Exergetic Control Charts (Variability Analysis in a Real Injection-moulding Industrial Application)

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Coagulopathy of Acute Sepsis

Coagulopathy is common in acute sepsis and may range from subclinical activation of blood coagulation (hypercoagulability), which may contribute to venous thromboembolism, to acute disseminated intravascular coagulation, characterized by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, eventually causing bleeding. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the pathogen leading to the overexpression of inflammatory mediators. The latter, along with the microorganism and its derivatives drive the major changes responsible for massive thrombin formation and fibrin deposition: (1) aberrant expression of tissue factor mainly by monocytes-macrophages, (2) impairment of anticoagulant pathways, orchestrated by dysfunctional endothelial cells (ECs), and (3) suppression of fibrinolysis because of the overproduction of plasminogen activator inhibitor-1 by ECs and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Neutrophils and other cells, upon activation or death, release nuclear materials (neutrophil extracellular traps and/or their components such as histones, DNA, lysosomal enzymes, and High Mobility Group Box-1), which have toxic, proinflammatory and prothrombotic properties thus contributing to clotting dysregulation. The ensuing microvascular thrombosis–ischemia significantly contributes to tissue injury and multiple organ dysfunction syndromes. These insights into the pathogenesis of sepsis-associated coagulopathy may have implications for the development of new diagnostic and therapeutic tools

Sepsis-Associated Disseminated Intravascular Coagulation and Thromboembolic Disease

Sepsis is almost invariably associated with haemostatic abnormalities ranging from subclinical activation of blood coagulation (hypercoagulability), which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), characterized by massive thrombin formation and widespread microvascular thrombosis, partly responsible of the multiple organ dysfunction syndrome (MODS), and subsequent consumption of platelets and coagulation proteins causing, in most severe cases, bleeding manifestations. There is general agreement that the key event underlying this life-threatening sepsis complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. Mechanistically, the latter, together with the micro-organism and its derivatives, causes DIC by 1) up-regulation of procoagulant molecules, primarily tissue factor (TF), which is produced mainly by stimulated monocytes-macrophages and by specific cells in target tissues; 2) impairment of physiological anticoagulant pathways (antithrombin, protein C pathway, tissue factor pathway inhibitor), which is orchestrated mainly by dysfunctional endothelial cells (ECs); and 3) suppression of fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1) by ECs and likely also to thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Notably, clotting enzymes non only lead to microvascular thrombosis but can also elicit cellular responses that amplify the inflammatory reactions. Inflammatory mediators can also cause, directly or indirectly, cell apoptosis or necrosis and recent evidence indicates that products released from dead cells, such as nuclear proteins (particularly extracellular histones), are able to propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenetic mechanisms of DIC and MODS may have important implications for the development of new therapeutic agents that could be potentially useful particularly for the management of severe sepsis

Histones differentially modulate the anticoagulant and profibrinolytic activities of heparin, heparin derivatives and dabigatran.

The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator–mediated clot lysis by turbidimetry, and thrombinactivatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparin

Industry 4.0 paradigm: The viewpoint of the small and medium enterprises

International audienceThe pervasive diffusion of Information and Communication technologies (ICT) and automation technologies are the prerequisite for the preconized fourth industrial revolution: the Industry 4.0 (I4.0). Despite the economical efforts of several governments all over the world, still there are few companies, especially small and medium enterprises (SMEs), that adopt or intend to adopt in the near future I4.0 solutions. This work focus on key issues for implementing the I4.0 solutions in SMEs by using a specific case example as a test bench of an Italian small manufacturing company. Requirements and constraints derived from the field experience are generalised to provide a clear view of the profound potentialities and difficulties of the first industrial revolution announced instead of being historically recognised. A preliminary classification is then provided in view to start conceiving a library of Industry 4.0 formal patterns to identify the maturity of a SME for deploying Industry 4.0 concepts and technologies

Gene expression signature induced by grape intake in healthy subjects reveals wide-spread beneficial effects on peripheral blood mononuclear cells

Abstract Using a transcriptomic approach, we performed a pilot study in healthy subjects to evaluate the changes in gene expression induced by grape consumption. Blood from twenty subjects was collected at baseline (T0), after 21 days of grape-rich diet (T1) and after one-month washout (T2). Gene expression profiling of peripheral blood mononuclear cells from six subjects identified 930 differentially expressed transcripts. Gene functional analysis revealed changes (at T1 and/or T2) suggestive of antithrombotic and anti-inflammatory effects, confirming and extending previous finding on the same subjects. Moreover, we observed several other favourable changes in the transcription of genes involved in crucial processes such as immune response, DNA and protein repair, autophagy and mitochondrial biogenesis. Finally, we detected significant changes in many long non-coding RNAs genes, whose regulatory functions are being increasingly appreciated. Altogether, our data suggest that a grape diet may exert its beneficial effects by targeting different strategic pathways

Contribution to the formalisation of data-driven invariant modelling constructs of Cyber-Physical Systems

La transformation numérique des entreprises manufacturières collaboratives en réseau nécessite la construction et l'application de modèles numériques représentant l'ensemble des ressources et des connaissances sur les processus. La modélisation d'une telle copie numérique du système physique pour effectuer une validation et une optimisation en temps réel est assez complexe et nécessite donc une grande quantité de données et quelques modèles de modélisation représentant la sémantique opérationnelle des éléments modélisés. En règle générale, l'action de modélisation a un type d'application localisé et spécifique. Fort de ce constat, le principal défi de la modélisation de la transformation numérique est de créer une approche invariante, à savoir un modèle décomposable et recomposable vers différentes applications. La thèse vise à identifier et formaliser des éléments de modélisation contribuant à construire des modèles informationnels et fonctionnels pour améliorer la durabilité des processus de fabrication et des produits, basés sur des composants en réseau. Ces éléments formels permettront alors de représenter la connaissance et sa relation profonde avec les processus de fabrication. Ils rendent ainsi les connaissances partagées plus facilement réutilisables et sont à la base des efforts de normalisation.The digital transformation of collaborative networked manufacturing enterprises requires the building and the applying digital models representing the set of resources and processes knowledge. Modelling such digital copy of the physical system to perform real-time validation and optimization is quite complex and thus needs a big amount of data and some modelling patterns representing the operational semantics of the modelled elements. Generally, the modelling action has a specific application type. For this reason, the core challenge of the digital transformation modelling is to create an invariant approach, namely a decomposable and re-composable model, towards different applications. This PhD thesis aims at identifying and formalising modelling constructs contributing at building informational and functional models for improving the sustainability of manufacturing processes and products based on networked components. The constructs will then allow representing knowledge and its deep relationship with the manufacturing processes. They make the shared knowledge more readily reusable and are at the basis of standardization efforts

Contribution à la formalisation d'invariants de modélisation de systèmes cyber-physiques, dirigés par les données

The digital transformation of collaborative networked manufacturing enterprises requires the building and the applying digital models representing the set of resources and processes knowledge. Modelling such digital copy of the physical system to perform real-time validation and optimization is quite complex and thus needs a big amount of data and some modelling patterns representing the operational semantics of the modelled elements. Generally, the modelling action has a specific application type. For this reason, the core challenge of the digital transformation modelling is to create an invariant approach, namely a decomposable and re-composable model, towards different applications. This PhD thesis aims at identifying and formalising modelling constructs contributing at building informational and functional models for improving the sustainability of manufacturing processes and products based on networked components. The constructs will then allow representing knowledge and its deep relationship with the manufacturing processes. They make the shared knowledge more readily reusable and are at the basis of standardization efforts.La transformation numérique des entreprises manufacturières collaboratives en réseau nécessite la construction et l'application de modèles numériques représentant l'ensemble des ressources et des connaissances sur les processus. La modélisation d'une telle copie numérique du système physique pour effectuer une validation et une optimisation en temps réel est assez complexe et nécessite donc une grande quantité de données et quelques modèles de modélisation représentant la sémantique opérationnelle des éléments modélisés. En règle générale, l'action de modélisation a un type d'application localisé et spécifique. Fort de ce constat, le principal défi de la modélisation de la transformation numérique est de créer une approche invariante, à savoir un modèle décomposable et recomposable vers différentes applications. La thèse vise à identifier et formaliser des éléments de modélisation contribuant à construire des modèles informationnels et fonctionnels pour améliorer la durabilité des processus de fabrication et des produits, basés sur des composants en réseau. Ces éléments formels permettront alors de représenter la connaissance et sa relation profonde avec les processus de fabrication. Ils rendent ainsi les connaissances partagées plus facilement réutilisables et sont à la base des efforts de normalisation

MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES www.mjhid.org ISSN 2035-3006 Review article Sepsis-Associated Associated Disseminated Intravascular Coagulation and Thromboembolic

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