Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bia

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Hormonally Active Women Tolerate Shock-Trauma Better Than Do Men: A Prospective Study of Over 4000 Trauma Patients

A prospective clinical series of 4106 patients was carried out testing the hypothesis that women would manifest a better preserved initial hemodynamic response and tissue perfusion after trauma than do men. Based on lactate levels and transfusion requirements, this hypothesis was validated in premenopausal women although the magnitude of injury was greater in women than in men

Savoirs locaux et agriculture durable au Yémen

Réalisé en partenariat avec le Centre Yéménite de Ressources Génétiques, ce numéro des ‘Cahiers du CEFAS’, qui fait suite à deux précédents ‘Cahiers du CFEY’, réunit une sélection de 19 articles issus du séminaire Place des pratiques et des techniques anciennes dans l’agriculture yéménite d’aujourd’hui : problèmes et perspectives, qui s’était tenu en juin 2000 à la Faculté d’Agriculture de Sanaa et dans les locaux du CEFAS. Plus de trente anthropologues, archéologues, géographes, historiens, agronomes et spécialistes du développement, étrangers et yéménites, ont pris la parole au cours de ces journées de rencontres et d’échanges.Loin d’un regard nostalgique sur l’image d’une agriculture yéménite immuable qui aurait échappé à toute modernisation ‘néfaste’ de ses pratiques et de ses techniques, et bien loin d’un débat remettant en question des avancées technologiques ‘excessives’ et leurs éventuels effets sur l’environnement et la qualité de l’alimentation, il fut davantage question ici de réfléchir aux interventions en matière de développement dans un pays principalement d’économie rurale et pour lequel toute politique de développement doit s’appuyer en priorité sur le travail de sa population paysanne.This third publication of ‘Cahiers du CEFAS’ –previously named ‘Cahiers du CFEY’- results from a partnership with the Yemeni Genetic Resources Center (YGRC) and consists of 19 articles selected from the seminar The place of ancient agricultural practices and techniques in Yemen today : problems and perspectives, held in June 2000, at the Faculty of Agriculture of Sanaa University and in the CEFAS. More than 30 anthropologists, archaeologists, geographers, historians, agronomists and development specialists, from Yemen and abroad, participated in the meetings. Far from being a nostalgic point of view on a potentially ‘unchanging’ Yemeni agriculture, protected from any ‘harmful’ modernisation of its practices and techniques, and at the same time, far from discrediting ‘excessive’ technological improvements and their effects on environment or food quality, this seminar was clearly dedicated to sharing ideas related to development operations in this mainly rural country, where any development policy has to, in all cases, rely upon farmers’ labour

Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks

DNA is packaged into chromatin, a highly compacted DNA-protein complex; therefore, all cellular processes that use the DNA as a template, including DNA repair, require a high degree of coordination between the DNA-repair machinery and chromatin modification/remodelling, which regulates the accessibility of DNA in chromatin. Recent studies have implicated histone acetyltransferase (HAT) complexes and chromatin acetylation in DNA repair; however, the precise underlying mechanism remains poorly understood. Here, we show that the HAT cofactor Trrap and Tip60 HAT bind to the chromatin surrounding sites of DNA double-strand breaks (DSBs) in vivo. Trrap depletion impairs both DNA-damage-induced histone H4 hyperacetylation and accumulation of repair molecules at sites of DSBs, resulting in defective homologous recombination (HR) repair, albeit with the presence of a functional ATM-dependent DNA-damage signalling cascade. Importantly, the impaired loading of repair proteins and the defect in DNA repair in Trrap-deficient cells can be counteracted by chromatin relaxation, indicating that the DNA-repair defect that was observed in the absence of Trrap is due to impeded chromatin accessibility at sites of DNA breaks. Thus, these data reveal that cells may use the same basic mechanism involving HAT complexes to regulate distinct cellular processes, such as transcription and DNA repair

DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma

Glaucoma is the leading cause of irreversible blindness and is characterized by slow and progressive degeneration of the optic nerve head axons and retinal ganglion cell (RGC), leading to loss of visual function. Although oxidative stress and/or alteration of mitochondrial (mt) dynamics induced by elevated intraocular pressure (IOP) are associated with this neurodegenerative disease, the mechanisms that regulate mt dysfunction-mediated glaucomatous neurodegeneration are poorly understood. Using a mouse model of glaucoma, DBA/2J (D2), which spontaneously develops elevated IOP, as well as an in vitro RGC culture system, we show here that oxidative stress, as evidenced by increasing superoxide dismutase 2 (SOD2) and mt transcription factor A (Tfam) protein expression, triggers mt fission and loss by increasing dynamin-related protein 1 (DRP1) in the retina of glaucomatous D2 mice as well as in cultured RGCs exposed to elevated hydrostatic pressure in vitro. DRP1 inhibition by overexpressing DRP1 K38A mutant blocks mt fission and triggers a subsequent reduction of oxidative stress, as evidenced by decreasing SOD2 and Tfam protein expression. DRP1 inhibition promotes RGC survival by increasing phosphorylation of Bad at serine 112 in the retina and preserves RGC axons by maintaining mt integrity in the glial lamina of glaucomatous D2 mice. These findings demonstrate an important vicious cycle involved in glaucomatous neurodegeneration that starts with elevated IOP producing oxidative stress; the oxidative stress then leads to mt fission and a specific form of mt dysfunction that generates further oxidative stress, thus perpetuating the cycle. Our findings suggest that DRP1 is a potential therapeutic target for ameliorating oxidative stress-mediated mt fission and dysfunction in RGC and its axons during glaucomatous neurodegeneration. Thus, DRP1 inhibition may provide a new therapeutic strategy for protecting both RGCs and their axons in glaucoma and other optic neuropathies