Targeting SARS-CoV-2 RBD Interface: a Supervised Computational Data-Driven Approach to Identify Potential Modulators

Coronavirus disease 2019 (COVID-19) has spread out as a pandemic threat affecting over 2 million people. The infectious process initiates via binding of SARS-CoV-2 Spike (S) glycoprotein to host angiotensin-converting enzyme 2 (ACE2). The interaction is mediated by the receptor-binding domain (RBD) of S glycoprotein, promoting host receptor recognition and binding to ACE2 peptidase domain (PD), thus representing a promising target for therapeutic intervention. Herein, we present a computational study aimed at identifying small molecules potentially able to target RBD. Although targeting PPI remains a challenge in drug discovery, our investigation highlights that interaction between SARS-CoV-2 RBD and ACE2 PD might be prone to small molecule modulation, due to the hydrophilic nature of the bi-molecular recognition process and the presence of druggable hot spots. The fundamental objective is to identify, and provide to the international scientific community, hit molecules potentially suitable to enter the drug discovery process, preclinical validation and development.     

Saccharomyces cerevisiae and Hanseniaspora uvarum mixed starter cultures: Influence of microbial/physical interactions on wine characteristics

The growing trend in the wine industry is the revaluation of the role of non-Saccharomyces yeasts, promoting the use of these yeasts in association with Saccharomyces cerevisiae. Non-Saccharomyces yeasts contribute to improve wine complexity and organoleptic composition. However, the use of mixed starters needs to better understand the effect of the interaction between these species during alcoholic fermentation. The aim of this study is to evaluate the influence of mixed starter cultures, composed by combination of different S. cerevisiae and Hanseniaspora uvarum strains, on wine characteristics and to investigate the role of cell-to-cell contact on the metabolites produced during alcoholic fermentation. In the first step, three H. uvarum and two S. cerevisiae strains, previously selected, were tested during mixed fermentations in natural red grape must in order to evaluate yeast population dynamics during inoculated fermentation and influence of mixed starter cultures on wine quality. One selected mixed starter was tested in a double-compartment fermentor in order to compare mixed inoculations of S. cerevisiae/H. uvarum with and without physical separation. Our results revealed that physical contact between S. cerevisiae and H. uvarum affected the viability of H. uvarum strain, influencing also the metabolic behaviour of the strains. Although different researches are available on the role of cell-to-cell contact-mediated interactions on cell viability of the strains included in the mixed starter, to our knowledge, very few studies have evaluated the influence of cell-to-cell contact on the chemical characteristics of wine.     

A water-soluble,mucoadhesive quaternary ammonium chitosan-methyl-β-cyclodextrin conjugate forming inclusion complexes with dexamethasone

The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water-soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices.

Open image in new window

     

Adoption and Use of Software in Land Use Planning Practice: A Multiple-Country Study

Planning Support Systems (PSS) are computer-based tools that assist professionals in land use planning activities. Although several researchers acknowledge the importance of such tools in planning practice, PSS use is limited due to their poor fit to users’ needs and expectations as well as to their low usability. This article presents a study carried out in three different countries, namely, Australia, Italy, and Switzerland, aiming at investigating in-depth the current situation regarding the adoption of PSS and identifying factors preventing their wider use, devoting particular attention to the quality of such systems from the point of view of their users. The study also aimed at analyzing planners’ expectations in order to identify relevant features that PSS should provide. The main part of the study consisted of 35 interviews with planning experts. A follow-up focus group with six further participants was also performed. The results confirmed some findings of previous studies but also revealed new insights. This article provides suggestions on how to address the emerging issues, as well as pathways for creating software that can be adopted and used with satisfaction in the planning practice.     

The puzzling afterglow of GRB 050721: a rebrightening seen in the optical but not in the X-ray

We present here the analysis of the early and late multiwavelength afterglow emission, as observed by Swift a small robotic telescope and very large telescope (VLT). We compare early observations with late afterglow observations obtained with Swift and the VLT and we observe an intense rebrightening in the optical band at about 1 day after the burst, which is not present in the X-ray band. The lack of detection in X-ray of such a strong rebrightening at lower energies may be described with a variable external density profile. In such a scenario, the combined X-ray and optical observations allow us to derive that the matter density located at approximately 1017 cm from the burst is approximately a factor of 10 higher than in the inner region. This is the first time in which a rebrightening has been observed in the optical afterglow of a gamma-ray burst that is clearly absent in the X-ray afterglow.     

BSA Hydrogel Beads Functionalized with a Specific Aptamer Library for Capturing Pseudomonas aeruginosa in Serum and Blood

Systemic blood stream infections are a major threat to human health and are dramatically increasing worldwide. Pseudomonas aeruginosa is a WHO-alerted multi-resistant pathogen of extreme importance as a cause of sepsis. Septicemia patients have significantly increased survival chances if sepsis is diagnosed in the early stages. Affinity materials can not only represent attractive tools for specific diagnostics of pathogens in the blood but can prospectively also serve as the technical foundation of therapeutic filtration devices. Based on the recently developed aptamers directed against P. aeruginosa, we here present aptamer-functionalized beads for specific binding of this pathogen in blood samples. These aptamer capture beads (ACBs) are manufactured by crosslinking bovine serum albumin (BSA) in an emulsion and subsequent functionalization with the amino-modified aptamers on the bead surface using the thiol- and amino-reactive bispecific crosslinker PEG₄-SPDP. Specific and quantitative binding of P. aeruginosa as the dedicated target of the ACBs was demonstrated in serum and blood. These initial but promising results may open new routes for the development of ACBs as a platform technology for fast and reliable diagnosis of bloodstream infections and, in the long term, blood filtration techniques in the fight against sepsis.     

Insulin Resistance and Cancer: In Search for a Causal Link

Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.     

Monitoring of perfluorinated compounds in edible fish from the Mediterranean Sea

Perfluorooctanoic acid (PFOA) and perfluorooctane sulphonate (PFOS) are environmental contaminants belonging to a chemical group known as perfluorinated compounds (PCFs). The United States Environmental Protection Agency (US EPA) considers both compounds to be carcinogenic. The goal of the present study was to evaluate the contamination levels of PFOS and PFOA in edible fish of the Mediterranean Sea. Twenty six fish muscles, 17 fish livers, five series of cephalopods (each composed of ten specimens) and thirteen series of bivalves (each composed of about 50 specimens) were used for the investigation. A fast sample treatment, followed by an LC–ESI–MS/MS method is described for the identification, and quantification of PFOA and PFOS in fish. The method was in-house-validated through the determination of precision, accuracy, specificity, calibration curve, decision limit (CCα), and detection capability (CCβ). The results showed PFOA and PFOS levels in fishes and molluscs lower than those reported for analogue matrices in different geographic areas. Therefore, our biomonitoring results did not show that the Mediterranean Sea had any particularly alarming pollution by PFCs, although it is located in a semi-closed basin with scarce water change. Nonetheless, a worrying element is that a few fish showed extremely high contamination by PFOA and PFOS. This finding needs further clarification in order to assess whether such unusual contamination is linked to “dot-like” pollutant release, which could explain the anomaly.     

Biosensing systems for the detection of bacterial quorum signaling molecules

Bacterial quorum sensing (QS) is a cell-to-cell communication phenomenon that allows bacteria to control the expression of certain specialized genes depending on their cell population size. Signaling molecules such N-acylhomoserine lactones (AHLs) mediate the communication, and their concentration reflects the bacterial population density. Quorum sensing regulates several processes including bacterial pathogenicity. We developed a method for the rapid, sensitive, and quantitative detection of AHLs in biological samples such as saliva and stools. The method is based on whole-cell sensing systems that employ QS regulatory systems as recognition elements and the luxCDABE gene cassette as a reporter. The method proved to be reproducible when applied to real samples and was able to detect low analyte concentrations down to 1 x 10(-9) M without requiring extensive sample preparation. We envision that this novel biosensing system could be employed in the diagnosis and management of various bacteria-related disorders, thus supporting the use of quorum sensing molecules as potential biomarkers of disease. Due to cost-effectiveness and high throughput, these biosensing systems could be successfully employed as a new tool for the screening of novel drugs that target quorum sensing mechanisms.