Alteration of mitochondrial oxidative phosphorylation in aged skeletal muscle involves modification of adenine nucleotide translocator

AbstractThe process of skeletal muscle aging is characterized by a progressive loss of muscle mass and functionality. The underlying mechanisms are highly complex and remain unclear. This study was designed to further investigate the consequences of aging on mitochondrial oxidative phosphorylation in rat gastrocnemius muscle, by comparing young (6 months) and aged (21 months) rats. Maximal oxidative phosphorylation capacity was clearly reduced in older rats, while mitochondrial efficiency was unaffected. Inner membrane properties were unaffected in aged rats since proton leak kinetics were identical to young rats. Application of top-down control analysis revealed a dysfunction of the phosphorylation module in older rats, responsible for a dysregulation of oxidative phosphorylation under low activities close to in vivo ATP turnover. This dysregulation is responsible for an impaired mitochondrial response toward changes in cellular ATP demand, leading to a decreased membrane potential which may in turn affect ROS production and ion homeostasis. Based on our data, we propose that modification of ANT properties with aging could partly explain these mitochondrial dysfunctions

Improved Energy Supply Regulation in Chronic Hypoxic Mouse Counteracts Hypoxia-Induced Altered Cardiac Energetics

Hypoxic states of the cardiovacular system are undoubtedly associated with the most frequent diseases of modern time. Therefore, understanding hypoxic resistance encountered after physiological adaptation such as chronic hypoxia, is crucial to better deal with hypoxic insult. In this study, we examine the role of energetic modifications induced by chronic hypoxia (CH) in the higher tolerance to oxygen deprivation.P-NMR), and to describe the integrated changes in cardiac energetics regulation by using Modular Control Analysis (MoCA). Oxygen reduction induced a concomitant decrease in RPP (−46%) and in [PCr] (−23%) in Control hearts while CH hearts energetics was unchanged. MoCA demonstrated that this adaptation to hypoxia is the direct consequence of the higher responsiveness (elasticity) of ATP production of CH hearts compared with Controls (−1.88±0.38 vs −0.89±0.41, p<0.01) measured under low oxygen perfusion. This higher elasticity induces an improved response of energy supply to cellular energy demand. The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.As suggested by the present study, the mechanisms responsible for this increase in elasticity and the consequent improved ability of CH heart metabolism to respond to oxygen deprivation could participate to limit the damages induced by hypoxia

Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control

Endogenous retroviruses (ERVs) are an inherited part of the eukaryotic genomes, and represent ∼400 000 loci in the human genome. Human endogenous retroviruses (HERVs) can be divided into distinct families, composed of phylogenetically related but structurally heterogeneous elements. The majority of HERVs are silent in most physiological contexts, whereas a significant expression is observed in pathological contexts, such as cancers. Owing to their repetitive nature, few of the active HERV elements have been accurately identified. In addition, there are no criteria defining the active promoters among HERV long-terminal repeats (LTRs). Hence, it is difficult to understand the HERV (de)regulation mechanisms and their implication on the physiopathology of the host. We developed a microarray to specifically detect the LTR-containing transcripts from the HERV-H, HERV-E, HERV-W and HERV-K(HML-2) families. HERV transcriptome was analyzed in the placenta and seven normal/tumoral match-pair samples. We identified six HERV-W loci overexpressed in testicular cancer, including a usually placenta-restricted transcript of ERVWE1. For each locus, specific overexpression was confirmed by quantitative RT-PCR, and comparison of the activity of U3 versus U5 regions suggested a U3-promoted transcription coupled with 5′R initiation. The analysis of DNA from tumoral versus normal tissue revealed that hypomethylation of U3 promoters in tumors is a prerequisite for their activation

The Physical Relationship between Infectivity and Prion Protein Aggregates Is Strain-Dependent

Prions are unconventional infectious agents thought to be primarily composed of PrPSc, a multimeric misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrPC). They cause fatal neurodegenerative diseases in both animals and humans. The disease phenotype is not uniform within species, and stable, self-propagating variations in PrPSc conformation could encode this ‘strain’ diversity. However, much remains to be learned about the physical relationship between the infectious agent and PrPSc aggregation state, and how this varies according to the strain. We applied a sedimentation velocity technique to a panel of natural, biologically cloned strains obtained by propagation of classical and atypical sheep scrapie and BSE infectious sources in transgenic mice expressing ovine PrP. Detergent-solubilized, infected brain homogenates were used as starting material. Solubilization conditions were optimized to separate PrPSc aggregates from PrPC. The distribution of PrPSc and infectivity in the gradient was determined by immunoblotting and mouse bioassay, respectively. As a general feature, a major proteinase K-resistant PrPSc peak was observed in the middle part of the gradient. This population approximately corresponds to multimers of 12–30 PrP molecules, if constituted of PrP only. For two strains, infectivity peaked in a markedly different region of the gradient. This most infectious component sedimented very slowly, suggesting small size oligomers and/or low density PrPSc aggregates. Extending this study to hamster prions passaged in hamster PrP transgenic mice revealed that the highly infectious, slowly sedimenting particles could be a feature of strains able to induce a rapidly lethal disease. Our findings suggest that prion infectious particles are subjected to marked strain-dependent variations, which in turn could influence the strain biological phenotype, in particular the replication dynamics

Evaluation de la pertinence de la lettre d'admission aux urgences Porte Madeleine (Orléans)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

COUT DE LA DERMOHYPODERMITE BACTERIENNE DES MEMBRES INFERIEURS (ETUDE RETROSPECTIVE SUR 31 CAS DE DERMOHYPODERMITE BACTERIENNE DES MEMBRES INFERIEURS HOSPITALISES EN 1998 A L'HOPITAL D'ORLEANS)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Causal discovery for time series with constraint-based model and PMIME measure

International audienceCausality defines the relationship between cause and effect. In multivariate time series field, this notion allows to characterize the links between several time series considering temporal lags. These phenomena are particularly important in medicine to analyze the effect of a drug for example, in manufacturing to detect the causes of an anomaly in a complex system or in social sciences... Most of the time, these complex systems do not rely on the assumption of linearity required in many machine learning methods. To circumvent this problem, we present in this paper a new approach for discovering causality in time series data that combines a causal discovery algorithm with an information theoretic-based measure. Hence the proposed method allows inferring both linear and non-linear relationships and building the underlying causal graph. We evaluate the performance of our approach on several simulated datasets, showing promising results

Découverte de causalité pour séries temporelles utilisant un modèle constraint-based et la mesure d'information PMIME

International audienceCausality defines the relationship between cause and effect. In multivariate time series field, this notion allows to characterize the links between several time series considering temporal lags. These phenomena are particularly important in medicine to analyze the effect of a drug for example, in manufacturing to detect the causes of an anomaly in a complex system Most of the time, those complex systems do not rely on the assumption of linearity required in many machine learning methods. To circumvent this problem, we present in this paper a new approach for discovering causality in time series data that combines a causal discovery algorithm with an information theoretic-based measure. Hence the proposed method allows inferring both linear and non-linear relationships and building the underlyingcausal graph. We evaluate the performance of our approach on several simulated datasets, showing promising results.La causalité est une notion qui définit les relations entre les causes et leurs effets. Dans le cadre des séries temporelles multivariées, cette notion permet de caractériser les liens entre plusieurs séries temporelles en considérant possiblement les décalages temporels. Par exemple, dans l'industrie elle détecte notamment les causes d'une anomalie dans un système complexe. En pratique, les systèmes complexes mesurés reposent peu souvent sur les hypothèses de données gaussiennes ou de linéarité entre les liens requises dans de nombreuses méthodes d'apprentissage automatique. Pour pallier ce problème, nous présentons dans ce papier une nouvelle approche pour établir les liens causaux entre séries temporelles qui combine un algorithme de découverte causale avec une mesure basée sur la théorie de l'information. Ainsi, l'approche proposée permet d'identifier des liens linéaires et non-linéaires et de construire le graphe causal sous-jacent. La méthode est évaluée sur différentes bases de données simulées issues de la littérature et montre des performances intéressantes

Parameter estimation in modeling phosphocreatine recovery in human skeletal muscle

International audienc