alors que l'échelle de temps de réorganisation des petites plaques dépend des mouvements des fosses et est ainsi plus rapide d'un ordre de grandeur. Afin d'effectuer des analyses quantitatives rapides, des méthodes d'analyse automatique de la surface et de l'intérieur des modèles ont été développées. La première technique concerne la détection automatique des plaques tectoniques à la surface des modèles (ADOPT). ADOPT est un outil de détection basé sur une technique de segmentation d'images utilisée pour détecter des bassins versants. Les champs à la surface des modèles sont transformés en reliefs, soit directement, soit après un processus de filtrage. Cette détection permet d'obtenir des polygones de plaques comparable aux analyses réalisées à la main. Une autre technique de détection a été mise au point pour étudier les panaches mantelliques [etc...]Plate tectonics theory describes first order surface motions at the surface of the Earth. Although it is agreed upon that convection in the mantle drives the plates, the relationships between deep dynamics and surface tectonics are still largely unknown. Until recently, mantle convection models could not produce surface tectonics that could be compared to that of the Earth. New global models are able to form large-scale ascending and descending mantle currents, as well as narrow regions of localized deformation at the surface where convergence and divergence occur. These models selfconsistently generate an expansion of the oceanic floor similar to that of the last 200 million years on Earth, and continental drift similar to what can be reconstructed with palaeomagnetism. This Ph.D. thesis constitutes one of the first attempts to use self-organised, spherical convection models in order to better understand surface tectonics. Here, the tectonics produced by the models is finely charaterized through the study of plate boundaries, their organisation and their velocities. The goal is to be able to compare qualitatively and quantitatively the results of convection computations with surface motions, as reconstructed using the rules of plate tectonics and field observations. Plate boundaries emerging from the models were first traced and analyzed by hand so as to understand the physics that govern the typical organization of the tectonics plates on Earth. It is characterised by seven large plates and several smaller ones, following a statistical distribution that suggests that two distinct physical processes control the plates’ layout. We have determined the processes responsible for this distribution while varying the strength of the lithosphere (the yield stress). In our models, the stronger the lithosphere, the greater the total subduction length and their curvature, and the fewer the small plates. By studying surface fragmentation with triple junctions, we showed that the formation of small plates is associated with oceanic trench curvature. Large plates, however, are controlled by the long wavelengths of the convection cells. These two processes involve two different reorganisation times, controlled either by the accretion and the subduction of the large plates (about 100 Myrs), or by trench motions for the smaller plates. In order to improve the efficiency of our analysis, we have developed automated methods to study the surface and the interior of the models. The first technique is about detecting the tectonic plates automatically at the surface of the models. It is called ADOPT. It is a tool based on image segmentation technique to detect the watersheds. The surface fields of the convection models are converted into a relief field, either directly or using a distance method. This automatic detection allows to obtain plates polygons similar to the hand analysis. Another technique of detection has been developed to study mantle plumes. These analyzes were used to determine the driving forces behind the plates layout, to quantify the timing of reorganizations and to evaluate the implication of the models rheology on the surface distribution. These new analytical tools and the constant evolution of the quality of mantle convection models allow us to improve our understanding of the link between mantle dynamics and surface tectonics, but also to target necessary improvements in the convection models use

ADOPT: a tool for Automatic Detection Of Tectonic Plates at the surface of convection models

Data and software for Automatic Detection of Tectonic Plate

Modification chimique de polyesters aliphatiques biorésorbables par voie anionique (une nouvelle voie d'accès à des copolyesters fonctionnalisés)

MONTPELLIER-BU Pharmacie (341722105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF