Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis. Differentiated HepaRG cells treated with the fatty acid sodium oleate (fatty dHepaRG) recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing STAT3-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-STAT3 binding sites were identified in fatty dHepaRG cells and several STAT3 and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of STAT3 activity decreased lipid accumulation and deregulated STAT3-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-STAT3-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging-dependent hepatic vesicular steatosis. Our results identified a microRNAs-phosphoSTAT3 pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting

Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.

he important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3- acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain

Factors associated with SARS-CoV-2 infection risk among healthcare workers of an italian university hospital

We report the results of a study on the cumulative incidence of SARS-CoV-2 infections in about 6000 workers of the University Hospital of Modena, Northern Italy, in the period March 2020–January 2021, and the relations with some individual and occupational factors. Overall, in healthcare workers (HCW) the cumulative incidence of COVID-19 during the period was 13.8%. Results confirm the role of overweight and obesity as significant risk factors for SARS-CoV-2 infection. Chronic respiratory diseases, including asthma, also proved to be significantly associated with the infection rate. Considering occupational factors, the COVID-19 risk was about threefold (OR: 2.7; 95% CI 1.7–4.5) greater in nurses and nurse aides than in non-HCW, and about double (OR: 1.9; 95% CI 1.2–3.2) in physicians. Interestingly, an association was also observed between infection risk and nightshifts at work (OR: 1.8; 95% CI 1.4–2.3), significantly related to the total number of shifts in the whole eleven-month period. Even if the vaccination campaign has now greatly modified the scenario of SARS-CoV-2 infections among HCW, the results of this study can be useful for further development of health and policy strategies to mitigate the occupational risk related to the new variants of coronavirus, and therefore the evolution of the pandemic

Factors Associated with SARS-CoV-2 Infection Evaluated by Antibody Response in a Sample of Workers from the Emilia-Romagna Region, Northern Italy

Factors associated with SARS-CoV-2 infection risk are still debated. This case–control study aims to investigate the possible relationship between SARS-CoV-2 infection, evaluated through antibody response, and the main sociodemographic, occupational, clinical-anamnestic, and biochemical factors in a population of Modena province (Northern Italy), mainly workers. Both workers who voluntarily joined the screening campaign proposed by companies and self-referred individuals who underwent serological testing were enrolled. Subjects with antibody positivity were recruited as cases (n = 166) and subjects tested negative (n = 239) as controls. A questionnaire on sociodemographic, occupational, and clinical data was administered through telephone interviews. Serum zinc/iron/copper/chromium/nickel, vitamins D/B12, folates, triglycerides, and LDL/HDL/total cholesterol were measured. Cases lived more often in urban areas (61.8% vs. 57%). Cases and controls did not differ significantly by working macrocategories, but the percentage of workers in the ceramic sector was higher among cases. Low adherence to preventive measures in the workplace was more frequent among seropositives. Folate concentration was significantly lower among cases. Therefore, adequate folate levels, living in rural areas, and good adherence to preventive strategies seem protective against infection. Workers in the ceramic sector seem to be at greater risk; specific factors involved are not defined, but preventive interventions are needed

Positron sources using channeling: A promising device for linear colliders

The need of intense and bright positron sources for linear colliders has urged the researches on polarized and unpolarized positrons. For 20 years, continuous theoretical and experimental investigations on unpolarized positron sources using axially channelled electrons in aligned monocrystals have pointed to efficient solutions concerning not only the source intensity, but also the minimization of the deposited energy. Simulations using the channelling programme of V. Strakhovenko associated to GEANT4, provided a description of such sources composed of tungsten crystals as photon radiators and amorphous tungsten as converters, the so-called hybrid source; the incident electron energies are taken between 5 and 10 GeV. Here, some applications are shown for CLIC, for which this source is the baseline, and also for ILC. The simulations are also concerning the test at KEK of such hybrid source, with a sweeping magnet separating the crystal radiator and an amorphous converter. Future developments on the simulation programme are also reported. The main issues for such sources are also analyzed

A Large Hadron Electron Collider at CERN

This document provides a brief overview of the recently published report on the design of the Large Hadron Electron Collider (LHeC), which comprises its physics programme, accelerator physics, technology and main detector concepts. The LHeC exploits and develops challenging, though principally existing, accelerator and detector technologies. This summary is complemented by brief illustrations of some of the highlights of the physics programme, which relies on a vastly extended kinematic range, luminosity and unprecedented precision in deep inelastic scattering. Illustrations are provided regarding high precision QCD, new physics (Higgs, SUSY) and electron-ion physics. The LHeC is designed to run synchronously with the LHC in the twenties and to achieve an integrated luminosity of O(100) fb$^{-1}$. It will become the cleanest high resolution microscope of mankind and will substantially extend as well as complement the investigation of the physics of the TeV energy scale, which has been enabled by the LHC

A Large Hadron Electron Collider at CERN

The physics programme and the design are described of a new collider for particle and nuclear physics, the Large Hadron Electron Collider (LHeC), in which a newly built electron beam of 60 GeV, to possibly 140 GeV, energy collides with the intense hadron beams of the LHC. Compared to the first ep collider, HERA, the kinematic range covered is extended by a factor of twenty in the negative four-momentum squared, Q2, and in the inverse Bjorken x, while with the design luminosity of 1033 cm-2 s-1 the LHeC is projected to exceed the integrated HERA luminosity by two orders of magnitude. The physics programme is devoted to an exploration of the energy frontier, complementing the LHC and its discovery potential for physics beyond the Standard Model with high precision deep inelastic scattering measurements. These are designed to investigate a variety of fundamental questions in strong and electroweak interactions. The LHeC thus continues the path of deep inelastic scattering (DIS) into unknown areas of physics and kinematics. The physics programme also includes electron-deuteron and electron-ion scattering in a (Q21/x) range extended by four orders of magnitude as compared to previous lepton-nucleus DIS experiments for novel investigations of neutron's and nuclear structure, the initial conditions of Quark-Gluon Plasma formation and further quantum chromodynamic phenomena. The LHeC may be realised either as a ring-ring or as a linac-ring collider. Optics and beam dynamics studies are presented for both versions, along with technical design considerations on the interaction region, magnets including new dipole prototypes, cryogenics, RF, and further components. A design study is also presented of a detector suitable to perform high precision DIS measurements in a wide range of acceptance using state-of-the art detector technology, which is modular and of limited size enabling its fast installation. The detector includes tagging devices for electron, photon, proton and neutron detection near to the beam pipe. Civil engineering and installation studies are presented for the accelerator and the detector. The LHeC can be built within a decade and thus be operated while the LHC runs in its high-luminosity phase. It so represents a major opportunity for progress in particle physics exploiting the investment made in the LHC