Characterization of the cargo of circulating extracellular vesicles in patients affected with idiopathic inflammatory myopathies and evaluation of clinical correlates in a cross-sectional comparative analysis from a monocentric cohort.

openBackground Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune disorders that comprise different clinical entities, characterized by different features. Although several myositis-specific and myositis-associated antibodies have been characterized, the molecular mechanisms underlying these conditions require further exploration. The research field on extracellular vescicles (EVs) is rapidly evolving, highlighting their role in intercellular communication. EVs convoy a cargo of proteins and nucleic acids, such as microRNA (miRNAs), that mediate immune-response regulation in autoimmune diseases. miRNAs regulate gene-expression post-transcriptionally and are involved in multiple molecular pathways of human disease. Evidence of EVs and miRNAs in IIM is still limited and undefined. Aim of the study This study aims to quantify the circulating EVs and characterize their cargo, with a specific focus on miRNAs content to propose novel biomarkers of IIM. Materials and methods A monocentric study was conducted including adult IIM patients (≥18 years old) followed at the Rheumatology Unit of Padua University Hospital, and age- and sex- matched healthy controls (HD). EVs were isolated from platelet-free plasma through size exclusion chromatography followed by ultrafiltration. EVs were quantified by nanoparticle tracking analysis (NTA) and. EV-miRNA cargo was investigated through Next-Generation Sequencing (NGS). Statistical analysis was performed with parametric Student-T test and one-way Anova (Bonferroni correction). Results Sixty-four consecutive IIM patients and sixty-five HDs were included in the study. NTA measurements of EVs concentration showed a significantly higher mean concentration of circulating EVs in IIM patients than in HD (p=0.0073). Across IIM subsets, patients affected with cancer associated myositis (CAM) displayed the highest levels of circulating EVs compared to no CAM patients (p=0.0060) and to HD (p=0.0004). Patients with circulating myositis-associated autoantibodies displayed significantly higher EV levels than HD (p=0.0363). Patients in clinical remission displayed higher levels of circulating EVs compared to those with active disease (p=0.0087). EVs levels were significantly reduced in IIM patients treated with rituximab (RTX) than in patients receiving other treatments (p<0.0001). NGS analysis detected EV-miRNAs with different expression profiles between IIM (n=47) and HDs (n=49): miR-223-3p (p=0.019), miR-15a-5p (p=0.0189), miR-451a (p=0.0074), miR-486-5p (p=0.0052), miR-32-5p (p=0.0146), and miR-222-3p (p=0.0282) were up-regulated in IIM, while miR-141-3p (p=0.0313), miR-142-3p (p=0.0244), and let-7a-5p (p=0.0003) were down-regulated in IIM patients vs. HDs. Other EV-miRNAs expression varied across IIM subsets: CAM patients displayed up-regulated expression of miR-143-3p compared to non-CAM patients (p=0.0085), while miR-148a-3p (p=0.0171) and miR-335-5p (p=0.0171) were up-regulated in dermatomyositis vs. polymyositis/ inclusion body myositis/anti-synthetase syndrome patients. Patients characterized by active disease displayed an up-regulated expression of miR-222-3p (p=0.002) and miR-151-3p (p=0.0233) and down-regulated expression of miR-363-3p (p=0.0001), miR-374a-5p (p=0.0258), miR-144-3p (p=0.0170), miR-181a-5p (p=0.0037) compared to those in clinical remission. Moreover, IIM patients receiving only glucocorticoids (GC) reported up-regulated expression of miR-4433b-5p (p=0.0439), miR-92a-3p (p=0.0111), let-7f-5p (p=0.0304), and down-regulated expression of miR-27a-3p (p=0.0486) compared to patients receiving GC in combination with immunosuppressants (IS). Conclusions Our results showed significantly increased concentration of circulating EVs in IIM patients. That is confirmed within specific disease phenotypes and pharmacological treatments. EV miRNAs exhibited a differential expression profile between IIM and HD, and significant differences were outlined among IIM subsets.Background Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune disorders that comprise different clinical entities, characterized by different features. Although several myositis-specific and myositis-associated antibodies have been characterized, the molecular mechanisms underlying these conditions require further exploration. The research field on extracellular vescicles (EVs) is rapidly evolving, highlighting their role in intercellular communication. EVs convoy a cargo of proteins and nucleic acids, such as microRNA (miRNAs), that mediate immune-response regulation in autoimmune diseases. miRNAs regulate gene-expression post-transcriptionally and are involved in multiple molecular pathways of human disease. Evidence of EVs and miRNAs in IIM is still limited and undefined. Aim of the study This study aims to quantify the circulating EVs and characterize their cargo, with a specific focus on miRNAs content to propose novel biomarkers of IIM. Materials and methods A monocentric study was conducted including adult IIM patients (≥18 years old) followed at the Rheumatology Unit of Padua University Hospital, and age- and sex- matched healthy controls (HD). EVs were isolated from platelet-free plasma through size exclusion chromatography followed by ultrafiltration. EVs were quantified by nanoparticle tracking analysis (NTA) and. EV-miRNA cargo was investigated through Next-Generation Sequencing (NGS). Statistical analysis was performed with parametric Student-T test and one-way Anova (Bonferroni correction). Results Sixty-four consecutive IIM patients and sixty-five HDs were included in the study. NTA measurements of EVs concentration showed a significantly higher mean concentration of circulating EVs in IIM patients than in HD (p=0.0073). Across IIM subsets, patients affected with cancer associated myositis (CAM) displayed the highest levels of circulating EVs compared to no CAM patients (p=0.0060) and to HD (p=0.0004). Patients with circulating myositis-associated autoantibodies displayed significantly higher EV levels than HD (p=0.0363). Patients in clinical remission displayed higher levels of circulating EVs compared to those with active disease (p=0.0087). EVs levels were significantly reduced in IIM patients treated with rituximab (RTX) than in patients receiving other treatments (p<0.0001). NGS analysis detected EV-miRNAs with different expression profiles between IIM (n=47) and HDs (n=49): miR-223-3p (p=0.019), miR-15a-5p (p=0.0189), miR-451a (p=0.0074), miR-486-5p (p=0.0052), miR-32-5p (p=0.0146), and miR-222-3p (p=0.0282) were up-regulated in IIM, while miR-141-3p (p=0.0313), miR-142-3p (p=0.0244), and let-7a-5p (p=0.0003) were down-regulated in IIM patients vs. HDs. Other EV-miRNAs expression varied across IIM subsets: CAM patients displayed up-regulated expression of miR-143-3p compared to non-CAM patients (p=0.0085), while miR-148a-3p (p=0.0171) and miR-335-5p (p=0.0171) were up-regulated in dermatomyositis vs. polymyositis/ inclusion body myositis/anti-synthetase syndrome patients. Patients characterized by active disease displayed an up-regulated expression of miR-222-3p (p=0.002) and miR-151-3p (p=0.0233) and down-regulated expression of miR-363-3p (p=0.0001), miR-374a-5p (p=0.0258), miR-144-3p (p=0.0170), miR-181a-5p (p=0.0037) compared to those in clinical remission. Moreover, IIM patients receiving only glucocorticoids (GC) reported up-regulated expression of miR-4433b-5p (p=0.0439), miR-92a-3p (p=0.0111), let-7f-5p (p=0.0304), and down-regulated expression of miR-27a-3p (p=0.0486) compared to patients receiving GC in combination with immunosuppressants (IS). Conclusions Our results showed significantly increased concentration of circulating EVs in IIM patients. That is confirmed within specific disease phenotypes and pharmacological treatments. EV miRNAs exhibited a differential expression profile between IIM and HD, and significant differences were outlined among IIM subsets

Estimation of synchronous generator participation in low-frequency oscillations damping based on synchronized phasor measurements

Large-scale centralized power systems interconnected by weak tie-lines is a typical feature of the state-of-the-industry power engineering. Another trend is distributed generation units integration with the resulting decrease of power system inertia constant and increasing sensitivity to small disturbances. In particular, in the case of significant power imbalance, periodic low-frequency oscillations of power system performance parameters may arise. Low frequency oscillations in power systems are inherently non-linear and non-stationary processes representing a superposition of numerous rotating masses movement components having mutual influence in a power region or power center. These situations imply the crucial role of monitoring each generator damping capability which is determined by the adjustment of the system regulators in use. To estimate the synchronous generator capability to maintain synchronous operation under deviating frequency and load angle conditions synchronizing torque and corresponding synchronizing power are proposed to be used. The possibility to determine the synchronous machine synchronizing power is subject to the presence of the load angle variation data with the techniques for defining load angle without direct measurement using a system of assumptions have been analyzed. Numerous simulations have shown that the effect of assumptions can be evaluated as acceptable. The main focus of the paper is the analysis of synchronizing power corresponding to the actual generator involved in the oscillations which had arisen after a disturbance in the Unified Energy System of Russia. The supposed cause of the oscillations is improper automatic excitation controller operation. © 2014 WIT Press.International Journal of Safety and Security Engineering;International Journal of Sustainable Development and Planning;WIT Transactions on Ecology and the Environmen

Review of the temperature and holding time effects on hydroxyapatite fabrication from the natural sources

Biomaterial development is currently being carried out to help people who have daily needs. Hydroxyapatite has biocompatibility properties and suitables for the use as a biomaterial. Hydroxyapatite can be found in natural sources sometimes as waste. One of the hydroxyapatite fabrication methods is calcination process. Calcination and sintering are used to obtain the desired Ca/P ratio of the hydroxyapatite. This paper reviews several research which have been published by researchers to withdraw the connection during calcination process, with respect to the temperature and holding time effects on hydroxyapatite fabrication from the natural organism. The effect of temperature and holding time determines the yield of Ca/P ratio which affects the resulting mechanical properties. Choosing the right temperature and holding time will produce Ca/P which meets the standar

Mechanical behavior modeling in the presence of strain aging

International audiencePiobert-Luders phenomenon is modeled by means ....

Assessing Systemic Risk of the European Insurance Industry

This paper investigates the systemic relevance of the insurance industry. We do it by analysing the systemic contribution of the insurance industry vis-á-vis other industries by applying three measures, namely the linear Granger causality test, conditional value at risk and marginal expected shortfall, to three groups, namely banks, insurers and non-financial companies listed in Europe over the last 14 years. Our evidence suggests that the insurance industry shows i) a persistent systemic relevance over time, ii) it plays a subordinate role in causing systemic risk compared to banks. In addition, iii) we do not find clear evidence on the higher systemic relevance of SIFI insurers compared to non-SIFIs

Insurance Activities and Systemic Risk

This paper investigates systemic risk in the insurance industry. We first analyze the systemic contribution of the insurance industry vis-`a-vis other industries by applying 3 measures, namely the linear Granger causality test, conditional value at risk and marginal expected shortfall, on 3 groups, namely banks, insurers and non-financial companies listed in Europe over the last 14 years. We then analyze the determinants of the systemic risk contribution within the insurance industry by using balance sheet level data in a broader sample. Our evidence suggests that i) the insurance industry shows a persistent systemic relevance over time and plays a subordinate role in causing systemic risk compared to banks, and that ii) within the industry, those insurers which engage more in non-insurance-related activities tend to pose more systemic risk. In addition, we are among the first to provide empirical evidence on the role of diversification as potential determinant of systemic risk in the insurance industry. Finally, we confirm that size is also a significant driver of systemic risk, whereas price-to-book ratio and leverage display counterintuitive results

Influence of dynamic strain ageing on ductile fracture of a C-Mn steel

International audienceDuctile fracture of a C-Mn steel was characterised by tensile tests performed in a largetemperature range (from 20 to 350°C) on round notched specimens. The experimentalresults revealed a sharp drop of fracture strain around 250°C. This corresponds to thedomain of dynamic strain ageing (DSA) occurrence. The Portevin-Le Chatelier (PLC) effect,which is the most classical effect of DSA, was modelled on round notched specimens with amechanical behaviour model including the strain ageing effect. Local approach to fracturewas applied to predict the ductile fracture using the Rice and Tracey criterion. Thepredictions are rather close to the experimental results for the low and high temperatures. Inthe DSA domain, the approach predicts a decrease of the fracture strain but with a lowermagnitude than the experimental one. Therefore, DSA has an effect on mechanical behaviour but also on fracture mechanisms. Consequently, the fracture criterion has to bemodified in the presence of DSA

Modélisation dynamique d'essais d'arrêt de fissure à l'aide d'un critère local en contrainte critique

Un critère local d'arrêt de fissure a récemment été proposé dans la littérature pour simuler la propagation de fissure de clivage dans un acier bainitique faiblement allié : la fissure se propage tant que la contrainte principale maximale atteint une contrainte critique dépendant de la température. Des essais d'arrêt de fissure isothermes ont été réalisés sur des différentes géométries. L'étude proposée montre que application du critère sur ces configurations permet de bien prédire les vitesses de propagation ainsi que les sauts de fissure à l'arrêt obtenus expérimentalement

Local Approach of the Charpy Test at Low Temperature

Charpy V-notch impact testing is widely used in the toughness assessment of large forged components, e.g. the pressure vessel for pressurised water reactors (PWR). At low temperature, A508 Cl.3 nuclear pressure vessel steel fails by cleavage fracture. The results reported here are part of both an experimental program and numerical investigations which aim at the establishment of a non-empirical relationship between the lower shelf Charpy V-notch energy, CVN, and the fracture toughness, KIc, of this material. Here, the applicability of the Beremin cleavage fracture model to the Charpy specimen is demonstrated