Integrated Approach Including Docking, MD Simulations, and Network Analysis Highlights the Action Mechanism of the Cardiac hERG Activator RPR260243

hERG is a voltage-gatedpotassium channel involved inthe heartcontraction whose defections are associated with the cardiac arrhythmiaLong QT Syndrome type 2. The activator RPR260243 (RPR) representsa possible candidate to pharmacologically treat LQTS2 because it enhancesthe opening of the channel. However, the molecular detail of its actionmechanism remains quite elusive. Here, we address the problem usinga combination of docking, molecular dynamics simulations, and networkanalysis. We show that the drug preferably binds at the interfacebetween the voltage sensor and the pore, enhancing the canonical activationpath and determining a whole-structure rearrangement of the channelthat slightly impairs inactivation

From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus

With an estimated 1 billion people affected across the globe, influenza is one of the most serious health concerns worldwide. Therapeutic treatments have encompassed a number of key functional viral proteins, mainly focused on the M2 proton channel and neuraminidase. This review highlights the efforts spent in targeting the M2 proton channel, which mediates the proton transport toward the interior of the viral particle as a preliminary step leading to the release of the fusion peptide in hemagglutinin and the fusion of the viral and endosomal membranes. Besides the structural and mechanistic aspects of the M2 proton channel, attention is paid to the challenges posed by the development of efficient small molecule inhibitors and the evolution toward novel ligands and scaffolds motivated by the emergence of resistant strains

Stellar population properties for a sample of hard X-ray AGNs

The aim of this paper is to study the stellar population of galaxies hosting an active galactic nucleus (AGN). We studied a sub-sample of hard X-ray emitting AGNs from the INTEGRAL and Swift catalogs which were previously identified and characterized through optical spectroscopy. Our analysis provides complementary information, namely age and metallicity, which is necessary to complete the panoramic view of such interesting objects. We selected hard X-ray emitting objects identified as AGNs by checking their optical spectra in search for absorption lines suitable for the stellar population analysis. We obtained a final sample consisting of 20 objects with redshift lower than 0.3. We used the full-spectrum fitting method and, in particular, the penalized pixel one applying the PPXF code. After masking all the regions affected by emission lines, we fitted the spectra with the MILES single stellar population templates and we derived mass-weighted ages and metallicities. Most of the objects in our sample show an old stellar population, but three of them are characterized by a bimodal distribution with a non negligible contribution from young stars. The values of the mass-weighted metallicity span a large range of metallicity with most of them slightly above the solar value. No relations between the stellar population properties and the morphological ones have been found.Comment: 10 pages, 8 postscript figures and 3 tables. A&A in pres

Caratterizzazione dell’ambiente marino dei Campi Flegrei. Risultati preliminari della campagna oceanografica RICAMAR 2013

The caldera of the Phlegraean Fields (also known as Campi Flegrei) is one of the most dangerous and populated volcanic area in the world, covering an area that comprises the western part of Naples and the Gulf of Pozzuoli. The main peculiarity of current volcanic activity is the gradual and periodic lift (positive or negative) of part of the Earth\u27s surface (bradyseism) combined, only during the positive phase, with a strong sismicity and surficial hydrotermal activity. Deformative models, calibrated using land-based measurements, highlighted the Gulf of Pozzuoli as the area with the largest deformation. Although the network of monitoring sensors on land is well developed and structured, there is a lack of sensing systems for the marine deformation. The activities of RIlievi per la Caratterizzazione dell’Ambiente MARino nel Golfo di Pozzuoli 2013 (RICAMAR2013) project - sinergically conducted by the Italian Navy\u27s Survey Vessel Ammiraglio Magnaghi , the Italian Hydrographic Office (IIM) and the Istituto Nazionale di Geofisica e Vulcanologia (INGV)- were targeted to fulfill this gap. In fact, the creation of marine observatories about the caldera\u27s phenomena will be based on the data collected during these bathymetric, magnetometric, stratigrafic and hydrologic surveys

Targeting the JAK/STAT Pathway: A Combined Ligand- And Target-Based Approach

Janus kinases (JAKs) are a family of proinflammatory enzymes able to mediate the immune responses and the inflammatory cascade by modulating multiple cytokine expressions as well as various growth factors. In the present study, the inhibition of the JAK-signal transducer and activator of transcription (STAT) signaling pathway is explored as a potential strategy for treating autoimmune and inflammatory disorders. A computationally driven approach aimed at identifying novel JAK inhibitors based on molecular topology, docking, and molecular dynamics simulations was carried out. For the best candidates selected, the inhibitory activity against JAK2 was evaluated in vitro. Two hit compounds with a novel chemical scaffold, 4 (IC50 = 0.81 μM) and 7 (IC50 = 0.64 μM), showed promising results when compared with the reference drug Tofacitinib (IC50 = 0.031 μM).This study was funded by the University of Valencia and Generalitat Valenciana (GVA) through postdoctoral grants no. UVINV_POSTDOC18-785681 and APOSTD/2019/055 (M.G-L.) and by the University of Bologna through research grant no. RFO2019 (P.R., S.C., and M.R.)

SARS-CoV-2 vaccination modelling for safe surgery to save lives : data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population.Peer reviewe