BARD1 mediates TGF-β signaling in pulmonary fibrosis

Background Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis. Methods We investigated BARD1 expression as a function of TGF-β in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. Results FL BARD1 and BARD1β were upregulated in response to TGF-β in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues. Conclusion Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β. In particular BARD1β might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment

A new Low Gain Avalanche Diode concept: the double-LGAD

This paper describes the new concept of the double-LGAD. The goal is to increase the charge at the input of the electronics, keeping a time resolution equal or better than a standard (single) LGAD; this has been realized by adding the charges of two coupled LGADs while still using a single front-end electronics. The study here reported has been done starting from single LGAD with a thickness of 25 \textmu{m}, 35 \textmu{m} and 50 \textmu{m}.Comment: arXiv admin note: text overlap with arXiv:2208.0571

New Eco-gas mixtures for the Extreme Energy Events MRPCs: results and plans

The Extreme Energy Events observatory is an extended muon telescope array, covering more than 10 degrees both in latitude and longitude. Its 59 muon telescopes are equipped with tracking detectors based on Multigap Resistive Plate Chamber technology with time resolution of the order of a few hundred picoseconds. The recent restrictions on greenhouse gases demand studies for new gas mixtures in compliance with the relative requirements. Tetrafluoropropene is one of the candidates for tetrafluoroethane substitution, since it is characterized by a Global Warming Power around 300 times lower than the gas mixtures used up to now. Several mixtures have been tested, measuring efficiency curves, charge distributions, streamer fractions and time resolutions. Results are presented for the whole set of mixtures and operating conditions, %. A set of tests on a real EEE telescope, with cosmic muons, are being performed at the CERN-01 EEE telescope. The tests are focusing on identifying a mixture with good performance at the low rates typical of an EEE telescope.Comment: 8 pages, 6 figures, proceedings for the "XIV Workshop on Resistive Plate Chambers and Related Detectors" (19-23 February 2018), Puerto Vallarta, Jalisco State, Mexic

A simulation tool for MRPC telescopes of the EEE project

The Extreme Energy Events (EEE) Project is mainly devoted to the study of the secondary cosmic ray radiation by using muon tracker telescopes made of three Multigap Resistive Plate Chambers (MRPC) each. The experiment consists of a telescope network mainly distributed across Italy, hosted in different building structures pertaining to high schools, universities and research centers. Therefore, the possibility to take into account the effects of these structures on collected data is important for the large physics programme of the project. A simulation tool, based on GEANT4 and using GEMC framework, has been implemented to take into account the muon interaction with EEE telescopes and to estimate the effects on data of the structures surrounding the experimental apparata.A dedicated event generator producing realistic muon distributions, detailed geometry and microscopic behavior of MRPCs have been included to produce experimental-like data. The comparison between simulated and experimental data, and the estimation of detector resolutions is here presented and discussed

INFN What Next: Ultra-relativistic Heavy-Ion Collisions

This document was prepared by the community that is active in Italy, within INFN (Istituto Nazionale di Fisica Nucleare), in the field of ultra-relativistic heavy-ion collisions. The experimental study of the phase diagram of strongly-interacting matter and of the Quark-Gluon Plasma (QGP) deconfined state will proceed, in the next 10-15 years, along two directions: the high-energy regime at RHIC and at the LHC, and the low-energy regime at FAIR, NICA, SPS and RHIC. The Italian community is strongly involved in the present and future programme of the ALICE experiment, the upgrade of which will open, in the 2020s, a new phase of high-precision characterisation of the QGP properties at the LHC. As a complement of this main activity, there is a growing interest in a possible future experiment at the SPS, which would target the search for the onset of deconfinement using dimuon measurements. On a longer timescale, the community looks with interest at the ongoing studies and discussions on a possible fixed-target programme using the LHC ion beams and on the Future Circular Collider.Comment: 99 pages, 56 figure

Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide’s anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6–11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies

First results on monolithic CMOS detector with internal gain

: In this paper we report on a set of characterisations carried out on the first monolithic LGAD prototype integrated in a customised 110 nm CMOS process having a depleted active volume thickness of 48 μm. This prototype is formed by a pixel array where each pixel has a total size of 100 μm × 250 μm and includes a high-speed front-end amplifier. After describing the sensor and the electronics architecture, both laboratory and in-beam measurements are reported and described. Optical characterisations performed with an IR pulsed laser setup have shown a sensor internal gain of about 2.5. With the same experimental setup, the electronic jitter was found to be between 50 ps and 150 ps, depending on the signal amplitude. Moreover, the analysis of a test beam performed at the Proton Synchrotron (PS) T10 facility of CERN with 10 GeV/c protons and pions indicated that the overall detector time resolution is in the range of 234 ps to 244 ps. Further TCAD investigations, based on the doping profile extracted from C(V) measurements, confirmed the multiplication gain measured on the test devices. Finally, TCAD simulations were used to tune the future doping concentration of the gain layer implant, targeting sensors with a higher avalanche gain. This adjustment is expected to enhance the timing performance of the sensors of the future productions, in order to cope with the high event rate expected in most of the near future high-energy and high-luminosity physics experiments, where the time resolution will be essential to disentangle overlapping events and it will also be crucial for Particle IDentification (PID

Direct detection of charged particles with SiPMs

The direct response of Silicon PhotoMultipliers being traversed by a MIP charged particle have been studied in a systematic way for the first time. Using beam test data, time resolution and the crosstalk probability have been measured. A characterization of the SiPM by means of a laser beam is also reported. The results obtained for different sensors indicate a measured time resolution around 40-70 ps. Although particles are expected to traverse only one SPAD per event, crosstalk measurements on different sensors indicate an unexpected higher value with respect to the one related to the sensor noise

Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase

A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues. Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility. Additionally, NOX4 may contribute directly or indirectly to alveolar epithelial cell death, while myofibroblasts themselves acquire an apoptosis-resistant phenotype. Thus, NOX4 may be responsible for the cardinal features of progressive fibrosis - myofibroblast activation and epithelial cell dysrepair. Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs