Optimisation de la politique de maintenance pour un système à dégradation graduelle stressé

International audienceThis paper investigates a maintenance policy allowing the maintenance cost optimization per unit of time combining statistical process control (SPC) and condition-based maintenance (CBM) policy. We consider a single-unit system with two failure modes which can be partially explained by several covariates. Failure modes are a continuous-state deterioration and a stress. A CBM policy is used for inspecting and replacing the system in order to balance the impacts of an excessive deterioration level whereas a control a classical control chart is used to monitor the stress covariate. Sensitivity analysis based on numerical results is proposed

Predictive maintenance policy for a gradually deteriorating system subject to stress

International audienceThis paper deals with a predictive maintenance policy for a continuously deteriorating system subject to stress. We consider a system with two failure mechanisms which are, respectively, due to an excessive deterioration level and a shock. To optimize the maintenance policy of the system, an approach combining statistical process control (SPC) and condition-based maintenance (CBM) is proposed. CBM policy is used to inspect and replace the system according to the observed deterioration level. SPC is used to monitor the stress covariate. In order to assess the performance of the proposed maintenance policy and to minimize the long-run expected maintenance cost per unit of time, a mathematical model for the maintained system cost is derived. Analysis based on numerical results are conducted to highlight the properties of the proposed maintenance policy in respect to the different maintenance parameters

Optimisation de la politique de maintenance pour un système à dégradation graduelle stressé

International audienceThis paper investigates a maintenance policy allowing the maintenance cost optimization per unit of time combining statistical process control (SPC) and condition-based maintenance (CBM) policy. We consider a single-unit system with two failure modes which can be partially explained by several covariates. Failure modes are a continuous-state deterioration and a stress. A CBM policy is used for inspecting and replacing the system in order to balance the impacts of an excessive deterioration level whereas a control a classical control chart is used to monitor the stress covariate. Sensitivity analysis based on numerical results is proposed

Aged Nicotinamide Riboside Kinase 2 Deficient Mice Present an Altered Response to Endurance Exercise Training

Background: Skeletal muscle aging is marked by the development of a sarcopenic phenotype, a global decline of muscle energetic capacities, and an intolerance to exercise. Among the metabolic disorders involved in this syndrome, NAD metabolism was shown to be altered in skeletalmuscle, with an important role for the NAMPT enzyme recycling the nicotinamide precursor. An alternative pathway for NAD biosynthesis has been described for the nicotinamide riboside vitamin B3 precursor used by the NMRK kinases, including the striated muscle-specific NMRK2.Aim: With this study, our goal is to explore the ability of 16-month-old Nmrk2−/− mice to perform endurance exercise and study the consequences on muscle adaptation to exercise.Methods: 10 control and 6 Nmrk2−/− mice were used and randomly assigned to sedentary and treadmill endurance training groups. After 9 weeks of training, heart and skeletal muscle samples were harvested and used for gene expression analysis, NAD levels measurements and immunohistochemistry staining.Results: Endurance training triggered a reduction in the expression of Cpt1b and AcadL genes involved in fatty acid catabolism in the heart of Nmrk2−/− mice, not in control mice. NAD levels were not altered in heart or skeletal muscle, nor at baseline neither after exercise training in any group. Myh7 gene encoding for the slow MHC-I was more strongly induced by exercise in Nmrk2−/− mice than in controls. Moreover, IL-15 expression levels is higher in Nmrk2−/− mice skeletal muscle at baseline compared to controls. No fiber type switch was observed in plantaris after exercise, but fast fibers diameter was reduced in aged control mice, not in Nmrk2−/− mice. No fiber type switch or diameter modification was observed in soleus muscle.Conclusion: In this study, we demonstrated for the first time a phenotype in old Nmrk2−/− mice in response to endurance exercise training. Although NMRK2 seems to be predominantly dispensable to maintain global NAD levels in heart and skeletal muscle, we demonstrated a maladaptive metabolic response to exercise in cardiac and skeletal muscle, showing that NMRK2 has a specific and restricted role in NAD signaling compared to the NAMPT pathway

Nmrk2 gene is upregulated in dilated cardiomyopathy and required for cardiac function and nad levels during aging

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential

Asymmetric Organocatalytic C-C Bond Forming Reactions with Organoboron Compounds: A Mechanistic Survey

The recent development of asymmetric organocatalytic C-C bond forming reactions involving organoboranes has attracted big interest in the synthetic community. Asymmetric organocatalytic additions to enones, aldehydes, ketones, imines, dienes, and related systems can be carried out with different organoboron compounds (boronic acids and esters and trifluoroborate salts) to give products with very good yields and enantiomeric ratios. In particular, many BINOL and α-hydroxyacid derivatives have been used as chiral organocatalysts. In this review, we describe the mechanisms that have been proposed based on theoretical and experimental studies for asymmetric organocatalytic C-C bond forming reactions with organoboron compounds. The mechanistic understanding that has been gained should contribute to the progress of this promising area of organic chemistry.Fil: Simonetti, Sebastián Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Pellegrinet, Silvina Carla. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentin

Effets de l’exercice et d’une modulation du métabolisme du NAD sur la fonction cardiaque et musculaire dans la cardiomyopathie dilatée

Heart failure is a complex and multifactorial syndrome characterized by a global reduction of cardiac metabolic capacities. Exercise is a well-known strategy used for the prevention of cardiovascular diseases and its beneficial effects on skeletal muscle metabolism are well established. However, its impact on cardiac tissue in a pathological context and notably in the context of dilated cardiomyopathy are still very poorly described. Moreover, NAD levels has been described to be altered with heart failure in humans and in different animal models. An alternative strategy to actual pharmacological treatments would be to use precursors of the vitamin B3 family to boost NAD biosynthesis and target more precisely the metabolic troubles associated with heart failure. Among those precursors, Nicotinamide Riboside (NR), used by NMRK kinases seems promising, but its effects have never been described in the heart and in the context of DCM. The objective of this thesis is to characterize the effects of exercise and of a modulation of NAD metabolism by NR on cardiac and skeletal muscle in the context of DCM, and the role played by NMRK2 kinase in modulating NAD levels and in response to NR. Our results described the beneficial role of exercise and NR supplementation of cardiac function in the context of DCM, even though the NMRK2 doesn’t seems to be essential to these effects.L’insuffisance cardiaque est un syndrome complexe et multifactoriel caractérisé par une atteinte globale des capacités métaboliques cardiaques. L’exercice est une stratégie bien connue de prévention des maladies cardiovasculaires et ses effets bénéfiques sur le métabolisme musculaire sont assez bien établis. En revanche, son impact sur le tissu cardiaque en condition pathologique et notamment dans le contexte de la cardiomyopathie dilatée (CMD) sont encore très peu décrits. D’autre part, les taux de NAD ont été décrit comme altérés dans le contexte de l’insuffisance cardiaque chez l’homme et dans différents modèles animaux. Une stratégie alternative aux traitements pharmacologiques actuels serait d’utiliser des précurseurs de la famille des vitamines B3 pour stimuler la biosynthèse du NAD+ et ainsi cibler plus directement les troubles métaboliques associés à l’insuffisance cardiaque. Parmi ces précurseurs, le Nicotinamide Riboside (NR), utilisé par les kinases NMRK semble être le plus prometteur, mais ses effets n’ont jamais été décrits dans le cœur et dans le contexte de la CMD. Cette thèse a pour objectif d’étudier les effets de l’exercice et de la modulation du métabolisme du NAD par le NR sur la fonction cardiaque et musculaire dans le contexte de la CMD, ainsi que le rôle de la kinase NMRK2 dans la modulation des taux de NAD et dans la réponse au NR. Les résultats obtenus ont permis de mettre en évidence le rôle bénéfique de l’exercice et de la supplémentation en NR sur la fonction cardiaque dans le contexte de la CMD, même si la kinase NMRK2 ne semble pas prendre une part essentielle à ces effets

POLITIQUES DE MAINTENANCE CONDITIONNELLE POUR UN SYSTEME A DEGRADATION CONTINUE SOUMIS A UN ENVIRONNEMENT STRESSANT

One of the challenges of maintenance optimisation is the development of decision-making models combining performance at the strategic level and at the operational level. A classic hypothesis is to consider that the degradation level of the system can be modelled by a stochastic process characterized in stationary state without taking into account the effects of the operating environment on the system. This hypothesis can be seen as one of the factors leading to gaps between expected performance and measured performance of maintenance policies. However, many works have been developed in the reliability field for the integration of the impact of these environmental conditions. The main objective of this manuscript is to develop maintenance decision tools for gradually deteriorating systems evolving in a stressful environment. First, we propose different ways to model the environment and its impact since it can directly influence the system failure or the degradation process. We express mutual relationships between environment and the degradation processes. Next, we propose and compare different adaptive maintenance policies which are based not only on the degradation level, but also on the stressful environment level. In addition, the proposed policies can be based either on an a priori knowledge of the system, or integrate the available online information on the environment. We will try throughout this manuscript to propose new maintenance approaches which combine theoretical expected performance on one side and operational reality and pragmatism on the other.L'un des challenges de l'optimisation de la maintenance est la production de modèles décisionnels conjuguant performance au niveau stratégique et au niveau opérationnel. Une hypothèse classique est de considérer que le niveau de dégradation du système peut être modélisé par un processus stochastique particulier caractérisé en régime stationnaire sans tenir compte des effets de l'environnement d'exploitation du système. Cette hypothèse peut être vue comme un des facteurs entraînant des écarts entre les performances attendues et celles mesurées. Par contre, de nombreux travaux sont développés dans le cadre de la fiabilité pour l'intégration de l'impact de l'environnement. L'objectif de ce manuscrit est de développer des outils d'aide à la décision de maintenance pour des systèmes à dégradation graduelle évoluant dans un environnement aléatoire stressant. Nous proposons différentes modélisations de l'environnement et de son impact sachant qu'il peut influencer soit la défaillance du système, soit le processus de dégradation. Nous explicitons les relations mutuelles entre l'environnement et le processus de dégradation et nous construisons différentes politiques de maintenance adaptatives qui se basent sur l'état de dégradation du système mais également sur l'évolution de l'environnement. De plus, les politiques proposées permettent de se baser soit uniquement sur une connaissance a priori du système, soit d'intégrer l'information disponible en ligne concernant l'environnement. Nous chercherons dans ce manuscrit à proposer de nouvelles approches de maintenance combinant performances théoriques attendues d'un côté et réalité et pragmatisme opérationnels d'un autre