L’effet du vieillissement sur les cellules souches neurales adultes

La neurogenèse persiste à l’âge adulte dans deux régions du système nerveux central (SNC) des mammifères : la zone sous-ventriculaire (SVZ) du cerveau antérieur et la zone sous-granulaire (SGZ) de l’hippocampe. Cette neurogenèse est possible grâce à la capacité de prolifération des cellules souches présentes dans les niches de la SVZ et la SGZ, mais en vieillissant, le cerveau subit une diminution dramatique du nombre de cellules souches neurales adultes (CSNa), une diminution de la prolifération cellulaire et une altération des niches de neurogenèse. Cependant, une importante question reste sans réponse : comment la perte tardive des CSNa est temporellement reliée aux changements de l’activité de prolifération et de la structure de la principale niche de neurogenèse (la SVZ)? Afin d’avoir un aperçu sur les événements initiaux, nous avons examiné les changements des CSNa et de leur niche dans la SVZ entre le jeune âge et l’âge moyen. La niche de la SVZ des souris d’âge moyen (12 mois) subit une réduction de l’expression des marqueurs de plusieurs sous-populations de précurseurs neuraux en comparaison avec les souris jeunes adultes (2 mois). Anatomiquement, cela est associé avec des anomalies cytologiques, incluant une atrophie générale de la SVZ, une perte de la couche de cellules sousépendymaires par endroit et l’accumulation de gouttelettes lipidiques de grande taille dans l’épendyme. Fonctionnellement, ces changements sont corrélés avec une diminution de l’activité de la SVZ et une réduction du nombre de nouveaux neurones arrivant aux bulbes olfactifs. Pour déterminer si les CSNa de la SVZ ont subi des changements visibles, nous avons évalué les paramètres clés des CSNa in vivo et in vitro. La culture cellulaire montre qu’un nombre équivalent de CSNa ayant la capacité de former des neurosphères peut être isolé du cerveau du jeune adulte et d’âge moyen. Cependant, à l’âge moyen, les précurseurs neuraux semblent moins sensibles aux facteurs de croissance durant leur différenciation in vitro. Les CSNa donnent des signes de latence in vivo puisque leur capacité d’incorporation et de rétention du BrdU diminue. Ensemble, ces données démontrent que, tôt dans le processus du vieillissement, les CSNa et leur niche dans la SVZ subissent des changements significatifs, et suggèrent que la perte de CSNa liée au vieillissement est secondaire à ces événements.Neurogenesis persists throughout the adulthood in two regions of the mammalian central nervous system (SNC): the sub-ventricular zone (SVZ) of the forebrain and the sub-granular zone (SGZ) of the hippocampus. Neurogenesis is possible due to the proliferation capacity of stem cells present within both the SVZ and SGZ niches, but with aging, the forebrain undergoes a drastic reduction in its number of adult neural stem cells (aNSCs), a decrease of cell proliferation and an alteration of the neurogenic niches. However, a key unresolved question remains: how the onset of aNSC loss is temporally related to changes of proliferating activity and to structural alterations within the principal stem cell niche (the SVZ)? To gain insights into the initial events leading to aging-associated aNSC loss, we investigated the changes occurring to aNSCs and the SVZ niche between young adulthood and middle-age. The SVZ niche of middle-aged mice (12-months-old) was found to display reduced expression of markers for multiple neural precursor sub-populations when compared to young adult mice (2-months-old). Anatomically, this was associated with significant cytological aberrations, including an overall atrophy of the SVZ, loss of sub-ependymal cells, and accumulation of large lipid droplets within the ependyma. Functionally, these changes correlated with diminished SVZ activity and reduced number of newly born neurons reaching the principal target tissue: the olfactory bulbs. To determine whether changes were evident at the level of the SVZ stem cells, we evaluated key in vitro and in vivo parameters of aNSCs. Tissue culture experiments showed that equal numbers of neurosphere-forming aNSCs could be isolated from young adult and middle-aged forebrains. However, at middle-age, neural precursors seemed to be less sensitive to growth factors during their in vitro differentiation and displayed signs of increased quiescence in vivo. Collectively, these findings demonstrate that, with early aging, aNCS and their SVZ niche go through significant changes, and suggest that aging-associated aNSC loss is secondary to these events

Financing for Development, the Monterrey Consensus: Achievements and Prospects

The International Conference on Financing for Development, held in Monterrey, Mexico, in March 2002, marked the beginning of a new international approach to dealing with issues of development finance. It resulted from a unique process that broke new ground in bringing together all relevant stakeholders in a manner that was unprecedented in inclusiveness. Under the umbrella of the United Nations, all parties involved in the financing for development process contributed to creating a policy framework, the Monterrey Consensus of the International Conference on Financing for Development, to guide their respective future efforts to deal with issues of financing development at the national, regional, international, and systemic levels. This paper presents a summary of the major recommendations of the Monterrey Conference

Application des méthodes de datation par luminescence optique à l'évolution des environnements désertiques : Sahara occidental (Maroc) et Îles Canaries orientales (Espagne)

Ce travail a été effectué dans le but paléoenvironnemental de dresser un cadre géochronologique aux alternances des phases arides et humides au Sahara Occidental et aux Iles Canaries Orientales. Il s'intégrait dans une étude multidisciplinaire sur les changements globaux (EPGC, Earth Processes in Global Change) menée dans le cadre du projet CLIP (Climate of the Past) sous l'égide de l'UNESCO (United Nations Educational, Scientific and Cultural Organization) et de l'IUGS (International Union of Geological Sciences). La datation par luminescence stimulée optiquement a été appliquée aux feldspaths et aux quartz (quand ce fut possible) d'échantillons représentant les phases humides de trois coupes: Tah au Sahara Occidental, la Rosa Negra à Fuerteventura et Mala à Lanzarote. Une correction du fading a été appliquée aux feldspaths. Différentes méthodes inhérentes à FOSL (additive, régénération, Australian slide method, SAR, SAAD et grains individuels) ont été utilisées afin de comparer les résultats pour pouvoir valider les âges obtenus en toute confiance, vu l'absence totale de contrôle chronologique. Au Sahara Occidental, au niveau de la coupe Tah, les différentes méthodes appliquées aux feldspaths aboutissent aux mêmes âges après correction pour le fading et ce, pour tous les échantillons. Ces âges correspondent également à ceux obtenus sur les quartzs des échantillons non saturés. On peut ainsi affirmer que la coupe Tah couvre les 110 derniers milliers d'années avec une phase humide prononcée à 105 ± 9, 109 ± 11 ka, puis 3 autres autour de 50 ± 5, 31 ± 3 puis 13 ±1 ka, la dernière étant datée par 14C. Aux îles Canaries Orientales, des difficultés d'ordre minéralogique, dues aux très fortes teneurs en carbonates et aux faibles quantité de quartz et de feldspaths, ont restreint l'application des différentes techniques. Les minéraux présents montrent des changements de sensibilité marqués, probablement à cause de leur origine volcanique récente. Seule la méthode SAR, qui a l'avantage de s'appliquer à des aliquotes uniques en corrigeant les changements de sensibilité, aboutit à des résultats fiables. Les quartzs n'ont pu être datés car ils sont saturés dans les niveaux les plus anciens et absents dans les niveaux sommitaux. Une fois la correction pour le fading appliquée, la coupe de la Rosa Negra à Fuerteventura montre l'existence de phases humides autour de 253 ±27, 190 ± 30 et 147 ± 25 ka. Au niveau de la coupe Mala à Lanzarote, les échantillons de base n'ont malheureusement pu être datés car les aliquotes émettent très peu en OSL ou sont très peu reproductibles. Cependant, deux phases humides sommitales autour de 191 ± 55 et de 130 ± 11 ka se corrèlent avec les niveaux sommitaux de la coupe de la Rosa Negra ce qui suggère que les lacunes observées à la Rosa Negra ont une signification régionale. La séquence, composée de la superposition des coupes la Rosa Negra et Mala, apparemment contemporaines, et de la coupe Tah, témoigne des variations climatiques au Sahara depuis 250 000 ans. Les différentes phases humides qui y sont représentées coïncident avec les limites des périodes interglaciaires ou interstadiaires déterminées par les variations des isotopes stables (ô18O) de carottes marines du Bassin Canarien, similaires à celles de la courbe SPECMAP. D'autre part, ces phases humides correspondent à celles enregistrées dans les travertins ou sous forme de hauts niveaux lacustres épars dans le reste du Sahara et au Sahel. A l'exception de l'épisode humide autour de 80 ka, correspondant au stade isotopique 5a dans le domaine marin, probablement érodé par la déflation éolienne, cette séquence est l'unique séquence continentale pratiquement continue couvrant plusieurs cycles climatiques dans l'environnement aride saharien

Français langue véhiculaire du savoir scientifique: Diagnostic des difficultés rencontrées par les étudiants des 1ères années de la faculté des sciences

Français langue véhiculaire du savoir scientifique:Diagnostic des difficultés rencontrées par lesétudiants des 1ères années de la faculté des science

Age-Related Changes in Astrocytic and Ependymal Cells of the Subventricular Zone

Neurogenesis persists in the adult subventricular zone (SVZ) of the mammalian brain. During aging, the SVZ neurogenic capacity undergoes a progressive decline, which is attributed to a decrease in the population of neural stem cells (NSCs). However, the behavior of the NSCs that remain in the aged brain is not fully understood. Here we performed a comparative ultrastructural study of the SVZ niche of 2-month-old and 24-month-old male C57BL/6 mice, focusing on the NSC population. Using thymidine-labeling, we showed that residual NSCs in the aged SVZ divide less frequently than those in young mice. We also provided evidence that ependymal cells are not newly generated during senescence, as others studies suggest. Remarkably, both astrocytes and ependymal cells accumulated a high number of intermediate filaments and dense bodies during aging, resembling reactive cells. A better understanding of the changes occurring in the neurogenic niche during aging will allow us to develop new strategies for fighting neurological disorders linked to senescence

Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia

Cerebral ischemia stimulates endogenous neurogenesis. However, the functional relevance of this phenomenon remains unclear because of poor survival and low neuronal differentiation rates of newborn cells. Therefore, further studies on mechanisms regulating neurogenesis under ischemic conditions are required, among which ephrin-ligands and ephrin-receptors (Eph) are an interesting target. Although Eph/ephrin proteins like ephrin-B3 are known to negatively regulate neurogenesis under physiological conditions, their role in cerebral ischemia is largely unknown. We therefore studied neurogenesis, brain injury and functional outcome in ephrin-B3−/− (knockout) and ephrin-B3+/+ (wild-type) mice submitted to cerebral ischemia. Induction of stroke resulted in enhanced cell proliferation and neuronal differentiation around the lesion site of ephrin-B3−/− compared to ephrin-B3+/+ mice. However, prominent post-ischemic neurogenesis in ephrin-B3−/− mice was accompanied by significantly increased ischemic injury and motor coordination deficits that persisted up to 4 weeks. Ischemic injury in ephrin-B3−/− mice was associated with a caspase-3-dependent activation of the signal transducer and activator of transcription 1 (STAT1). Whereas inhibition of caspase-3 had no effect on brain injury in ephrin-B3+/+ animals, infarct size in ephrin-B3−/− mice was strongly reduced, suggesting that aggravated brain injury in these animals might involve a caspase-3-dependent activation of STAT1. In conclusion, post-ischemic neurogenesis in ephrin-B3−/− mice is strongly enhanced, but fails to contribute to functional recovery because of caspase-3-mediated aggravation of ischemic injury in these animals. Our results suggest that ephrin-B3 might be an interesting target for overcoming some of the limitations of further cell-based therapies in stroke

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease