Sentimental et engagé : le roman Aïcha la rebelle d’Halima Ben Haddou

Halima Ben Haddou fait partie des pionnières de la littérature marocaine féminine d’expression française. Au moment de sa publication, en 1982, son premier roman, intitulé Aïcha la rebelle, connaît un vif succès et devient un best-seller. Bien qu’il soit un des premiers romans francophones écrit par une femme au Maroc, ce roman a vite été oublié par la critique. Notre étude part du constat que son hybridité générique le rend difficile à classer parmi les genres littéraires conventionnels. Est-ce un roman sentimental ou un roman engagé? Ou appartient-il simplement à ce que l’on qualifie de littérature féminine? Ce mémoire vise à étudier trois dimensions importantes de l’œuvre Aïcha la rebelle : la dimension sentimentale, la dimension engagée et la dimension féminine. Ainsi, nous examinons tout d’abord comment le roman Aïcha la rebelle se rapproche du roman sentimental traditionnel tout en s’écartant de certaines conventions génériques. Ensuite, nous analysons l’aspect engagé du roman en abordant des thèmes tels que le colonialisme et les questions identitaires. Finalement, nous nous intéressons à savoir de quelle manière le roman développe l’idée d’un certain féminisme spécifique et d’une écriture féminine touchant l’univers féminin oriental.Halima Ben Haddou is one of the first morocan women who have written novels in french. When her first novel, Aïcha la rebelle, was published in 1982, it got a great success. However, this novel has been forgotten later by critics. Aïcha la rebelle’s generic hybridity makes it difficult to be classified among conventional literary genres; it makes us wonder whether it is a sentimental novel or a committed one, or it is simply what is called women’s writing. This thesis aims to study three important dimensions of Aïcha la rebelle: the sentimental dimension, the committed dimension, and the feminine dimension. First of all, we examine how Aïcha la rebelle novel approaches the traditional sentimental novels while breaking certain generic conventions. Then, we analyze the engaged aspect of the novel by examining themes such as colonialism and identity issues. Finally, we see how Aïcha la rebelle develops the idea of certain specific feminism and feminine writing which touches the eastern feminine universe

Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis

Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by combining single cell sequencing and in vivo approaches, a population of human pre-valvular endocardial cells (HPVCs) can be derived from pluripotent stem cells. HPVCs express gene patterns conforming to the E9.0 mouse atrio-ventricular canal (AVC) endocardium signature. HPVCs treated with BMP2, cultured on mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, undergo endothelial-to-mesenchymal transition and express markers of valve interstitial cells of different valvular layers, demonstrating cell specificity. Extending this model to patient-specific induced pluripotent stem cells recapitulates features of mitral valve prolapse and identified dysregulation of the SHH pathway. Concurrently increased ECM secretion can be rescued by SHH inhibition, thus providing a putative therapeutic target. In summary, we report a human cell model of valvulogenesis that faithfully recapitulates valve disease in a dish.We thank the Leducq Fondation for supporting Tui Neri, and funding this research under the framework of the MITRAL network and for generously awarding us for the equipment of our cell imaging facility in the frame of their program “Equipement de Recherche et Plateformes Technologiques” (ERPT to M.P.), the Genopole at Evry and the Fondation de la recherche Medicale (grant DEQ20100318280) for supporting the laboratory of Michel Puceat. Part of this work in South Carolina University was conducted in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Other funding sources: National Heart Lung and Blood Institute: RO1-HL33756 (R.R.M.), COBRE P20RR016434–07 (R.R.M., R.A. N.), P20RR016434–09S1 (R.R.M. and R.A.N.); American Heart Association: 11SDG5270006 (R.A.N.); National Science Foundation: EPS-0902795 (R.R.M. and R.A. N.); American Heart Association: 10SDG2630130 (A.C.Z.), NIH: P01HD032573 (A.C. Z.), NIH: U54 HL108460 (A.C.Z), NCATS: UL1TR000100 (A.C.Z.); EH was supported by a fellowship of the Ministere de la recherche et de l’éducation in France.TM-M was supported by a fellowship from the Fondation Foulon Delalande and the Leducq Foundation. P.v.V. was sponsored by a UC San Diego Cardiovascular Scholarship Award and a Postdoctoral Fellowship from the California Institute for Regenerative Medicine (CIRM) Interdisciplinary Stem Cell Training Program II. S.M.E. was funded by a grant from the National Heart, Lung, and Blood Institute (HL-117649). A.T. is supported by the National Heart, Lung, and Blood Institute (R01-HL134664).S

Towards understanding the heterogeneity of endocardial cells at the origin of different cell types in the mitral valve

Les défauts de la valve mitrale incluant le prolapse est associé à d'autres malformations cardiaques congénitales. les cellules endocardiques du canal atrioventriculaire (CAV) subissent une transition épithélio-mésenchymateuse (endoMT) au jour E9.0 chez la souris pour donner les différentes types cellulaires de la valve mitrale. L'identité de ces cellules est toujours inconnues. Le but de cette étude est d'identifier les cellules endocardiques qui sont capable de subir l'EndoMT et ainsi savoir si ces cellules sont déjà spécifiés pour donner un type cellulaire valvulaire. les CAV des souris ont été disséqués des embryons de souris E9.5 génétiquement marqués par le tie2cre.tdTomato. de même les valve mitrailles embryonnaires et néonatales ont été disséquées et une analyse de la cellule unique (single cell RNA-seq) a été effectué. cette technique a prouvé qu'une sous population des cellules endocardiques est capable de subir l'endoMT et d'autres populations sont bien spécifiées pour donner les différentes types des cellules valvulaires. une marquage génétique des cellules endocardiques avec le rapporteur CAGCrERT2 et le promoteur Brainbow a été utilisé pour l'analyse clonale. les clones ont été analysés au jour E16.5 dans la valve mitrale embryonnaire. On a observé différentes comportements des clones. En conclusion, nos résultats montrent bien l'hétérogénéité des cellules endocardiques du CAV, parmi lesquelles de populations stricts sont à l'origine de diverse types de cellules de la valve mitrale, ainsi que différentes types de clones contribuent à la formation des feuillets matures de la valve mitrale.Congenital defect of mitral valve including prolapse is often associated with other congenital heart malformations. A subset of endocardial cells of the atrioventricular canal undergoes endothelial-to-mesenchymal transition at embryonic day E9.0 in mice to give rise to valve progenitors, and future mitral or tricuspid diverse valvular cell types. The identity and fate of those cells remain unknown. The aim of this study was dual: to identify specific endocardial cells capable to undergo EMT and to investigate whether those cells are multipotent or unipotent and thus, already committed towards a specific valvular cell type. AVCs were dissected from E9.5 genetically labelled mouse embryonic hearts. Mitral valve leaflets were further dissected from E16.5 and P0 Tie2Tdt mouse hearts. Single cell sequencing of tomato+ endocardial cells was then performed. This approach uncovered a restricted population of pro-EMT endocardial cells and further distinct populations of valve progenitors giving rise to different cell types in E16.5 and P0 mitral valve. Genetic labeling of endocardial cells was performed in CAGERT2Cre+/-; Brainbow+/- embryos and Cre was induced with a low dose of tamoxifen at E8.5, prior to EndoMT. Cell clones were analyzed in E16.5 hearts. Labelled hearts were first screened following a statistical and probabilistic analysis of coloured fragments. We observed different behaviour of clones. Collectively, our data reveal endocardial cell heterogeneity including a restricted subset of progenitors at the origin of diverse valvular cells and distinct types of clonal contribution of these cells to maturing leaflets

Pathophysiology of Myelodysplastic Syndromes

Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments

A single cell transcriptomic and clonal analysis depicts valvulogenesis

Mitral valve prolapse is often associated with several congenital heart malformations. During development, endocardial cells of the atrioventricular canal undergo endothelial to mesenchymal transition (EndMT) to give rise to the different mitral valvular cells. However, our understanding of the identity and fate decisions of these endocardial cells during development is lacking. Here, using single-cell RNA sequencing (scRNA-seq) of genetically labeled AVC endocardial cells at E9.5 in murine heart, we uncovered and genetically characterized a restricted population of pro-EndMT cells and further distinct populations of valve progenitors that together contribute to different endothelial and interstitial valvular cells in E16.5 embryonic and P0 postnatal murine mitral valve. Moreover, by genetically labeling endocardial cells using CAG ERT2Cre+/- / Brainbow +/- mice at embryonic stage E8.5, prior to EndMT, we observed specific modes of growth of endocardial derived clones in E16.5 embryonic mitral valve. Collectively, our data reveal the identity of specified endocardial cells and the distinct types of clonal contribution of these cells to the formation of the mitral valve. They further open the path towards finding new cell targets for a therapeutic approach of congenital and acquired valve diseases

Birth, cell fate and behavior of progenitors at the origin of the cardiac mitral valve

International audienc

Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation

International audienceMyelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1 . Molecular bases of these divergences are poorly understood. Here we find that SF3B1 -mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1 - or SRSF2 -mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1 -mutated patients, SF3B1 -mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1 -mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1 -mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target