Analyse du comportement de l'abdomen lors d'un choc automobile pour l'amélioration de la biofidélité et de la prédiction des lésions abdominales par le mannequin de choc THOR

Abdominal injuries represent a small proportion (5%) of road crash injuries but their proportion increases considerably with regard to serious and severe injuries (16%). The abdomen of the Test device for Human Occupant Restraint (THOR), intended to be used in future frontal impact assessments, needs further developments regarding its biofidelity and injury criterion. The work performed in this thesis project was in three folds: Firstly, the main parameters of the THOR and Post Mortem Human Subjects (PMHS) abdomen responses under impactor and seatbelt loadings were identified using a lumped element model. The comparison between the THOR and the PMHS mechanical parameters highlighted desired changes for THOR abdomen biofidelity improvement. It was found that THOR material viscosity should be increased by 5 and that interaction with the pelvis flesh should be modified as it increased by 8 the abdomen stiffness. These changes were included in the Finite Element (FE) model of an existing abdomen prototype which is equipped with Abdominal Pressure Twin Sensors (APTS) to quantify the abdomen load. Secondly, the response of the prototype was evaluated in sled test simulations which showed that the prototype abdomen had little influence on the dummy overall kinematics but that the torso flexion could increase the pressure in the APTS. This led to additional recommendations regarding the abdomen design. Finally, for the abdominal injury criterion definition, the APTS pressure was correlated with organ injuries as reported in published PMHS tests or as predicted by THUMS human FE model.Les blessures de l'abdomen représentent une faible proportion (5%) des blessures lors d'accidents de la route mais elle augmente fortement pour les blessures sérieuses à séÏres (16%). L'abdomen du mannequin THOR (Test device for Human Occupant Restraint), qui va être utilisé dans les futures réglementations de choc frontal, nécessite des améliorations de sa biofidélité et un critère de blessure. Le travail présenté est en trois parties : Premièrement, les paramètres principaux de la réponse mécanique de l'abdomen du THOR et de Sujets Humain Post Mortem (SHPM) sous chargements impacteur et ceinture furent identifiés à l'aide d'un modèle mécanique simplifié. La comparaison des paramètres mécaniques du THOR et des SHPM a mis en évidence les changements nécessaires pour l'amélioration de la biofidélité de l'abdomen du THOR. Il apparaît que la viscosité quivalente du THOR doit être augmentée d'un facteur 5 et que l'interaction avec la pièce bassin doit être modifiée du fait qu'elle augmentait la rigidité d'un facteur 8. Ces changements furent inclus dans le modèle Éléments Finis (EF) d'un abdomen prototype incluant des capteurs de pression APTS (Abdominal Pressure Twin Sensors) pour caractériser le chargement de l'abdomen. Deuxièmement, la réponse mécanique du prototype a été évaluée en simulations d'essais chariot, ce qui a montré que l'abdomen prototype a peu d'influence sur la cinématique globale du mannequin mais que la flexion du tronc peut faire augmenter la pression dans les APTS. Cela a mené à des recommandations supplémentaires au niveau de la conception de l'abdomen. Finalement, en vue de définir un critère de blessure pour l'abdomen, la pression des APTS a été corrélée aux blessures des organes décrites dans les études sur SHPM de la littérature ou prédites par le modèle EF humain THUMS

RNA granules: the good, the bad and the ugly

Processing bodies (PBs) and Stress Granules (SGs) are the founding members of a new class of RNA granules, known as mRNA silencing foci, as they harbour transcripts circumstantially excluded from the translationally active pool. PBs and SGs are able to release mRNAs thus allowing their translation. PBs are constitutive, but respond to stimuli that affect mRNA translation and decay, whereas SGs are specifically induced upon cellular stress, which triggers a global translational silencing by several pathways, including phosphorylation of the key translation initiation factor eIF2alpha, and tRNA cleavage among others. PBs and SGs with different compositions may coexist in a single cell. These macromolecular aggregates are highly conserved through evolution, from unicellular organisms to vertebrate neurons. Their dynamics is regulated by several signaling pathways, and depends on microfilaments and microtubules, and the cognate molecular motors myosin, dynein, and kinesin. SGs share features with aggresomes and related aggregates of unfolded proteins frequently present in neurodegenerative diseases, and may play a role in the pathology. Virus infections may induce or impair SG formation. Besides being important for mRNA regulation upon stress, SGs modulate the signaling balancing apoptosis and cell survival. Finally, the formation of Nuclear Stress Bodies (nSBs), which share components with SGs, and the assembly of additional cytosolic aggregates containing RNA -the UV granules and the Ire1 foci-, all of them induced by specific cell damage factors, contribute to cell survival.Fil: Thomas, Maria Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Loschi, Mariela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Desbats, Maria Andrea. Fundación Instituto Leloir; ArgentinaFil: Boccaccio, Graciela Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentin

Molecular and cellular studies reveal folding defects of human ornithine aminotransferase variants associated with gyrate atrophy of the choroid and retina

The deficit of human ornithine aminotransferase (hOAT) is responsible for gyrate atrophy (GA), a rare recessive inherited disorder. Although more than 60 disease-associated mutations have been identified to date, the molecular mechanisms explaining how each mutation leads to the deficit of OAT are mostly unknown. To fill this gap, we considered six representative missense mutations present in homozygous patients concerning residues spread over the hOAT structure. E. coli expression, spectroscopic, kinetic and bioinformatic analyses, reveal that the R154L and G237D mutations induce a catalytic more than a folding defect, the Q90E and R271K mutations mainly impact folding efficiency, while the E318K and C394Y mutations give rise to both folding and catalytic defects. In a human cellular model of disease folding-defective variants, although at a different extent, display reduced protein levels and/or specific activity, due to increased aggregation and/or degradation propensity. The supplementation with Vitamin B6, to mimic a treatment strategy available for GA patients, does not significantly improve the expression/activity of folding-defective variants, in contrast with the clinical responsiveness of patients bearing the E318K mutation. Thus, we speculate that the action of vitamin B6 could be also independent of hOAT. Overall, these data represent a further effort toward a comprehensive analysis of GA pathogenesis at molecular and cellular level, with important relapses for the improvement of genotype/phenotype correlations and the development of novel treatments

Molecular characterization of the human COQ5 C-methyltransferase in coenzyme Q10 biosynthesis

Under a Creative Commons license.Coq5 catalyzes the only C-methylation involved in the biosynthesis of coenzyme Q (Q or ubiquinone) in humans and yeast Saccharomyces cerevisiae. As one of eleven polypeptides required for Q production in yeast, Coq5 has also been shown to assemble with the multi-subunit complex termed the CoQ-synthome. In humans, mutations in several COQ genes cause primary Q deficiency, and a decrease in Q biosynthesis is associated with mitochondrial, cardiovascular, kidney and neurodegenerative diseases. In this study, we characterize the human COQ5 polypeptide and examine its complementation of yeast coq5 point and null mutants. We show that human COQ5 RNA is expressed in all tissues and that the COQ5 polypeptide is associated with the mitochondrial inner membrane on the matrix side. Previous work in yeast has shown that point mutations within or adjacent to conserved COQ5 methyltransferase motifs result in a loss of Coq5 function but not Coq5 steady state levels. Here, we show that stabilization of the CoQ-synthome within coq5 point mutants or by over-expression of COQ8 in coq5 null mutants permits the human COQ5 homolog to partially restore coq5 mutant growth on respiratory media and Q6 content. Immunoblotting against the human COQ5 polypeptide in isolated yeast mitochondria shows that the human Coq5 polypeptide migrates in two-dimensional blue-native/SDS-PAGE at the same high molecular mass as other yeast Coq proteins. The results presented suggest that human and Escherichia coli Coq5 homologs expressed in yeast retain C-methyltransferase activity but are capable of rescuing the coq5 yeast mutants only when the CoQ-synthome is assembled.Open Access funded by Telethon (Italy).Peer Reviewe

M2000 : an astrometric catalog in the Bordeaux Carte du Ciel zone +11 degrees < {delta} < +18 degrees

During four years, systematic observations have been conducted in drift scan mode with the Bordeaux automated meridian circle in the declination band [+11 ; +18]. The resulting astrometric catalog includes about 2 300 000 stars down to the magnitude limit V_M=16.3. Nearly all stars (96%) have been observed at least 6 times, the catalog being complete down to V_M=15.4. The median internal standard error in position is about 35 mas in the V_M magnitude range [11 ; 15], which degrades to about 50 mas when the faintest stars are considered. M2000 provides also one band photometry with a median internal standard error of 0.04 mag. Comparisons with the Hipparcos and bright part of Tycho-2 catalogs have enabled to estimate external errors in position to be lower than 40 mas. In this zone and at epoch 1998, the faint part of Tycho-2 is found to have an accuracy of 116 mas in alpha instead of 82 mas deduced from the model-based standard errors given in the catalog.Comment: The catalogue can be fetched directly from: ftp://cdsarc.u-strasbg.fr/cats/I/272 or queried from: http://vizier.u-strasbg.fr/viz-bin/VizieR?-source=I/272 More information at : http://www.observ.u-bordeaux.fr/~soubiran/m2000.ht

Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients. In addition, SBMA muscle was characterized by the presence of a large number of hypertrophic fibers, with oxidative fibers having a larger size compared with glycolytic fibers. Polyglutamine-expanded AR expression was decreased in whole muscle, yet enriched in the nucleus, and localized to mitochondria. Ultrastructural analysis revealed myofibrillar disorganization and streaming in zones lacking mitochondria and degenerating mitochondria. Using molecular (mtDNA copy number), biochemical (citrate synthase and respiratory chain enzymes) and morphological (dark blue area in nicotinamide adenine dinucleotide-stained muscle cross-sections) analyses, we found a depletion of the mitochondria associated with enhanced mitophagy. Mass spectrometry analysis revealed an increase of phosphatidylethanolamines and phosphatidylserines in mitochondria isolated from SBMA muscles, as well as a 50% depletion of cardiolipin associated with decreased expression of the cardiolipin synthase gene. These observations suggest a causative link between nuclear polyglutamine-expanded AR accumulation, depletion of mitochondrial mass, increased mitophagy and altered mitochondrial membrane composition in SBMA muscle patients. Given the central role of mitochondria in cell bioenergetics, therapeutic approaches toward improving the mitochondrial network are worth considering to support SBMA patients

Quelle R&D Mener pour le Développement Des Réseaux D'énergie De Demain ? Les Propositions de L'ancre en 2015

Feuille de route sur les réseaux électriques et stockage élaborée par le GP10 Réseaux et Stockages de l'Energie de l'ANCRECette feuille de route concerne les réseaux d’énergie électrique, de chaleur et de froid, les réseaux de gaz (hydrogène, gaz naturel), leurs stockages associés, ainsi que leurs couplages à venir dans le cadre de la transition énergétique et des évolutionsqui l’accompagneront, que ce soit sur les modes de production d’énergie ou sur l’évolution des usages.Le focus est porté sur les réseaux électriques qui seront les premiers impactés par cette transition énergétique. Hormisquelques éléments très spécifiques aux réseaux électriques (et qui seront notés dans le texte par une couleur différente)il est à souligner que la quasi-totalité des considérations et axes de R&D évoqués pour les réseauxélectriques et le développement de leur « intelligence » et/ou de leur flexibilité s’appliquentégalement aux autres réseaux d’énergie. Par ailleurs, si le groupe programmatique« Réseaux et Stockage » de l’ANCRE (GP10) s’est largement appuyé sur les nombreuses feuilles de route émises tant au niveau national, dont celles de l’ADEME, qu’européen, il a également souhaité s’en démarquer en insistantlargement et en détaillant les recherches scientifiques et technologiques à mener face aux verrous actuellement identifiés

Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence

Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a \u3b2-thalassemia mouse model

Anemia in \u3b2-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired \u3b1-globin chains impose substantial oxidative stress on \u3b2-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for \u3b2-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in \u3b2-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2\u3b1 axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing \u3b2-thalassemia\u2013related liver iron overload. In ex vivo studies on erythroid precursors from patients with \u3b2-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for \u3b2-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials