A framework for Model-Driven Engineering of resilient software-controlled systems

AbstractEmergent paradigms of Industry 4.0 and Industrial Internet of Things expect cyber-physical systems to reliably provide services overcoming disruptions in operative conditions and adapting to changes in architectural and functional requirements. In this paper, we describe a hardware/software framework supporting operation and maintenance of software-controlled systems enhancing resilience by promoting a Model-Driven Engineering (MDE) process to automatically derive structural configurations and failure models from reliability artifacts. Specifically, a reflective architecture developed around digital twins enables representation and control of system Configuration Items properly derived from SysML Block Definition Diagrams, providing support for variation. Besides, a plurality of distributed analytic agents for qualitative evaluation over executable failure models empowers the system with runtime self-assessment and dynamic adaptation capabilities. We describe the framework architecture outlining roles and responsibilities in a System of Systems perspective, providing salient design traits about digital twins and data analytic agents for failure propagation modeling and analysis. We discuss a prototype implementation following the MDE approach, highlighting self-recovery and self-adaptation properties on a real cyber-physical system for vehicle access control to Limited Traffic Zones

Granulocyte- and monocyte-platelet adhesion index in coronary and peripheral blood after extracorporeal circulation and reperfusion

Background: Neutrophil-granulocyte and mononuclear-cell functional changes occur during cardiopulmonary bypass and cardiovascular surgery. Leukocyte-platelet interaction, leading to generation of heterotypic co-aggregates, represents an amplification mechanism of local inflammatory response and tissue damage. Methods: Samples of 20 patients were drawn from coronary sinus before cardioplegia and after reperfusion, as well as from peripheral blood at 5 and 24 hours postoperatively. Granulocyte and monocyte expression of CD162, CD15s, CD18 and CD11b were quantified by flow cytometry at the different times. Parallel variations of leukocyte-platelet conjugates (percentages) and a derived (cell number-normalized) leukocyte-platelet adhesion index were measured using antibodies against CD45, CD14 and CD41a. The evaluation of platelet functional state was carried out using antibodies against CD62P (P-selectin) and PAC-1. Results: Monocyte and granulocyte cell number increased in coronary blood at reperfusion and in peripheral blood post-operatively. A different course characterized the changes of the leukocyte-platelet adhesion index with respect to the variations of circulating leukocyte-platelet co-aggregates . Leukocyte molecules expression showed no significant variations for CD15s on both leukocyte subsets, while a significant up-modulation for CD162 was observed on monocytes at 24 hours after extracorporeal circulation (P=0.0002), and for CD11b on granulocytes at 5 hours post-operatively (P=0.033). A loss of CD162 expression was observed at reperfusion (P=0.0038) on granulocytes, associated to a down-modulation of CD18 (P=0.0033) and CD11b (P=0.0184) in peripheral blood at 24 hours. No significant up-regulation of platelet activatory molecules was found at reperfusion, as well as post-operatively, when compared with the before-cardioplegia derived data. Conclusions: The variations of a normalized leukocyte-platelet adhesion index seem to reflect the leukocyte-platelet functional interaction more accurately than the measurements of cellular conjugates. The absence of platelet activation suggests that the leukocyte membrane modifications play a main role in controlling the formation and stability of heterotypic leukocyte-platelet co-aggregates after cardiac surgery with extracorporeal circulation

Von Willebrand Factor Antigen Predicts Response to Double Dose of Aspirin and Clopidogrel by PFA-100 in Patients Undergoing Primary Angioplasty for St Elevation Myocardial Infarction

Von Willebrand factor (VWF) is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100) with Collagen/Epinephrine (CEPI) is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR). The objective of this study was to verify the effect of double dose (DD) of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, n=58) or DD of aspirin and clopidogrel (DD, n=58), maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2). At Times 1 and 2 we observed a significantly higher CEPI closure times (CT) in DD as compared to SD (P<0.001). Delta of CEPI-CT (T1-T0) was significantly related to VWF (P<0.001) and inversely related to ADAMTS-13 (0.01). Responders had a significantly higher level of VWF at T0. Finally, in a multivariate model analysis, VWF and ADAMTS-13 in resulted significant predictors of CEPI-CT response (P=0.02). HRP detected by PFA-100 in acute myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF

Targeted DNA oxidation by LSD1–SMAD2/3 primes TGF-β1/ EMT genes for activation or repression

Abstract The epithelial-to-mesenchymal transition (EMT) is a complex transcriptional program induced by transforming growth factor β1 (TGF-β1). Histone lysine-specific demethylase 1 (LSD1) has been recognized as a key mediator of EMT in cancer cells, but the precise mechanism that underlies the activation and repression of EMT genes still remains elusive. Here, we characterized the early events induced by TGF-β1 during EMT initiation and establishment. TGF-β1 triggered, 30–90 min post-treatment, a nuclear oxidative wave throughout the genome, documented by confocal microscopy and mass spectrometry, mediated by LSD1. LSD1 was recruited with phosphorylated SMAD2/3 to the promoters of prototypic genes activated and repressed by TGF-β1. After 90 min, phospho-SMAD2/3 downregulation reduced the complex and LSD1 was then recruited with the newly synthesized SNAI1 and repressors, NCoR1 and HDAC3, to the promoters of TGF-β1-repressed genes such as the Wnt soluble inhibitor factor 1 gene (WIF1), a change that induced a late oxidative burst. However, TGF-β1 early (90 min) repression of transcription also required synchronous signaling by reactive oxygen species and the stress-activated kinase c-Jun N-terminal kinase. These data elucidate the early events elicited by TGF-β1 and the priming role of DNA oxidation that marks TGF-β1-induced and -repressed genes involved in the EMT

Von Willebrand Factor Antigen Predicts Response to Double Dose of Aspirin and Clopidogrel by PFA-100 in Patients Undergoing Primary Angioplasty for St Elevation Myocardial Infarction

Von Willebrand factor (VWF) is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100) with Collagen/Epinephrine (CEPI) is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR). The objective of this study was to verify the effect of double dose (DD) of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, = 58) or DD of aspirin and clopidogrel (DD, = 58), maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2). At Times 1 and 2 we observed a significantly higher CEPI closure times (CT) in DD as compared to SD ( &lt; 0.001). Delta of CEPI-CT( 1 − 0) was significantly related to VWF ( &lt; 0.001) and inversely related to ADAMTS-13 (0.01). Responders had a significantly higher level of VWF at 0. Finally, in a multivariate model analysis, VWF and ADAMTS-13 in resulted significant predictors of CEPI-CT response ( = 0.02). HRP detected by PFA-100 in acute myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF