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Skeletal muscle (SM) acts as a secretory organ, capable of releasing myokines and extracellular vesicles (SM‐EVs) that impact myogenesis and homeostasis. While age‐related changes have been previously reported in murine SM‐EVs, no study has comprehensively profiled SM‐EV in human models. To this end, we provide the first comprehensive comparison of SM‐EVs from young and old human primary skeletal muscle cells (HPMCs) to map changes associated with SM ageing. HPMCs, isolated from young (24 ± 1.7 years old) and older (69 ± 2.6 years old) participants, were immunomagnetically sorted based on the presence of the myogenic marker CD56 (N‐CAM) and cultured as pure (100% CD56+) or mixed populations (MP: 90% CD56+). SM‐EVs were isolated using an optimised protocol combining ultrafiltration and size exclusion chromatography (UF + SEC) and their biological content was extensively characterised using Raman spectroscopy (RS) and liquid chromatography mass spectrometry (LC‐MS). Minimal variations in basic EV parameters (particle number, size, protein markers) were observed between young and old populations. However, biochemical fingerprinting by RS highlighted increased protein (amide I), lipid (phospholipids and phosphatidylcholine) and hypoxanthine signatures for older SM‐EVs. Through LC‐MS, we identified 84 shared proteins with functions principally related to cell homeostasis, muscle maintenance and transcriptional regulation. Significantly, SM‐EVs from older participants were comparatively enriched in proteins involved in oxidative stress and DNA/RNA mutagenesis, such as E3 ubiquitin‐protein ligase TTC3 (TTC3), little elongation complex subunit 1 (ICE1) and Acetyl‐CoA carboxylase 1 (ACACA). These data suggest SM‐EVs could provide an alternative pathway for homeostasis and detoxification during SM ageing.

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing 1 – 4 . Several genetic interventions have been found to ameliorate old brain function 5 – 8 , but systematic functional testing of genes in old NSCs—and more generally in old cells—has not been done. Here we develop in vitro and in vivo high-throughput CRISPR–Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR–Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4 , which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age. Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing. CRISPR–Cas9 screens in cultures of young and old neural stem cells (NSCs) and in vivo in old mice identify gene knockouts that can boost old NSC activation and neurogenesis, with Slc2a4 , which encodes the glucose transporter GLUT4, showing particular efficacy.

The aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs), which may underlie age-associated defects in sensory and cognitive functions1-6. While mechanisms that restore old NSC function have started to be identified7-23, the role of lipids - especially complex lipids - in NSC aging remains largely unclear. Using lipidomic profiling by mass spectrometry, we identify age-related lipidomic signatures in young and old quiescent NSCs in vitro and in vivo. These analyses reveal drastic changes in several complex membrane lipid classes, including phospholipids and sphingolipids in old NSCs. Moreover, poly-unsaturated fatty acids (PUFAs) strikingly increase across complex lipid classes in quiescent NSCs during aging. Age-related changes in complex lipid levels and side chain composition are largely occurring in plasma membrane lipids, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we find that aging is accompanied by modifications in plasma membrane biophysical properties, with a decrease in plasma membrane order in old quiescent NSCs in vitro and in vivo. To determine the functional role of plasma membrane lipids in aging NSCs, we performed genetic and supplementation studies. Knockout of Mboat2, which encodes a phospholipid acyltransferase, exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. As Mboat2 expression declines with age, Mboat2 deficiency may drive NSC decline during aging. Interestingly, supplementation of plasma membrane lipids derived from young NSCs boosts the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs in old individuals, which has important implications for countering brain decline during aging. Competing Interest Statement The authors have declared no competing interest.

Purpose This study investigated whether muscle cooling and its associated effects on skeletal muscle oxidative responses, blood gases, and hormonal concentrations influenced energy metabolism during cycling. Methods Twelve healthy participants (Males: seven; Females: five) performed two steady-state exercise sessions at 70% of ventilatory threshold on a cycle ergometer. Participants completed one session with pre-exercise leg cooling until muscle temperature ( T m ) decreased by 6 °C (LCO), and a separate session without cooling (CON). They exercised until T m returned to baseline and for an additional 30 min. Cardiovascular, respiratory, metabolic, hemodynamic variables, and skeletal muscle tissue oxidative responses were assessed continuously. Venous blood samples were collected to assess blood gases, and hormones. Results Heart rate, stroke volume, and cardiac output all increased across time but were not different between conditions. V̇O 2 was greater in LCO when muscle temperature was restored until the end of exercise ( p  < 0.05). Cycling in the LCO condition induced lower oxygen availability, tissue oxygenation, blood pH, sO 2 %, and pO 2 ( p  < 0.05). Insulin concentrations were also higher in LCO vs. CON ( p  < 0.05). Importantly, stoichiometric equations from respiratory gases indicated no differences in fat and CHO oxidation between conditions. Conclusion The present study demonstrated that despite muscle cooling and the associated oxidative and biochemical changes, energy metabolism remained unaltered during cycling. Whether lower local and systemic oxygen availability is counteracted via a cold-induced activation of lipid metabolism pathways needs to be further investigated.

Fat oxidation during exercise is associated with cardio-metabolic benefits, but the extent of which whole-body exercise modality elicits the greatest fat oxidation remains unclear. We investigated the effects of treadmill, elliptical and rowing exercise on fat oxidation in healthy individuals. Nine healthy males participated in three, peak oxygen consumption tests, on a treadmill, elliptical and rowing ergometer. Indirect calorimetry was used to assess maximal oxygen consumption (V̇O2peak), maximal fat oxidation (MFO) rates, and the exercise intensity MFO occurred (Fatmax). Mixed venous blood was collected to assess lactate and blood gases concentrations. While V̇O2peak was similar between exercise modalities, MFO rates were higher on the treadmill (mean ± SD; 0.61 ± 0.06 g·min-1) compared to both the elliptical (0.41 ± 0.08 g·min-1, p = 0.022) and the rower (0.40 ± 0.08 g·min-1, p = 0.017). Fatmax values were also significantly higher on the treadmill (56.0 ± 6.2 %V̇O2peak) compared to both the elliptical (36.8 ± 5.4 %V̇O2peak, p = 0.049) and rower (31.6 ± 5.0 %V̇O2peak, p = 0.021). Post-exercise blood lactate concentrations were also significantly lower following treadmill exercise (p = 0.021). Exercising on a treadmill maximizes fat oxidation to a greater extent than elliptical and rowing exercises, and remains an important exercise modality to improve fat oxidation, and consequently, cardio-metabolic health.

Genetic associations with macroscopic brain structure can provide insights into brain function and disease. However, specific associations with measures of local brain folding are largely under-explored. Here, we conducted large-scale genome- and exome-wide associations of regional cortical sulcal measures derived from magnetic resonance imaging scans of 40,169 individuals in UK Biobank. We discovered 388 regional brain folding associations across 77 genetic loci, with genes in associated loci enriched for expression in the cerebral cortex, neuronal development processes, and differential regulation during early brain development. We integrated brain eQTLs to refine genes for various loci, implicated several genes involved in neurodevelopmental disorders, and highlighted global genetic correlations with neuropsychiatric phenotypes. We provide an interactive 3D visualisation of our summary associations, emphasising added resolution of regional analyses. Our results offer new insights into the genetic architecture of brain folding and provide a resource for future studies of sulcal morphology in health and disease. Genetic associations with particular patterns of brain folding may provide insight into brain development and function. Here, the authors identify and replicate 388 genetic associations with brain sulcal morphology across 40,169 UK Biobank MRI scans, revealing insights into the processes guiding cortical development and genetic correlations with neuropsychiatric phenotypes.

Muscle strength is highly heritable and predictive for multiple adverse health outcomes including mortality. Here, we present a rare protein-coding variant association study in 340,319 individuals for hand grip strength, a proxy measure of muscle strength. We show that the exome-wide burden of rare protein-truncating and damaging missense variants is associated with a reduction in hand grip strength. We identify six significant hand grip strength genes, KDM5B , OBSCN , GIGYF1 , TTN , RB1CC1 , and EIF3J . In the example of the titin ( TTN) locus we demonstrate a convergence of rare with common variant association signals and uncover genetic relationships between reduced hand grip strength and disease. Finally, we identify shared mechanisms between brain and muscle function and uncover additive effects between rare and common genetic variation on muscle strength. Here, the authors provide an exome study of hand grip strength, a proxy of generalized muscle strength. They identify six exome-wide significant genes, with links to disease, and additivity of rare and common genetic variant effects on muscle strength.

Pour une partie de la population, évoquer la police génère souvent de vives émotions. Une meilleure compréhension du milieu policier s’avère alors primordiale afin de saisir toute la complexité du métier ainsi que son évolution.Portraits de la police au Québec s’intéresse aux services de police municipaux ainsi qu’aux personnes policières et civiles qui y travaillent. D’une part, il examine les enjeux du domaine de la sécurité publique, dont la question des réformes. D’autre part, il traite du quotidien à travers les activités réalisées de façon journalière par la police, de la gestion des émotions dans un contexte extrême et de l’appartenance à la profession.Les aspirants-policiers y exploreront les rouages de l’organisation où ils travailleront et les différentes facettes du métier. D’un point de vue plus réflexif, les personnes policières en exercice, certaines personnes intervenantes du milieu social et gestionnaires découvriront des aspects utiles pour mieux exercer leur métier.Des problématiques précises liées à la complexité de la gestion des organisations publiques seront également abordées dans le but de démystifier la réalité des personnes policières.Bien que le milieu policier n’ait pas été réformé depuis plus de 20 ans, des réflexions ont été entamées par la ministre de la Sécurité publique en 2019-2020 à son propos et par le projet de loi 14 du ministre François Bonnardel en 2023. De nouveaux enjeux de sécurité ont émergé ces dernières années, notamment en matière de cybercriminalité et de santé mentale, dont certains de ceux-ci seront discutés dans ce livre.

The 2022 multicountry mpox outbreak concurrent with the ongoing Coronavirus Disease 2019 (COVID-19) pandemic further highlighted the need for genomic surveillance and rapid pathogen whole-genome sequencing. While metagenomic sequencing approaches have been used to sequence many of the early mpox infections, these methods are resource intensive and require samples with high viral DNA concentrations. Given the atypical clinical presentation of cases associated with the outbreak and uncertainty regarding viral load across both the course of infection and anatomical body sites, there was an urgent need for a more sensitive and broadly applicable sequencing approach. Highly multiplexed amplicon-based sequencing (PrimalSeq) was initially developed for sequencing of Zika virus, and later adapted as the main sequencing approach for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we used PrimalScheme to develop a primer scheme for human monkeypox virus that can be used with many sequencing and bioinformatics pipelines implemented in public health laboratories during the COVID-19 pandemic. We sequenced clinical specimens that tested presumptively positive for human monkeypox virus with amplicon-based and metagenomic sequencing approaches. We found notably higher genome coverage across the virus genome, with minimal amplicon drop-outs, in using the amplicon-based sequencing approach, particularly in higher PCR cycle threshold (Ct) (lower DNA titer) samples. Further testing demonstrated that Ct value correlated with the number of sequencing reads and influenced the percent genome coverage. To maximize genome coverage when resources are limited, we recommend selecting samples with a PCR Ct below 31 Ct and generating 1 million sequencing reads per sample. To support national and international public health genomic surveillance efforts, we sent out primer pool aliquots to 10 laboratories across the United States, United Kingdom, Brazil, and Portugal. These public health laboratories successfully implemented the human monkeypox virus primer scheme in various amplicon sequencing workflows and with different sample types across a range of Ct values. Thus, we show that amplicon-based sequencing can provide a rapidly deployable, cost-effective, and flexible approach to pathogen whole-genome sequencing in response to newly emerging pathogens. Importantly, through the implementation of our primer scheme into existing SARS-CoV-2 workflows and across a range of sample types and sequencing platforms, we further demonstrate the potential of this approach for rapid outbreak response.

Background. Sexual and gender minority youth (SGMY) experience health inequities compared with cisgender heterosexuals, and these inequities are heightened in areas with high structural stigma. Quantitative research shows school assets (e.g., adult support) are associated with better health for SGMY. Though some qualitative studies elucidated how school staff support SGMY, none have triangulated such strategies in a geographically and sociodemographically diverse sample of school staff and SGMY. This paper describes a multi-perspective qualitative study design and offers lessons learned from conducting such a study. Methods. Using a novel stratified sampling frame, we interviewed 60 SGMY and 29 school staff who attended/worked at high schools in U.S. states with low, medium, and high structural stigma. To ensure sociodemographic diversity, we constructed sampling quotas, and recruited SGMY using social media and staff using a multi-pronged approach. Results. The stratified sampling strategy met our goal of enrolling diverse SGMY and staff participants. SGMY participants attended schools in low (n = 20), medium (n = 22), and high (n = 18) structural stigma states. We enrolled 18 cisgender girls, 18 cisgender boys, and 24 gender minority youth. Fifty-three percent of SGMY were youth of color, and 45% attended schools in rural areas. School staff participants worked at schools in low (n = 11), medium (n = 11), and high (n = 7) structural stigma states. School staff participants were 55% heterosexual, 91% cisgender, and had diverse roles (e.g., teacher, principal, librarian, and nurse). Conclusions. This paper describes new methods for collecting qualitative data from diverse SGMY and school staff. Some lessons learned from this study include the importance of using trauma-informed interviewing methods, having a suicidality safety protocol, establishing a priori sampling quotas, and creating tailored social media advertisements. With these data we will explore the heterogeneity of SGMY and school staff experiences across varying structural stigma levels, yielding foundational information for future school-based interventions.