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The present study aimed to examine the effects of the Spanish confinement derived from the COVID-19 crisis on children and their families, accounting for child’s age. A range of child negative (e.g., conduct problems) and positive outcomes (e.g., routine maintenance) were examined, along with a set of parent-related variables, including resilience, perceived distress, emotional problems, parenting distress and specific parenting practices (e.g., structured or avoidant parenting), which were modeled through path analysis to better understand child adjustment. Data were collected in April 2020, with information for the present study provided by 940 (89.6%) mothers, 102 (9.7%) fathers and 7 (0.7%) different caregivers, who informed on 1049 Spanish children (50.4% girls) aged 3 to 12 years (Mage = 7.29; SD = 2.39). The results suggested that, according to parents’ information, most children did not show important changes in behavior, although some increasing rates were observed for both negative and positive outcomes. Child adjustment was influenced by a chain of effects, derived from parents’ perceived distress and emotional response to the COVID-19 crisis, via parenting distress and specific parenting practices. While parenting distress in particular triggered child negative outcomes, specific parenting practices were more closely related to child positive outcomes. These findings may help to better inform, for potential future outbreaks, effective guidelines and prevention programs aimed at promoting the child’s well-being in the family.

RNA viruses have notoriously high mutation rates due to error-prone replication by their RNA polymerase. However, natural selection concentrates variability in a few key viral proteins. To test whether this stems from different mutation tolerance profiles among viral proteins, we measured the effect of >40,000 non-synonymous mutations across the full proteome of coxsackievirus B3 as well as >97% of all possible codon deletions in the nonstructural proteins. We find significant variation in mutational tolerance within and between individual viral proteins, which correlated with both general and protein-specific structural and functional attributes. Furthermore, mutational fitness effects remained stable across cell lines, suggesting selection pressures are mostly conserved across environments. In addition to providing a rich dataset for understanding virus biology and evolution, our results illustrate that incorporation of mutational tolerance data into druggable pocket discovery can aid in selecting targets with high barriers to drug resistance.

Despite their fundamental role in resolving viral infections, our understanding of how polyclonal neutralizing antibody responses target non-enveloped viruses remains limited. To define these responses, we obtained the full antigenic profile of multiple human and mouse polyclonal sera targeting the capsid of a prototypical picornavirus, coxsackievirus B3. Our results uncover significant variation in the breadth and strength of neutralization sites targeted by individual human polyclonal responses, which contrasted with homogenous responses observed in experimentally infected mice. We further use these comprehensive antigenic profiles to define key structural and evolutionary parameters that are predictive of escape, assess epitope dominance at the population level, and reveal a need for at least two mutations to achieve significant escape from multiple sera. Overall, our data provide a comprehensive analysis of how polyclonal sera target a non-enveloped viral capsid and help define both immune dominance and escape at the population level. Neutralizing antibodies are key to resolving viral infections and confer long-term protection. This work provides a detailed analysis of how murine and human sera neutralize a non-enveloped human virus, coxsackievirus B3, and how the virus can escape them.

Introduction/objectivesThe use of non-occupational post-exposure prophylaxis (nPEP) emerges as a strategic intervention to reduce HIV infection risk following sexual encounters in our setting. Notwithstanding, there is a scarcity of contemporary data regarding adherence to this treatment, its effectiveness and tolerance. Our study aims to delve into these factors among individuals who have resorted to nPEP after high-risk sexual encounters.MethodsWe conducted a retrospective observational study of cases administered nPEP for HIV from 1 January 2018 to 31 December 2021 at a tertiary hospital in Madrid. The study included all adults over 18 years who sought care at the emergency department of the Fundación Jiménez Díaz Hospital following a risky sexual encounter and were subsequently recommended HIV nPEP treatment.Results878 individuals received nPEP for HIV and underwent initial serological tests. Of these, 621 had comprehensive follow-ups. The prescribed regimen for all was raltegravir (RAL) 1200 mg combined with tenofovir/emtricitabine (TDF/FTC) 245/200 mg daily for 28 days. The study revealed a 1.1% rate (n=10) of previously undetected infection and a 0.16% (n=1) failure rate of nPEP. Regarding regimen tolerability, 5.6% (n=35) experienced symptoms linked to the treatment, yet none necessitated discontinuation of the regimen. On the contrary, six per cent (n=53) reported symptoms consistent with an STI during one of the medical visits; specifically, 4.4% had urethritis, and 1.6% had proctitis.ConclusionnPEP with RAL/TDF/FTC demonstrates high efficacy and safety, contingent on proper adherence. There is an observed increase in STI prevalence in this cohort, with nearly half of the participants not engaging in appropriate follow-up after initiating nPEP.

Acute kidney injury (AKI) involves nephron injury leading to irreversible nephron loss, ie, chronic kidney disease (CKD). Both AKI and CKD are associated with distinct histological patterns of tissue injury, but kidney atrophy in CKD involves tissue remodeling with interstitial inflammation and scarring. No doubt, nephron atrophy, inflammation, fibrosis, and renal dysfunction are associated with each other, but their hierarchical relationships remain speculative. To better understand the pathophysiology, we provide an overview of the fundamental danger response programs that assure host survival upon traumatic injury from as early as the first multicellular organisms, ie, bleeding control by coagulation, infection control by inflammation, epithelial barrier restoration by re-epithelialization, and tissue stabilization by mesenchymal repair. Although these processes assure survival in the majority of the populations, their dysregulation causes kidney disease in a minority. We discuss how, in genetically heterogeneous population, genetic variants shift balances and modulate danger responses toward kidney disease. We further discuss how classic kidney disease entities develop from an insufficient or overshooting activation of these danger response programs. Finally, we discuss molecular pathways linking, for example, inflammation and regeneration or inflammation and fibrosis. Understanding the causative and hierarchical relationships and the molecular links between the danger response programs should help to identify molecular targets to modulate kidney injury and to improve outcomes for kidney disease patients.

Hydrogen sulfide (H2S/HS–) can be formed in mammalian tissues and exert physiological effects. It can react with metal centers and oxidized thiol products such as disulfides (RSSR) and sulfenic acids (RSOH). Reactions with oxidized thiol products form persulfides (RSSH/RSS–). Persulfides have been proposed to transduce the signaling effects of H2S through the modification of critical cysteines. They are more nucleophilic and acidic than thiols and, contrary to thiols, also possess electrophilic character. In this review, we summarize the biochemistry of hydrogen sulfide and persulfides, focusing on redox aspects. We describe biologically relevant one- and two-electron oxidants and their reactions with H2S and persulfides, as well as the fates of the oxidation products. The biological implications are discussed.

Summary Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4+ lymphocytes (CD28null T cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole-genome DNA methylation and gene expression profiles of CD28null T cells and its CD28+ counterpart. A comparative analysis revealed that 296 genes are differentially methylated between the two cell subsets. A total of 160 genes associated with cytotoxicity (e.g. GRZB,TYROBP, and RUNX3) and cytokine/chemokine signaling (e.g. CX3CR1,CD27, and IL-1R) are demethylated in CD28null T cells, while 136 de novo-methylated genes matched defects in the TCR signaling pathway (e.g. ITK,TXK,CD3G, and LCK). TCR-landscape analysis confirmed that CD28null T cells have an oligo/monoclonal expansion over the polyclonal background of CD28+ T cells, but feature a V[beta] family repertoire specific to each individual. We reported that CD28null T cells show a preactivation state characterized by a higher level of expression of inflammasome-related genes that leads to the release of IL-1[beta] when activated. Overall, our results demonstrate that CD28null T cells have a unique DNA methylation landscape, which is associated with differences in gene expression, contributing to the functionality of these cells. Understanding these epigenetic regulatory mechanisms could suggest novel therapeutic strategies to prevent the accumulation and activation of these cells during aging.

The substantial waste generated during the processing of hides and skins as well as at other stages of manufacturing is a recurring issue in the leather industry that this article attempts to address. To investigate the mechanical and thermal characteristics of the resultant composites, this study suggests using leather waste from the bovine leather industry, analyzes the tanning process, and assesses the viability of mixing this waste with natural rubber (TSR-20). Without the inclusion of leather waste, the resulting composites had exceptional tensile strength, surpassing 100% of rubber’s strength. The effective interaction of the recycled leather particles with the natural rubber matrix was evidenced using the Lorentz–Park equation. This better performance points to a competitive relationship between rubber and leather waste. The samples’ density was 10% greater than that of polybutadiene elastomers and 10% greater than that of natural leather, while the hardness was comparable to that of PVC, which is frequently utilized in the design of general-purpose soles. This suggests that waste from the leather industry can be efficiently utilized in sustainable applications, particularly in the production of leather goods and shoes, helping to valorize waste that is typically discarded. Furthermore, by encouraging the use of recycled resources in the creation of new compounds, this plan provides the rubber sector with a sustainable option. To optimize this proposal, perhaps will be necessary to identify different vulcanization systems to improve the physical mechanical properties and other uses derived from the optimizations realized. This composite can be applied in the fashion industry in order to develop new trends around the application of waste and residues for a natural design line. Through the research process, it was possible to integrate the residues into the natural rubber matrix, as evidenced in the characterization process.

We thank Cristina B. Mendoza for excellent technical assistance and Dr.Peter Andrews for providing us reagents. Conceived and designed the experiments: BS MFF CLL. Performed the experiments: BS VC STS. Analyzed the data: BS RMR MABG CLL. Contributed reagents/materials/analysis tools: RMR FO JO JC HM. Wrote the paper: BS HM MFF CLL.

Hydrogen sulfide (H(2)S) is mainly known for its toxicity but has recently been shown to be produced endogenously in mammalian tissues and to be associated with physiological regulatory functions. To better understand the role of biomembranes in modulating its biological distribution and effects; we measured the partition coefficient of H(2)S in models of biological membranes. The partition coefficients were found to be 2.1±0.2, 1.9±0.5 and 2.0±0.6 in n-octanol, hexane and dilauroylphosphatidylcholine liposome membranes relative to water, respectively (25°C). This two-fold higher concentration of H(2)S in the membrane translates into a rapid membrane permeability, P(m) = 3 cm s(-1). We used a mathematical model in three dimensions to gain insight into the diffusion of total sulfide in tissues. This model shows that the sphere of action of sulfide produced by a single cell expands to involve more than 200 neighboring cells, and that the resistance imposed by lipid membranes has a significant effect on the diffusional spread of sulfide at pH 7.4, increasing local concentrations. These results support the role of hydrogen sulfide as a paracrine signaling molecule and reveal advantageous pharmacokinetic properties for its therapeutic applications.