Differential susceptibility of male and female germ cells to glucocorticoid-mediated signaling.

While physiologic stress has long been known to impair mammalian reproductive capacity through hormonal dysregulation, mounting evidence now suggests that stress experienced prior to or during gestation may also negatively impact the health of future offspring. Rodent models of gestational physiologic stress can induce neurologic and behavioral changes that persist for up to three generations, suggesting that stress signals can induce lasting epigenetic changes in the germline. Treatment with glucocorticoid stress hormones is sufficient to recapitulate the transgenerational changes seen in physiologic stress models. These hormones are known to bind and activate the glucocorticoid receptor (GR), a ligand-inducible transcription factor, thus implicating GR-mediated signaling as a potential contributor to the transgenerational inheritance of stress-induced phenotypes. Here, we demonstrate dynamic spatiotemporal regulation of GR expression in the mouse germline, showing expression in the fetal oocyte as well as the perinatal and adult spermatogonia. Functionally, we find that fetal oocytes are intrinsically buffered against changes in GR signaling, as neither genetic deletion of GR nor GR agonism with dexamethasone altered the transcriptional landscape or the progression of fetal oocytes through meiosis. In contrast, our studies revealed that the male germline is susceptible to glucocorticoid-mediated signaling, specifically by regulating RNA splicing within the spermatogonia, although this does not abrogate fertility. Together, our work suggests a sexually dimorphic function for GR in the germline, and represents an important step towards understanding the mechanisms by which stress can modulate the transmission of genetic information through the germline.

Ancestry-based differences in the immune phenotype are associated with lupus activity.

Systemic lupus erythematosus (SLE) affects 1 in 537 Black women, which is >2-fold more than White women. Black patients develop the disease at a younger age, have more severe symptoms, and have a greater chance of early mortality. We used a multiomics approach to uncover ancestry-associated immune alterations in patients with SLE and healthy controls that may contribute biologically to disease disparities. Cell composition, signaling, epigenetics, and proteomics were evaluated by mass cytometry; droplet-based single-cell transcriptomics and proteomics; and bead-based multiplex soluble mediator levels in plasma. We observed altered whole blood frequencies and enhanced activity in CD8+ T cells, B cells, monocytes, and DCs in Black patients with more active disease. Epigenetic modifications in CD8+ T cells (H3K27ac) could distinguish disease activity level in Black patients and differentiate Black from White patient samples. TLR3/4/7/8/9-related gene expression was elevated in immune cells from Black patients with SLE, and TLR7/8/9 and IFN-α phospho-signaling and cytokine responses were heightened even in immune cells from healthy Black control patients compared with White individuals. TLR stimulation of healthy immune cells recapitulated the ancestry-associated SLE immunophenotypes. This multiomic resource defines ancestry-associated immune phenotypes that differ between Black and White patients with SLE, which may influence the course and severity of SLE and other diseases.

Differential susceptibility of male and female germ cells to glucocorticoid-mediated signaling.

While physiologic stress has long been known to impair mammalian reproductive capacity through hormonal dysregulation, mounting evidence now suggests that stress experienced prior to or during gestation may also negatively impact the health of future offspring. Rodent models of gestational physiologic stress can induce neurologic and behavioral changes that persist for up to three generations, suggesting that stress signals can induce lasting epigenetic changes in the germline. Treatment with glucocorticoid stress hormones is sufficient to recapitulate the transgenerational changes seen in physiologic stress models. These hormones are known to bind and activate the glucocorticoid receptor (GR), a ligand-inducible transcription factor, thus implicating GR-mediated signaling as a potential contributor to the transgenerational inheritance of stress-induced phenotypes. Here we demonstrate dynamic spatiotemporal regulation of GR expression in the mouse germline, showing expression in the fetal oocyte as well as the perinatal and adult spermatogonia. Functionally, we find that fetal oocytes are intrinsically buffered against changes in GR signaling, as neither genetic deletion of GR nor GR agonism with dexamethasone altered the transcriptional landscape or the progression of fetal oocytes through meiosis. In contrast, our studies revealed that the male germline is susceptible to glucocorticoid-mediated signaling, specifically by regulating RNA splicing within the spermatogonia, although this does not abrogate fertility. Together, our work suggests a sexually dimorphic function for GR in the germline, and represents an important step towards understanding the mechanisms by which stress can modulate the transmission of genetic information through the germline.

A Roadmap for Three-Dimensional Analysis of the Intact Mouse Ovary.

Recent advances in tissue clearing methodologies have enabled three-dimensional (3D) visualization of the ovary and, consequently, in-depth exploration of the dynamic changes occurring at the single-cell level. Here we describe methods for whole-mount immunofluorescence, clearing, imaging, and analysis of whole ovarian tissue in 3D throughout murine development and aging.

World Heart Federation Cholesterol Roadmap 2022.

Background: Atherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death, disability and healthcare expenditure globally. Preventing the accumulation of cholesterol-containing atherogenic lipoproteins in the vessel wall is central to any healthcare strategy to prevent ASCVD. Advances in current concepts about reducing cumulative exposure to apolipoprotein B (apo B) cholesterol-containing lipoproteins and the emergence of novel therapies provide new opportunities to better prevent ASCVD. The present update of the World Heart Federation Cholesterol Roadmap provides a conceptual framework for the development of national policies and health systems approaches, so that potential roadblocks to cholesterol management and thus ASCVD prevention can be overcome. Methods: Through a review of published guidelines and research papers since 2017, and consultation with a committee composed of experts in clinical management of dyslipidaemias and health systems research in low-and-middle income countries (LMICs), this Roadmap identifies (1) key principles to effective ASCVD prevention (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMICs; and (4) potential strategies for overcoming these. Results: Reducing the future burden of ASCVD will require diverse approaches throughout the life-course. These include: a greater focus on primordial prevention; availability of affordable cholesterol testing; availability of universal cholesterol screening for inherited dyslipidaemias; risk stratification moving beyond 10-year risk to look at lifetime risk with adequate risk estimators; wider availability of affordable cholesterol-lowering therapies which should include statins as essential medications globally; use of adequate doses of potent statin regimens; and combination therapies with ezetimibe or other therapies in order to attain and maintain robust reductions in LDL-C in those at highest risk. Continuing efforts are needed on health literacy for both the public and healthcare providers, utilising multi-disciplinary teams in healthcare and applications that quantify both ASCVD risk and benefits of treatment as well as increased adherence to therapies. Conclusions: The adverse effects of LDL-cholesterol and apo B containing lipoprotein exposure are cumulative and result in ASCVD. These are preventable by implementation of different strategies, aimed at efficiently tackling atherosclerosis at different stages throughout the human life-course. Preventive strategies should therefore be updated to implement health policy, lifestyle changes and when needed pharmacotherapies earlier with investment in, and a shift in focus towards, early preventive strategies that preserve cardiovascular health rather than treat the consequences of ASCVD.

Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

[Extension of cervix cancer screening by visual methods to the community health centres in the district of Bamako]. / Extension du depistage du cancer du col uterin par inspection visuelle aux centres de sante communautaires du district de Bamako.

Cervix cancer remains a public health problem in developing countries. These results are an assessment for multicentric study based on visual inspection of the cervix after application of acetiq acid (VIA) and lugol's iodine (VILI). The aim of this study is to determine the feasibility and the impact of this screening in the community health centres "CSCOM" in the district of Bamako. It was a prospective and multicentric study through 8 CSCOM, 3 Reference Centres "CSRéf", Hôpital Gabriel Touré (HGT) and National Institute of Public Health (INRSP) in Bamako. During 28 months, 5016 women aged through 25-49 years were screened. After their consent and questionnaire filling, the patient is comfortably settled for visual test. The repartition of screened patients by health level is: CSCOM (19.24% : 965/5016), CSRéf (48.64% : 2440/5016), HGT (32.12% : 1611/5016). In general, the positivity of tests was: 5.2% (VIA) and 6.8% (VILI). The positive women at the CSCOM level were oriented to the CSRéf or the HGT for the colposcopy, possible biopsy or care. At all 177 biopsies were done, and histological diagnosis were: 67 dysplasias, 3 early invasive carcinomas, 69 invasive carcinomas and 38 inflammatory metaplasic lesions or nonconclusives aspects. Patients with dysplasias or cancers were treated by cryotherapy, loop electrosurgical excision procedure (LEEP), cold-knife conization or surgery. This study showed that screening of cervical cancer by visual inspection is workable at CSCOM level. We wish a large diffusion of the method to the whole of the country.

Extension du depistage du cancer du col uterin par inspection visuelle aux centres de sante communautaire du District de Bamako

Le cancer du col de l'uterus demeure un probleme de sante publique dans les pays en developpement. Le present travail constitue un bilan d'une etude multicentrique basee sur l'inspection visuelle du col apres application d'acide acetique (IVA) et de lugol (IVL). L'objectif assigne a ce travail est de determiner la faisabilite et l'impact de ce depistage au niveau des centres de sante communautaires du district de Bamako. Il s'agissait d'une etude prospective multicentrique a travers 8 CSCOM; 3 Centres de Sante de Reference (CSRef); l'Hopital Gabriel Toure (HGT) et l'Institut National de Recherche en Sante Publique (INRSP) de Bamako. Sur une periode de 28 mois; 5016 femmes agees de 25 a 49 ans ont ete depistees. Apres un consentement eclaire; la fiche d'enquete est remplie. La patiente etait confortablement installee sur une table gynecologique pour le depistage. La repartition des femmes depistees selon le niveau de la pyramide sanitaire se fait comme suit : CSCOM (19;24: 965/5016); CSRef (48;64: 2440/5016); HGT (32;12: 1611/5016). De facon generale; la positivite des tests etait la suivante : 5;2pour l'IVA et 6;8pour l'IVL. Les femmes positives au niveau des CSCOM etaient orientees vers un CSRef ou l'HGT pour la colposcopie; une biopsie eventuelle et la prise en charge. Sur 177 biopsies effectuees; les diagnostics suivants ont ete observes : 67 dysplasies; 3 carcinomes micro-invasifs; 69 carcinomes invasifs et 38 lesions inflammatoires; metaplasiques ou non concluantes. Les patientes presentant des lesions dysplasiques ou tumorales ont ete traitees par cryotherapie; conisation; resection a l'anse diathermique ou par la chirurgie. Ce travail montre que le depistage du cancer du col par les methodes visuelles est realisable au niveau des CSCOM. Nous recommandons une large diffusion de la methode sur tout le territoire national

Etude de l'état nutritionnel des enfants d'âge préscolaire dans un quartier du district de Bamako Bankoni (Mali)

Une enquete exhaustive realisee chez les enfants de 6 a 36 mois du quartier de Bankoni (quartier pauvre du district de Bamako) a revele que la malnutrition proteino-energetique est un probleme de sante publique; car les niveaux de prevalence de la maigreur est de 13;1 pour cent; le retard de croissance statural 24;1 pour cent et l'insuffisance ponderale 30;8 pour cent. Cette etude a aussi mis en evidence des variations de prevalence assez importantes entre les differents secteurs etudies d'une entite administrative apparemment homogene. Deux secteurs (Flabougou et Plateau) ont des niveaux de prevalence eleves pour tous les indices. Pour un meilleur ciblage des interventions et du systeme de surveillance; les etudes epidemiologiques en milieu urbain doivent se baser sur des decoupages homogenes; qui ne correspondent pas toujours aux entites administratives. Dans ce cadre une approche geographique et anthropologique permettrait d'identifier des zones homogenes en matiere de malnutrition proteino-energetique