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Abstract.The present study aimed to adapt and validate a Spanish version of the Ruminative Thought Style Questionnaire (RTSQ) and test for measurement invariance of the RTSQ across college students in the US, Spain, and Argentina (n= 1,632). Additionally, we examined/compared across these countries, criterion-related (i.e., concurrent) validity of RTSQ factors (i.e., problem-focused thoughts, counterfactual thinking, repetitive thoughts, and anticipatory thoughts) on constructs theoretically-associated with rumination. Consistent with previous findings, we found that a 15-item 4-factor RTSQ provided a more adequate model compared to single-factor CFA models (15- and 20-item versions) in every country. The reliability and validity of the subscales for the Spanish version were satisfactory-to-good in Spain and Argentina. Using multigroup confirmatory factor analyses, we found the 15-item 4-factor version of the RTSQ to be invariant across countries and sex. Bivariate correlations provided evidence for the criterion-related validity of the 4-factor RTSQ across the countries. Our findings suggest that self-report items of the RTSQ convey the same meaning, and that responses to those items load onto the same set of factors, across languages and cultures of administration. Taken together, our findings serve as a foundation for future cross-cultural work testing models in which rumination is a central facet.

Centre National d’Etudes Spatiales (CNES) is currently developing a new instrument called Détecteur Radiation Energétique Adaptable et Miniaturisé (DREAM) in order to measure electrons and protons in the Earth magnetosphere. Compared to the instrument Influence sur les Composants Avancés des Radiations de l’Espace—Nouvelle Génération (ICARE-NG), DREAM is compatible with nanosatellite cubesats. In this article, we present the instrument architecture, new sensors design, hardware improvements, and first results. Response functions for protons and electrons sensors are calculated using GEometry ANd Tracking (GEANT4) simulations. The calculation of predicted count rates of particles is performed.

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

Macrocycles, including macrocyclic peptides, have shown promise for targeting challenging protein–protein interactions (PPIs). One PPI of high interest is between Kelch-like ECH-Associated Protein-1 (KEAP1) and Nuclear Factor (Erythroid-derived 2)-like 2 (Nrf2). Guided by X-ray crystallography, NMR, modeling, and machine learning, we show that the full 20 nM binding affinity of Nrf2 for KEAP1 can be recapitulated in a cyclic 7-mer peptide, c[(D)-β-homoAla-DPETGE]. This compound was identified from the Nrf2-derived linear peptide GDEETGE (KD= 4.3 μM) solely by optimizing the conformation of the cyclic compound, without changing any KEAP1 interacting residue. X-ray crystal structures were determined for each linear and cyclic peptide variant bound to KEAP1. Despite large variations in affinity, no obvious differences in the conformation of the peptide binding residues or in the interactions they made with KEAP1 were observed. However, analysis of the X-ray structures by machine learning showed that locations of strain in the bound ligand could be identified through patterns of subangstrom distortions from the geometry observed for unstrained linear peptides. We show that optimizing the cyclic peptide affinity was driven partly through conformational preorganization associated with a proline substitution at position 78 and with the geometry of the noninteracting residue Asp77 and partly by decreasing strain in the ETGE motif itself. This approach may have utility in dissecting the trade-off between conformational preorganization and strain in other ligand–receptor systems. We also identify a pair of conserved hydrophobic residues flanking the core DxETGE motif which play a conformational role in facilitating the high-affinity binding of Nrf2 to KEAP1.

•First report on whole-genome analysis of extensively drug-resistant NDM-6 producing uropathogenic C. werkmaniiST104.•A BaeSR two-component system regulating production of multidrug efflux proteins was identified in C. werkmaniiAK-8.•ntBLAST results showed AK-8 to possess 69.60% genetic identity with Escherichia coli536.•The AK-8 genome encodes 21 chemoreceptors aiding in colonisation and pathogenesis.

Development of small molecule inhibitors of protein–protein interactions (PPIs) is hampered by our poor understanding of the druggability of PPI target sites. Here, we describe the combined application of alanine-scanning mutagenesis, fragment screening, and FTMap computational hot spot mapping to evaluate the energetics and druggability of the highly charged PPI interface between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2 like 2 (Nrf2), an important drug target. FTMap identifies four binding energy hot spots at the active site. Only two of these are exploited by Nrf2, which alanine scanning of both proteins shows to bind primarily through E79 and E82 interacting with KEAP1 residues S363, R380, R415, R483, and S508. We identify fragment hits and obtain X-ray complex structures for three fragments via crystal soaking using a new crystal form of KEAP1. Combining these results provides a comprehensive and quantitative picture of the origins of binding energy at the interface. Our findings additionally reveal non-native interactions that might be exploited in the design of uncharged synthetic ligands to occupy the same site on KEAP1 that has evolved to bind the highly charged DEETGE binding loop of Nrf2. These include π-stacking with KEAP1 Y525 and interactions at an FTMap-identified hot spot deep in the binding site. Finally, we discuss how the complementary information provided by alanine-scanning mutagenesis, fragment screening, and computational hot spot mapping can be integrated to more comprehensively evaluate PPI druggability.

The aim of this quality improvement project was to improve patients' knowledge about their vitamin B12 deficiency by developing an information leaflet and engaging nursing staff in providing this educational tool to patients with the condition. Following two ‘plan, do, study, act’ cycles to test and improve implementation of the leaflet, the nursing team met the goal of 100% compliance with providing educational information to patients. An increase in patient knowledge following provision of the leaflet was predicted, and achieved.

Research has highlighted the role of neuroticism, rumination, and depression in predicting suicidal thoughts, but studies on how these variables interplay are scarce. The aims of the present study were to test a model in which emotional stability (i.e., low neuroticism) would act as an antecedent and moderator of rumination and depressed mood in the prediction of suicidal ideation (i.e., moderated serial-mediation), and to explore their replicability across four countries and sex, among college students as an at-risk-group for suicide.

Disease emergence events regularly result from human activities such as agriculture, which frequently brings large populations of genetically uniform hosts into contact with potential pathogens. Although viruses cause nearly 50% of emerging plant diseases, there is little systematic information about virus distribution across agro-ecological interfaces and large gaps in understanding of virus diversity in nature. Here we applied a novel landscape-scale geometagenomics approach to examine relationships between agricultural land use and distributions of plant-associated viruses in two Mediterranean-climate biodiversity hotspots (Western Cape region of South Africa and Rhône river delta region of France). In total, we analysed 1725 geo-referenced plant samples collected over two years from 4.5 × 4.5 km2grids spanning farmlands and adjacent uncultivated vegetation. We found substantial virus prevalence (25.8–35.7%) in all ecosystems, but prevalence and identified family-level virus diversity were greatest in cultivated areas, with some virus families displaying strong agricultural associations. Our survey revealed 94 previously unknown virus species, primarily from uncultivated plants. This is the first effort to systematically evaluate plant-associated viromes across broad agro-ecological interfaces. Our findings indicate that agriculture substantially influences plant virus distributions and highlight the extent of current ignorance about the diversity and roles of viruses in nature.

During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.