Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.     

Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation

Mitral valve prolapse (MVP) associated with severe mitral regurgitation is a debilitating disease with no pharmacological therapies available. MicroRNAs (miRNA) represent an emerging class of circulating biomarkers that have never been evaluated in MVP human plasma. Our aim was to identify a possible miRNA signature that is able to discriminate MVP patients from healthy subjects (CTRL) and to shed light on the putative altered molecular pathways in MVP. We evaluated a plasma miRNA profile using Human MicroRNA Card A followed by real-time PCR validations. In addition, to assess the discriminative power of selected miRNAs, we implemented a machine learning analysis. MiRNA profiling and validations revealed that miR-140-3p, 150-5p, 210-3p, 451a, and 487a-3p were significantly upregulated in MVP, while miR-223-3p, 323a-3p, 340-5p, and 361-5p were significantly downregulated in MVP compared to CTRL (p ≤ 0.01). Functional analysis identified several biological processes possible linked to MVP. In addition, machine learning analysis correctly classified MVP patients from CTRL with high accuracy (0.93) and an area under the receiving operator characteristic curve (AUC) of 0.97. To the best of our knowledge, this is the first study performed on human plasma, showing a strong association between miRNAs and MVP. Thus, a circulating molecular signature could be used as a first-line, fast, and cheap screening tool for MVP identification.     

Moulded pulp products manufacturing with thermoforming

For an effective optimization of pulp thermoforming and of the moulded pulp products manufactured by this process, a full understanding of the process physics combined with full knowledge of the pressing equipment is necessary. For this reason, in this Addendum, we clarify how the process parameters “Holding time,” “Vacuum time,” “Cycle time,” and “Temperature” were interpreted and subsequently defined for the analysis of the process and product‐related outputs of the thermoforming experiments.     

Modelling of electricity savings in the Danish households sector: from the energy system to the end-user

In this paper, we examine the value of investing in energy-efficient household appliances from both an energy system and end-user perspectives. We consider a set of appliance categories constituting the majority of the electricity consumption in the private household sector, and focus on the stock of products which need to be replaced. First, we look at the energy system and investigate whether investing in improved energy efficiency can compete with the cost of electricity supply from existing or new power plants. To assess the analysis, Balmorel, a linear optimization model for the heat and power sectors, has been extended in order to endogenously determine the best possible investments in more efficient home appliances. Second, we propose a method to relate the optimal energy system solution to the end-user choices by incorporating consumer behaviour and electricity price addition due to taxes. The model is non-exclusively tested on the Danish energy system under different scenarios. Computational experiments show that several energy efficiency measures in the household sector should be regarded as valuable investments (e.g. an efficient lighting system) while others would require some form of support to become profitable. The analysis quantifies energy and economic savings from the consumer side and reveals the impacts on the Danish power system and surrounding countries. Compared to a business-as-usual energy scenario, the end-user attains net economic savings in the range of 30–40 EUR per year, and the system can benefit of an annual electricity demand reduction of 140–150 GWh. The paper enriches the existing literature about energy efficiency modelling in households, contributing with novel models, methods, and findings related to the Danish case.     

Graphene nanoplatelets composite membranes for thermal comfort enhancement in performance textiles

The advent of 2D nanostructured materials as advanced fillers for polymer matrix composites has opened the doors to a plethora of new industrial applications requiring both electric and thermal management. Unique properties, in fact, can arise from accurate selection and processing of 2D fillers and their matrix. Here, we report an innovative family of nanocomposite membranes based on polyurethane (PU) and graphene nanoplatelets (GNPs), designed to improve thermal comfort in functional textiles. GNP particles were thoroughly characterized (through Raman, atomic force microscopy, high-resolution TEM, scanning electron microscope), and showed high crystallinity (I_D/I_G = 0.127), low thickness (D50 < 6–8 layers), and high lateral dimensions (D50 ≈ 3 μm). When GNPs were loaded (up to 10% wt/wt) into the PU matrix, their homogeneous dispersion resulted in an increase of the in-plane thermal conductivity of composite membranes up to 471%. The thermal dissipation of membranes, alone or coupled with cotton fabric, was further evaluated by means of an ad hoc system designed to simulate a human forearm. The results obtained provide a new strategy for the preparation of membranes suitable for technical textiles, with improved thermal comfort.     

Distribution of POPs,pesticides and antibiotic residues in organic honeys from different production areas

Demand for honey is increasing, especially if it is organic and if its nutritional properties are linked to untreated environments in order to guarantee quality for health. Sources of contamination of honey can be divided into environmental and apicultural. Therefore, the distribution of persistent organic pollutants, pesticides and antibiotic residues from geographical areas with different contamination sources (high anthropic impact, intensive farming, husbandry and low anthropic impact) was investigated in order to confirm the potential transfer of xenobiotics into the supply chain and to give beekeepers tools for the selection of areas dedicated to organic production. The presence of polychlorinated biphenyls, polybrominated diphenyl ether and polycyclic aromatic hydrocarbons was confirmed, not only in proximity to highly urbanised centres, where the concentrations were higher, but in all environment contexts, confirming their ubiquity. No antibiotics or neonicotinoids were detected in 95 organic honeys, demonstrating the absence of apicultural treatments and consequently the good quality of honey of different areas. These results are important due to the undefined regulatory European situation on honey antibiotic limits.     

Design of a Cost‐Reduced Flexible Plant for Supercritical Fluid‐Assisted Applications

A novel batch plant for supercritical CO₂ applications is proposed which is not equipped with expensive components, such as high‐pressure pumps, making it particularly suitable for bench‐scale use. For the first time, the use of a hanging scale is suggested to weigh the amount of CO₂ required for the experiment and the use of the thermodynamics to reach the working conditions. The rig is able to cover different applications, e.g., aerogel drying, impregnation, and extraction, showing high flexibility. An approximate cost analysis has been performed considering as a reference a 150‐mL vessel. It has been calculated that both the setup and running costs are considerably lower than the common batch and semicontinuous rigs.     

Creating an Holistic Emergency Alert Management Platform

ABSTRACT

Extreme natural events require effective emergency procedures to minimize adverse effects on a region’s population and economy. Such procedures typically involve the effort of several different teams of first responders (e.g., fire fighters, public administrations, police departments, utility companies), hence coordination is fundamental to the effectiveness of the response to the emergency that must be supported with adequate infrastructures. Nonetheless, first responders often rely on manual processes, in the life cycle of extreme events, which do not change consistently with the type of shock or affected population. The aim of this paper is to present a technology transfer process to improve both the emergency alert process and the knowledge of disaster-type safety procedures through the implementation of a proposed platform. We also highlight a pilot application on a post-disaster case study—the province of L’Aquila (Abruzzi) in Italy.