A novel strategy for molecular interfaces optimization: the case of ferritin-transferrin receptor interaction

Protein-protein interactions regulate almost all cellular functions and rely on a fine tune of surface amino acids properties involved on both molecular partners. The disruption of a molecular association can be caused even by a single residue mutation, often leading to a pathological modification of a biochemical pathway. Therefore the evaluation of the effects of amino acid substitutions on binding, and the ad hoc design of protein-protein interfaces, is one of the biggest challenges in computational biology. Here, we present a novel strategy for computational mutation and optimization of protein-protein interfaces. Modeling the interaction surface properties using the Zernike polynomials, we describe the shape and electrostatics of binding sites with an ordered set of descriptors, making possible the evaluation of complementarity between interacting surfaces. With a Monte Carlo approach, we obtain protein mutants with controlled molecular complementarities. Applying this strategy to the relevant case of the interaction between Ferritin and Transferrin Receptor, we obtain a set of Ferritin mutants with increased or decreased complementarity. The extensive molecular dynamics validation of the method results confirms its efficacy, showing that this strategy represents a very promising approach in designing correct molecular interfaces

GARFIELD + RCo Digital Upgrade: a Modern Set-up for Mass and Charge Identification of Heavy Ion Reaction Products

An upgraded GARFIELD + Ring Counter (RCo) apparatus is presented with improved performances as far as electronics and detectors are concerned. On one side fast sampling digital read out has been extended to all detectors, allowing for an important simplification of the signal processing chain together with an enriched extracted information. On the other side a relevant improvement has been made in the forward part of the setup (RCo): an increased granularity of the CsI(Tl) crystals and a higher homogeneity in the silicon detector resistivity. The renewed performances of the GARFIELD + RCo array make it suitable for nuclear reaction measurements both with stable and with Radioactive Ion Beams (RIB), like the ones foreseen for the SPES facility, where the Physics of Isospin can be studied.Comment: 13 pages, 19 figures - paper submitted to Eur. Phys. J.

Adolescent Development and the Parent–Adolescent Relationship in Diverse Family Forms Created by Assisted Reproduction

Assisted reproduction techniques (ARTs) are employed by single individuals and couples who are not otherwise able to conceive spontaneously. While the use of ARTs is increasing, research is lacking on the attempts made by adolescent offspring conceived via ARTs to integrate their ART conception into their identity and negotiate a connection with, and autonomy from, their parents. The present article reviews studies investigating adolescent development and the parent–adolescent relationship in diverse family forms created by ARTs (mainly heterosexual and lesbian parent families), and discusses the results in light of attachment, identity development, and emotional distance regulation theories. Overall, the results indicate that the psychological adjustment of adolescents conceived via ARTs is not undermined by the manner of their conception, and that they enjoy positive relationships with their parents with no difference from those enjoyed by spontaneously conceived adolescents. However, it remains unknown whether the development of a reproductive identity in adolescence is likely to influence adolescents’ interest in searching for or contacting their donors, surrogates, and/or donor siblings. The results suggest the relevance of considering the parent–adolescent relationship, disclosure, and identity formation issues when planning psychological counseling and support interventions with ART parents and their adolescent offspring, and emphasize the need to further investigate these aspects in diverse ART families, including single-, gay-, bisexual-, and trans*-parent families

Negative parental responses to coming out and family functioning in a sample of lesbian and gay young adults

Parental responses to youths' coming out (CO) are crucial to the subsequent adjustment of children and family. The present study investigated the negative parental reaction to the disclosure of same-sex attraction and the differences between maternal and paternal responses, as reported by their homosexual daughters and sons. Participants' perceptions of their parents' reactions (evaluated through the Perceived Parental Reactions Scale, PPRS), age at coming out, gender, parental political orientation, and religiosity involvement, the family functioning (assessed through the Family Adaptability and Cohesion Evaluation Scales, FACES IV), were assessed in 164 Italian gay and lesbian young adults. Pearson correlation coefficients were calculated to assess the relation between family functioning and parental reaction to CO. The paired sample t-test was used to compare mothers and fathers' scores on the PPRS. Hierarchical multiple regression was conducted to analyze the relevance of each variable. No differences were found between mothers and fathers in their reaction to the disclosure. The analysis showed that a negative reaction to coming out was predicted by parents' right-wing political conservatism, strong religious beliefs, and higher scores in the scales Rigid and Enmeshed. Findings confirm that a negative parental reaction is the result of poor family resources to face a stressful situation and a strong belief in traditional values. These results have important implications in both clinical and social fields

Sibling relationships and family functioning in siblings of early adolescents, adolescents and young adults with autism spectrum disorder

The purpose of the study was to investigate how family functioning (defined as the ability that family members hold to manage stressful events, and intimate and social relationships), the degree to which family members feel happy and fulfilled with each other (called family satisfaction), and the demographical characteristics of siblings (age and gender) impacted on sibling relationships. The Circumplex Model of Marital and Family Systems and Behavioral Systems constituted the theoretical frameworks that guided our study. Eighty-six typically developing adolescents and young adults having a sister or a brother with autism spectrum disorder were enrolled. Results indicated that the youngest age group (early adolescents) reported to engage more frequently in negative behaviors with their siblings with ASD than the two older age groups (middle adolescents and young adults). No significant differences were found among the three age groups regarding behaviors derived from attachment, caregiving and affiliative systems. Family satisfaction and age significantly predicted behaviors during sibling interactions. Suggestions on prevention and intervention programs were discussed in order to prevent parentification among typically developing siblings and decrease episodes of quarrels and overt conflicts between brothers and sisters with and without AS

A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition

Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin–trypanothione reductase–NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis

Tritiated Steel Micro-Particles: Computational Dosimetry and Prediction of Radiation-Induced DNA Damage for In Vitro Cell Culture Exposures.

Biological effects of radioactive particles can be experimentally investigated in vitro as a function of particle concentration, specific activity and exposure time. However, a careful dosimetric analysis is needed to elucidate the role of radiation emitted by radioactive products in inducing cyto- and geno-toxicity: the quantification of radiation dose is essential to eventually inform dose-risk correlations. This is even more fundamental when radioactive particles are short-range emitters and when they have a chemical speciation that might further concur to the heterogeneity of energy deposition at the cellular and sub-cellular level. To this aim, we need to use computational models. In this work, we made use of a Monte Carlo radiation transport code to perform a computational dosimetric reconstruction for in vitro exposure of cells to tritiated steel particles of micrometric size. Particles of this kind have been identified as worth of attention in nuclear power industry and research: tritium easily permeates in steel elements of nuclear reactor machinery, and mechanical operations on these elements (e.g., sawing) during decommissioning of old facilities can result in particle dispersion, leading to human exposure via inhalation. Considering the software replica of a representative in vitro setup to study the effect of such particles, we therefore modelled the radiation field due to the presence of particles in proximity of cells. We developed a computational approach to reconstruct the dose range to individual cell nuclei in contact with a particle, as well as the fraction of "hit" cells and the average dose for the whole cell population, as a function of particle concentration in the culture medium. The dosimetric analysis also provided the basis to make predictions on tritium-induced DNA damage: we estimated the dose-dependent expected yield of DNA double strand breaks due to tritiated steel particle radiation, as an indicator of their expected biological effectiveness

LGBT+ Training needs for health and social care professionals: a cross-cultural comparison among seven European countries

Introduction Research suggests that specific training on LGBT+ issues may improve the competencies and skills of health and social care (HSC) professionals, which reduces the negative attitudes toward LGBT+ people. Despite this, there seems to be a lack of coverage of LGBT+ needs in HSC education. The present study aims to explore the specific LGBT+ training needs of HSC professionals and to examine the relationship between these training needs and the four dimensions of the Papadopoulos model, i.e. cultural awareness, cultural knowledge, cultural sensitivity, and cultural competence. Methods The research used data from a cross-cultural project, “Intercultural Education for Nurses in Europe (IENE9),” which was administered to 412 HSC academics and workers (62% females; Mage=46.06, SDage=10.48) between February 2020 and July 2020, in seven European countries: UK (coordinator), Denmark, Spain, Germany, Cyprus, Italy, and Romania. Results Hierarchical multiple regression showed that higher training needs were associated with cultural awareness, cultural knowledge, and cultural competence. The need for training on LGBT+ issues was higher for Cyprus, Romania, Spain, Italy, and the UK, compared with Denmark (no differences between Germany and Denmark were found). Conclusions We believe that there has been a lack of focus on the LGBT+ training needs of HSC professionals: Greater efforts are required to develop a culturally competent and compassionate LGBT+ curriculum. Social Policy Implications Findings from the present study will inform the development of a free, Massive Open Online Course (MOOC), for culturally competent and compassionate HSC professionals in Europe to improve the quality of their car