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The Strongyloides genus of parasitic nematodes have a fascinating life cycle and biology, but are also important pathogens of people and a World Health Organization-defined neglected tropical disease. Here, a community of Strongyloides researchers have posed thirteen major questions about Strongyloides biology and infection that sets a Strongyloides research agenda for the future. This article is part of the Theo Murphy meeting issue Strongyloides: omics to worm-free populations.

Earthquake hazard analyses rely on seismogenic source models. These are designed in various fashions, such as point sources or area sources, but the most effective is the three-dimensional representation of geological faults. We here refer to such models as fault sources. This study presents the European Fault-Source Model 2020 (EFSM20), which was one of the primary input datasets of the recently released European Seismic Hazard Model 2020. The EFSM20 compilation was entirely based on reusable data from existing active fault regional compilations that were first blended and harmonized and then augmented by a set of derived parameters. These additional parameters were devised to enable users to formulate earthquake rate forecasts based on a seismic-moment balancing approach. EFSM20 considers two main categories of seismogenic faults: crustal faults and subduction systems, which include the subduction interface and intraslab faults. The compiled dataset covers an area from the Mid-Atlantic Ridge to the Caucasus and from northern Africa to Iceland. It includes 1248 crustal faults spanning a total length of ∼95 100 km and four subduction systems, namely the Gibraltar, Calabrian, Hellenic, and Cyprus arcs, for a total length of ∼2120 km. The model focuses on an area encompassing a buffer of 300 km around all European countries (except for Overseas Countries and Territories) and a maximum of 300 km depth for the subducting slabs. All the parameters required to develop a seismic source model for earthquake hazard analysis were determined for crustal faults and subduction systems. A statistical distribution of relevant seismotectonic parameters, such as faulting mechanisms, slip rates, moment rates, and prospective maximum magnitudes, is presented and discussed to address unsettled points in view of future updates and improvements. The dataset, identified by the DOI https://doi.org/10.13127/efsm20 (Basili et al., 2022), is distributed as machine-readable files using open standards (Open Geospatial Consortium).

Abstract Evolutionary annotation of genome maintenance (GM) proteins has conventionally been established by remote relationships within protein sequence databases. However, often no significant relationship can be established. Highly sensitive approaches to attain remote homologies based on iterative profile-to-profile methods have been developed. Still, these methods have not been systematically applied in the evolutionary annotation of GM proteins. Here, by applying profile-to-profile models, we systematically survey the repertoire of GM proteins from bacteria to man. We identify multiple GM protein candidates and annotate domains in numerous established GM proteins, among other PARP, OB-fold, Macro, TUDOR, SAP, BRCT, KU, MYB (SANT), and nuclease domains. We experimentally validate OB-fold and MIS18 (Yippee) domains in SPIDR and FAM72 protein families, respectively. Our results indicate that, surprisingly, despite the immense interest and long-term research efforts, the repertoire of genome stability caretakers is still not fully appreciated.

Abstract The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.

Abstract S-nitrosylation is a post-translational modification in which nitric oxide (NO) binds to the thiol group of cysteine, generating an S-nitrosothiol (SNO) adduct. S-nitrosylation has different physiological roles, and its alteration has also been linked to a growing list of pathologies, including cancer. SNO can affect the function and stability of different proteins, such as the mitochondrial chaperone TRAP1. Interestingly, the SNO site (C501) of TRAP1 is in the proximity of another cysteine (C527). This feature suggests that the S-nitrosylated C501 could engage in a disulfide bridge with C527 in TRAP1, resembling the well-known ability of S-nitrosylated cysteines to resolve in disulfide bridge with vicinal cysteines. We used enhanced sampling simulations and in-vitro biochemical assays to address the structural mechanisms induced by TRAP1 S-nitrosylation. We showed that the SNO site induces conformational changes in the proximal cysteine and favors conformations suitable for disulfide bridge formation. We explored 4172 known S-nitrosylated proteins using high-throughput structural analyses. Furthermore, we used a coarse-grained model for 44 protein targets to account for protein flexibility. This resulted in the identification of up to 1248 proximal cysteines, which could sense the redox state of the SNO site, opening new perspectives on the biological effects of redox switches. In addition, we devised two bioinformatic workflows ( https://github.com/ELELAB/SNO_investigation_pipelines ) to identify proximal or vicinal cysteines for a SNO site with accompanying structural annotations. Finally, we analyzed mutations in tumor suppressors or oncogenes in connection with the conformational switch induced by S-nitrosylation. We classified the variants as neutral, stabilizing, or destabilizing for the propensity to be S-nitrosylated and undergo the population-shift mechanism. The methods applied here provide a comprehensive toolkit for future high-throughput studies of new protein candidates, variant classification, and a rich data source for the research community in the NO field.

Abstract Background Strongyloidiasis is a neglected tropical disease affecting an estimated 600 million people, particularly in resource-limited settings. The infection can persist lifelong due to unusual auto-infective cycle of Strongyloides stercoralis. The lack of a diagnostic gold standard and limited knowledge of the mechanisms underpinning this chronic infection are key issues in disease management. To date, only a few proteomics studies have been conducted to elucidate the molecular mechanisms associated with Strongyloides parasitism or to highlight novel immunological markers, with the result that our knowledge of S. stercoralis proteome remains limited. This study aims at expanding the characterization of S. stercoralis infective larvae (iL3) in order to further explore the mechanisms of parasitism and to highlight possible novel targets for serodiagnosis. Methods iL3 obtained from an infected subject were analysed by high-throughput tandem mass spectrometry. To achieve a more comprehensive characterization of the iL3 proteome we analysed the experimental dataset using an automatic search strategy combined with manual annotation, which included gene ontology (GO) analysis, InterPro annotation, assessment of the homology with Homo sapiens and other pathogens of clinical importance and B-cell epitope prediction. Results Our pipeline identified 430 S. stercoralis proteins, 187 (43%) of which were uncharacterized. Oxidoreductases and peptidases were amongst the most represented protein categories, as highlighted by molecular function GO analyses, while membrane and mitochondrial proteins were the most represented cellular component GO categories. A high proportion of proteins bearing the CAP, SCP or thioredoxin domain or belonging to cysteine-rich secretory, transthyretin-like or peptidase protein families were also identified. Additionally, we highlighted nine proteins displaying low homology with H. sapiens or other related pathogens and bearing amino acid sequences with immunogenic properties. Conclusions Our comprehensive description and annotation of the S. stercoralis iL3 proteome contribute to expanding the ‘omics characterization of this parasite and provide experimental evidence on the most represented proteins associated with S. stercoralis parasitism, as inferred from genomic and transcriptomic data. Moreover, novel candidate immunogenic proteins to be evaluated as novel serological diagnostic markers are highlighted. Graphical Abstract

The tumor immune microenvironment is an important prognostic determinant in colorectal cancer (CRC). Here the authors show that tumor infiltrating neutrophils expressing high levels of CD15 interact with CD8+ T effector memory skewing them to produce GZMK, associated with tumor progression in CRC patients.

Abstract Cancer genomics and cancer mutation databases have made an available wealth of information about missense mutations found in cancer patient samples. Contextualizing by means of annotation and predicting the effect of amino acid change help identify which ones are more likely to have a pathogenic impact. Those can be validated by means of experimental approaches that assess the impact of protein mutations on the cellular functions or their tumorigenic potential. Here, we propose the integrative bioinformatic approach Cancermuts, implemented as a Python package. Cancermuts is able to gather known missense cancer mutations from databases such as cBioPortal and COSMIC, and annotate them with the pathogenicity score REVEL as well as information on their source. It is also able to add annotations about the protein context these mutations are found in, such as post-translational modification sites, structured/unstructured regions, presence of short linear motifs, and more. We applied Cancermuts to the intrinsically disordered protein AMBRA1, a key regulator of many cellular processes frequently deregulated in cancer. By these means, we classified mutations of AMBRA1 in melanoma, where AMBRA1 is highly mutated and displays a tumor-suppressive role. Next, based on REVEL score, position along the sequence, and their local context, we applied cellular and molecular approaches to validate the predicted pathogenicity of a subset of mutations in an in vitro melanoma model. By doing so, we have identified two AMBRA1 mutations which show enhanced tumorigenic potential and are worth further investigation, highlighting the usefulness of the tool. Cancermuts can be used on any protein targets starting from minimal information, and it is available at https://www.github.com/ELELAB/cancermuts as free software.

IntroductionObesity and eating disorders are considered to be part of a broad spectrum of disorders associated with weight issues and maladaptive eating styles. Several studies show that psychopathological and personality characteristics contribute to the development and maintenance of obesity and dysfunctional eating behaviors, showing a bidirectional relationship. The purpose of this study was to understand the role of psychopathological factors and personality dimensions on dysfunctional eating behaviors in a sample of individuals with obesity.MethodsThe study was conducted with 96 individuals with obesity (31 males and 65 females) who underwent psychological assessment. The instruments administered included the Cognitive Behavioral Assessment 2.0 - Primary Scales, the Minnesota Multiphasic Personality Inventory-2, and the Eating Disorder Inventory. Relationships between dysfunctional eating behaviors and personality and psychopathological factors were explored through mediation analysis.Results and discussionOur results showed that difficulties related to impulse control and behavior, along with negative and dysphoric emotions, may be associated with difficulties in eating behavior. Mediation analysis showed that the combination of depressive and obsessive-compulsive symptomatology may exacerbate or contribute to the occurrence of eating disorders. These psychopathological aspects should be taken into account during the assessment of patients who decide to undergo bariatric surgery and should be targets of specific psychological interventions.

Objectives This study aimed to observe the effect of different finger rest positions on the muscular activity of the hand, forearm, arm, shoulder, thorax, and neck, as well as on the angular deviation from the neutral position of the neck, trunk, upper arm, and forearm on the working side during pre-clinical procedures. Methods An experimental laboratory study was performed. Response variables were muscle activation of the abductor pollicis, brachioradialis, biceps brachii, deltoid, pectoralis major, and right sternocleidomastoid muscles and angular deviation from the neutral position of the neck, trunk, arm, and forearm during simulated clinical procedures. Independent variable was finger-rest position during cavity preparation (no finger rest, usual rest, and ergonomic rest). Class I cavity preparations (N = 120) were performed on artificial first molars (16, 26, 36, and 46) (N = 120). Muscular activation was assessed by surface electromyography and angular deviations using Software for Postural Assessment (SAPO) version 0.69. One-way analysis of variance and Tukey’s or Games-Howell’s post-hoc tests were performed (α = 0.05). Results For the sternocleidomastoid muscle, there was no statistically significant difference between the different rest positions. For the deltoid muscle, work with no finger rest resulted in greater muscle activation (p < 0.001) during work on tooth 36. Regarding the pectoralis major and right brachioradialis muscles, we observed that for both teeth 16 and 26, working with ergonomic rest showed less muscle activation. Muscle activation of the right biceps brachii was higher for work with no rest in both the upper and lower arches, differing significantly only from the usual rest in tooth 16 (p < 0.001), usual rest and ergonomic rest in teeth 26 and 46 (p < 0.001), and only ergonomic rest in tooth 36 (p = 0.044). In the right abductor pollicis muscle, work with ergonomic rest resulted in less muscle activation for cavity preparation in teeth 16, 26, and 36, which was significantly different from work with no rest (p = 0.029, p < 0.001, and p = 0.013, respectively). Regarding angular deviation, it was observed that for tooth 16, there was a greater angular deviation of the arm when performing cavity preparations with no finger rest. For teeth 26 and 46, the ergonomic finger rest provided lower angular deviation from the neutral position of the right arm. For tooth 36, ergonomic rest provided less angular deviation from the neutral neck position. Conclusion In general, the use of non-active finger rest during simulated cavity preparations, regardless of the type of rest, provided less muscle activation and angular deviation from the neutral position of the body’s upper extremity when performing pre-clinical procedures.

The RAS is a hormonal system playing a pivotal role in the control of blood pressure and electrolyte homeostasis, the alteration of which is associated with different pathologies, including acute respiratory distress syndrome (ARDS). As such, it is not surprising that a number of studies have attempted to elucidate the role and balance of the renin–angiotensin system (RAS) in COVID-19. In this review article, we will describe the evidence collected regarding the two main enzymes of the RAS (i.e., ACE and ACE2) and their principal molecular products (i.e., AngII and Ang1-7) in SARS-CoV-2 infection, with the overarching goal of drawing conclusions on their possible role as clinical markers in association with disease severity, progression, and outcome. Moreover, we will bring into the picture new experimental data regarding the systemic activity of ACE and ACE2 as well as the concentration of AngII and Ang1-7 in a cohort of 47 COVID-19 patients hospitalized at the IRCCS Sacro Cuore-Don Calabria Hospital (Negrar, Italy) between March and April 2020. Finally, we will discuss the possibility of considering this systemic pathway as a clinical marker for COVID-19.

Background: Currently approved vaccines are highly effective in protecting against hospitalization and severe COVID-19 infections. How pre-existing immunity responds to new variants with mutated antigens is crucial information for elucidating the functional interplay between antibodies and B and T cell responses during infection with new SARS-CoV-2 variants. Methods: In this study, we monitored the dynamics and persistence of the immune response versus different SARS-CoV-2 variants of concern that emerged during the pandemic period (2021–2022) in a cohort of vaccinated healthcare workers, who experienced breakthrough infection in the Pre-Delta, Delta, and Omicron waves. We evaluated both the humoral and cell-mediated responses after infection. We also evaluated the anti-SARS-CoV-2 antibodies levels produced by infection in comparison with those produced after vaccination. Results: Our results highlighted that the immune response against the Delta VOC mainly involved an adaptive humoral and switched memory B cells component, even 3 months after the last vaccine dose, conversely showing a high percentage of depleted adaptive T cells. Omicron infections triggered a consistent production of non-vaccine-associated anti-N antibodies, probably to balance the spike epitope immune escape mechanisms. Conclusion: Our results suggest a direct dependence between the VOC and different humoral and B and T cell balances in the post-infection period, despite the administration of a different number of vaccine doses and the elapsed time since the last vaccination.

Abstract The prompt identification of faults responsible for moderate‐to‐large earthquakes is fundamental for understanding the likelihood of further, potentially damaging events. This is increasingly challenging when the activated fault is an offshore buried thrust, where neither coseismic surface ruptures nor GPS/InSAR deformation data are available after an earthquake. We show that on 9 November 2022, an Mw 5.5 earthquake offshore Pesaro ruptured a portion of the buried Northern Apennines thrust front (the Cornelia thrust system [CTS]). By post‐processing and interpreting the seismic reflection profiles crossing this thrust system, we determined that the activated fault (CTS) is an arcuate 30‐km‐long, NW‐SE striking, SW dipping thrust and that older structures at its footwall possibly influenced its position and geometry. The activation of adjacent segments of the thrust system is a plausible scenario that deserves to be further investigated to understand the full earthquake potential of this offshore seismogenic source.

Traditional family norms often have persistent effects on household decisions. We question whether kinship ancestries of postmarital residence still affect household consumption sharing. We estimate a model of resource allocation using expenditure surveys for Ghana and Malawi, two countries in which patrilocal and matrilocal traditions coexist. Ancestral patrilocality coincides with a 10% lower resource share for women, contributing to a higher prevalence of poverty among women. Women's resource shares increase with age, a pattern more pronounced for matrilocal groups. These results indicate how a combination of cultural and demographic factors may be used to improve policies targeted at poor individuals. [ABSTRACT FROM AUTHOR]

Better employment quality can improve personal well-being, social cohesion, and inclusive growth and development. Yet good quality jobs – associated with greater well-being – are less accessible to women than men. While it is understood that policies balancing family and work lead to greater female labour participation, this paper investigates whether one such policy – increased childcare – improves the quality of jobs where mothers are employed. The context we analyse is a nationwide school reform in Chile that extended school schedules for primary school-aged children, providing childcare services. We combine administrative data of the phase-in of the policy with panel data of individual mothers' employment outcomes and socio-economic characteristics. We estimate a fixed-effects model that controls for mothers' unobserved heterogeneity and identifies the effect of the policy from plausibly exogenous temporal and spatial variations in access to schools with long schedules and exogenous exposure to the policy. We find a positive effect of childcare on several measures of employment quality and gender gaps within the couple. Our evidence suggests that the mechanism driving the impact is the implicit subsidy to the cost of childcare, affecting the opportunity cost of mothers' time. In addition, we find heterogeneous results by mothers' education level. Access to childcare through longer primary school schedules can increase household welfare and can play a role in reducing income and gender inequalities. [ABSTRACT FROM AUTHOR]

While technological advancements and their deep integration in connected and automated vehicles is a central aspect in the evolving trend of automotive industry, they also depict a growing size attack surface for malicious actors: the latter ones typically aim at exploiting known and unknown security vulnerabilities, with potentially disastrous consequences on the safety of vehicles, people, and infrastructures. In recent years, remarkable efforts have been spent to mitigate security vulnerabilities in intelligent and connected vehicles, in particular in the inside of vehicles, the so-called intra-vehicle networks. Despite those efforts, securing intra-vehicle networks remains a non-trivial task due to their heterogeneous and increasingly complex context. Starting from the above remarks and motivated by the industrial research and innovation project EMERGE, in this paper we report on a novel cryptographic hardware-software solution that we have designed and developed for securing the intra-vehicle network of intelligent connected vehicles: the Crypto-Engine. The Crypto-Engine relies on a lightweight hybrid-key cryptographic scheme to provide confidentiality and authentication without compromising the normal communication performance. We tested the Crypto-Engine and demonstrated that, once configured according to application-defined performance requirements, it can authenticate parties and secure the communications with a negligible overhead.