siRNA screen identifies QPCT as a druggable target for Huntington's disease.

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development

Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Abstract: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Evaluation of nanostructured coatings for the protection of apuan marble stone

Nowadays the use of multifunctional nanomaterials has significantly increased with interesting applications for the cultural heritage conservation sector, leading to the definition and use of products with innovative properties. Therefore, a preliminary validation of the performances and behavior over time of these treatments becomes an unavoidable key point for a correct use of these products before being applied to historical materials, in order to avoid irreparable damage over time. In this direction, the aim of this study was to evaluate the effectiveness of the treatment with multifunctional nanostructured products on Apuan marble. The focus of the work was to test methods to accelerate aging, in order to simulate different environmental agents of degradation to which marble in historical buildings can be exposed. Stone samples were examined after exposition to high temperature cycles in a muffle furnace, treatments in saline solution, cycles of thermal shock and aging by SO2 action in presence of humidity. After each artificial aging cycle, resulting changes in appearance were noticed and chemicalphysical properties were measured in order to compare differences between fresh and treated samples. The protective qualities of the coatings were evaluated using the following tests: contact angle; photocatalytic properties by methylene blue degradation tests; photodegradation kinetics of pollutants under UVA irradiation. Before and after the treatments, scanning electron microscopy equipped by microanalysis detector (SEM-EDS) was also used to evaluate changes in the surface morphology of the samples. The results showed effects of degradation in the rock samples due to aging after each test and all the products applied to the sample surface seemed to be very efficient in relation to their functions

Microwave-Assisted Vacuum Synthesis of TiO2 Nanocrystalline Powders in One-Pot, One-Step Procedure

A new method for fast and simple synthesis of crystalline TiO2 nanoparticles with photocatalytic activity was developed by carrying out a classic sol–gel reaction directly under vacuum. The use of microwaves for fast heating of the reaction medium further reduces synthesis times. When the solvent is completely removed by vacuum, the product is obtained in the form of a powder that can be easily redispersed in water to yield a stable nanoparticle suspension, exhibiting a comparable photocatalytic activity with respect to a commercial product. The present methodology can, therefore, be considered a process intensification procedure for the production of nanotitania

Design of TiO₂-Surfactin Hybrid Systems with Multifunctional Properties

In recent years, multifunctional inorganic−organic hybrid materials have been widely investigated in order to determine their potential synergetic, antagonist, or independent effects in terms of reactivity. The aim of this study was to design and characterize a new hybrid material by coupling well-known photocatalytic TiO2 nanoparticles with sodium surfactin (SS), a biosurfactant showing high binding affinity for metal cations as well as the ability to interact with and disrupt microorganisms’ cell membranes. We used both chemical and colloidal synthesis methodologies and investigated how different TiO2:SS weight ratios affected colloidal, physicochemical, and functional properties. We discovered a clear breaking point between TiO2 and SS single-component trends and identified different ranges of applicability by considering different functional properties such as photocatalytic, heavy metal sorption capacity, and antibacterial properties. At low SS contents, the photocatalytic properties of TiO2 are preserved (conversion of organic dye = 99% after 40 min), and the hybrid system can be used in advanced oxidation processes, taking advantage of the additional antimicrobial SS properties. At high SS contents, the TiO2 photoactivity is inhibited, and the hybrid can be usefully exploited as a UV blocker in cosmetics, avoiding undesired oxidative effects (UV adsorption in the range between 300–400 nm). Around the breaking point (TiO2:SS 1:1), the hybrid material preserves the high surface area of TiO2 (specific surface area around 180 m2/g) and demonstrates NOx depletion of up to 100% in 80 min, together with improved adhesion of hybrid antibacterial coating. The last design demonstrated the best results for the concurrent removal of inorganic, organic, and biological pollutants in water/soil remediation applications

On the optical alignment of the PLATO cameras

PLATO is an exoplanet hunting mission from the European Space Agency. It is a medium-class mission, with alaunch foreseen in 2026. Its prime objective is to uncover Earth-sized planets residing in the habitable zone of theirhost star. The payload consists of 26 cameras with a very wide field-of-view. While the operational temperatureof the cameras will be−80◦C, the focal plane of each camera will be integrated with its telescope assembly(bearing the optics) at room temperature. The degradation of the optical quality at ambient, combined with thedetector dark current and with the very high accuracy required from the alignment process bring a number ofinteresting challenges. In the present article, we review the alignment concept, present optical simulations of themeasurements at ambient along with their analysis, and present an error budget for the optical measurements.The derivation of this error budget is easily applicable to all optical measurements to be performed during thealignment, i.e. the definition of the best image plane at the operational temperature and the optical alignmentitself, at room temperature

A comparison between the opto-thermo-mechanical model and lab measurements for CHEOPS

CHEOPS is the first small class mission adopted by ESA in the framework of the Cosmic Vision 2015-2025. Its launch is foreseen in early 2019. CHEOPS aims to get transits follow-up measurements of already known exo-planets, hosted by near bright stars (V<12). Thanks to its ultra-high precision photometry, CHEOPS science goal is accurately measure the radii of planets in the super-Earth to Neptune mass range (1<Mplanet/MEarth<20). The knowledge of the radius by transit measurements, combined with the determination of planet mass through radial velocity techniques, will allow the determination/refinement of the bulk density for a large number of small planets during the scheduled 3.5 years life mission. The instrument is mainly composed of a 320 mm aperture diameter Ritchey-Chretien telescope and a Back End Optics, delivering a de-focused star image onto the focal plane. In this paper we describe the opto-thermo-mechanical model of the instrument and the measurements obtained during the opto-mechanical integration and alignment phase at Leonardo company premises, highlighting the level of congruence between the predictions and measurements