Search

DNA methylation is associated with gene silencing, but its clinical role in cardiovascular diseases (CVDs) remains to be elucidated. We hypothesized that extracellular vesicles (EVs) may carry epigenetic changes, showing themselves as a potentially valuable non-invasive diagnostic liquid biopsy. We isolated and characterized circulating EVs of acute coronary syndrome (ACS) patients and assessed their role on DNA methylation in epigenetic modifications.EVs were recovered from plasma of 19 ACS patients and 50 healthy subjects (HS). Flow cytometry, qRT-PCR, and Western blot (WB) were performed to evaluate both intra-vesicular and intra-cellular signals. ShinyGO, PANTHER, and STRING tools were used to perform GO and PPI network analyses.ACS-derived EVs showed increased levels of DNA methyltransferases (DNMTs) (p0.001) and Ten-eleven translocation (TET) genes reduction. Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B, were significantly increased in plasma ACS-EVs. DNA methylation analysis on PBMCs from healthy donors treated with HS- and ACS-derived EVs showed an important role of DNMTs carried by EVs. PPI network analysis evidenced that ACS-EVs induced changes in PBMC methylome. In the most enriched subnetwork, the hub gene SRC was connected to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, BAIAP2 genes that were showed to have many molecular effects on various cell types into onset of several CVDs. Modulation in gene expression after ACS-EVs treatment was confirmed for SRC, NOTCH1, FOXO3, RXRA, DGKG and BAIAP2 (p0.05).Our data showed an important role for ACS-derived EVs in gene expression modulation through de novo DNA methylation signals, and modulating signalling pathways in target cells.

Background Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. Research Question The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19. Study Design and Methods This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity. Results Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002). Interpretation A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.

Purpose Circulating extracellular vesicles (EVs) are raising considerable interest as a non-invasive diagnostic tool.We aimed to investigate differences in plasma-derived EV surface protein profiles as a biomarker to be used in combination with endomyocardial biopsies (EMBs) for the diagnosis of allograft rejection. Methods Plasma was collected from 90 patients (53 training cohort, 37 validation cohort) before EMB. EV concentration was assessed by nanoparticle tracking analysis. EV surface antigens were measured using a multiplex flow cytometry assay composed of 37 fluorescently labeled capture bead populations coated with specific antibodies directed against respective EV surface epitopes. According to differential EV-markers expression two diagnostic model were built and validated through supervised learning algorithms (linear discriminant analysis-LDA- and random forest model- RF) Results The concentration of EVs was significantly increased and their diameter decreased in patients undergoing rejection as compared with negative ones. The trend was highly significant for both antibody-mediated rejection and acute cellular rejection (p Conclusion Circulating EVs are highly promising as a new tool to characterize cardiac allograft rejection and to be complementary to EMB monitoring

We study the pre-equilibrium dipole response in the charge-asymmetric reaction $^{132}$Sn+$^{58}$Ni at $E_{lab}=10$ MeV/A, within a semi-classical transport model employing effective interactions for the nuclear mean-field. In particular, we adopt the recently introduced SAMi-J Skyrme interactions, whose parameters are specifically tuned to improve the description of spin-isospin properties of nuclei. Within the same framework, we also discuss pre-equilibrium nucleon emission. Our results show that both mechanisms, i.e., pre-equilibrium dipole oscillations and nucleon emission, are sensitive to the symmetry energy below the saturation density $\rho_0$ (in the range $0.6\rho_0-\rho_0$), to the effective mass and to the nucleon-nucleon cross section. Finally, a covariant analysis is applied to study the correlations between the model parameters and observables of experimental interest., Comment: 6 pages, 4 figures

Background Despite being widely recognized as the most common form of secondary hypertension, among the general hypertensive population the true prevalence of primary aldosteronism (PA) and its main subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), remains a matter of debate. Objectives This study sought to determine the prevalence and clinical phenotype of PA in a large cohort of unselected patients with hypertension, consecutively referred to our hypertension unit, by 19 general practitioners from Torino, Italy. Methods Following withdrawal from all interfering medications, patients were screened for PA using the ratio of serum aldosterone to plasma renin activity. PA was diagnosed according to Endocrine Society guidelines. The diagnosis was confirmed or excluded by an intravenous saline infusion test or captopril challenge test and subtype differentiation was performed by adrenal computed tomography scanning and adrenal vein sampling, using strict criteria to define successful cannulation and lateralization of aldosterone production. Results A total of 1,672 primary care patients with hypertension (569 newly diagnosed and 1,103 patients already diagnosed with arterial hypertension) were included in the study. A total of 99 patients (5.9%) were diagnosed with PA and conclusive subtype differentiation by adrenal vein sampling was made in 91 patients (27 patients with an APA and 64 patients with BAH). The overall prevalence of PA increased with the severity of hypertension, from 3.9% in stage 1 hypertension to 11.8% in stage 3 hypertension. Patients with PA more frequently displayed target organ damage and cardiovascular events compared with those without PA, independent of confounding variables. Conclusions Our results demonstrated that PA is a frequent cause of secondary hypertension, even in the general population of patients with hypertension, and indicates that most of these patients should be screened for PA.

Over the last years, Projected Entangled Pair States have demonstrated great power for the study of many body systems, as they naturally describe ground states of gapped many body Hamiltonians, and suggest a constructive way to encode and classify their symmetries. The PEPS study is not only limited to global symmetries, but has also been extended and applied for local symmetries, allowing to use them for the description of states in lattice gauge theories. In this paper we discuss PEPS with a local, SU(2) gauge symmetry, and demonstrate the use of PEPS features and techniques for the study of a simple family of many body states with a non-Abelian gauge symmetry. We present, in particular, the construction of fermionic PEPS able to describe both two-color fermionic matter and the degrees of freedom of an SU(2) gauge field with a suitable truncation., Comment: 48 pages, 26 Figures

Tensor networks, and in particular Projected Entangled Pair States (PEPS), are a powerful tool for the study of quantum many body physics, thanks to both their built-in ability of classifying and studying symmetries, and the efficient numerical calculations they allow. In this work, we introduce a way to extend the set of symmetric PEPS in order to include local gauge invariance and investigate lattice gauge theories with fermionic matter. To this purpose, we provide as a case study and first example, the construction of a fermionic PEPS, based on Gaussian schemes, invariant under both global and local U ( 1 ) gauge transformations. The obtained states correspond to a truncated U ( 1 ) lattice gauge theory in 2+1 dimensions, involving both the gauge field and fermionic matter. For the global symmetry (pure fermionic) case, these PEPS can be studied in terms of spinless fermions subject to a p-wave superconducting pairing. For the local symmetry (fermions and gauge fields) case, we find confined and deconfined phases in the pure gauge limit, and we discuss the screening properties of the phases arising in the presence of dynamical matter.

Objective To evaluate whether γ-aminobutyric acid receptors are involved in human sperm acrosome reaction induced by the follicular fluid (FF). Design Random selection of normal sperm samples. Setting Normal men in an university clinic of andrology. Patient(s) Men with normal sperm analysis parameters. Intervention(s) None. Main outcome measure(s) Acrosome reaction on motile spermatozoa. Result(s) Follicular fluid stimulated the acrosome reaction dose-dependently. The effect of a maximally effective concentration of FF (30%, vol/vol) was significantly suppressed by bicuculline, a GABAA receptor antagonist, and saclofen, a GABAB receptor antagonist, added concomitantly. Each of the two antagonists used alone was devoid of effect. Because the GABAA receptor is linked to the chloride channel, we tested whether picrotoxin, a blocker of this channel, could modulate the effects of the FF. Picrotoxin alone did not have any effect on the acrosome reaction induced by the FF, whereas it had a significant suppressive effect if coincubated with saclofen. The acrosome reaction induced by the FF was also inhibited by picrotoxin plus verapamil, a calcium channel blocker, whereas verapamil alone had no significant effect. This suggested that both chloride and calcium ions mediated the acrosome reaction induced by the FF. Conclusion(s) The simultaneous blockade of GABAA and GABAB receptors suppressed the acrosome reaction induced by the FF. This finding suggested that GABA receptors play a physiologic role in sperm activation and shed further light on the mechanism of FF action on human sperm acrosome reaction.