Astrocytes reverted to a neural progenitor-like state with transforming growth factor alpha are sensitized to cancerous transformation.

International audienceGliomas, the most frequent primitive central nervous system tumors, have been suggested to originate from astrocytes or from neural progenitors/stem cells. However, the precise identity of the cells at the origin of gliomas remains a matter of debate because no pre-neoplastic state has been yet identified. Transforming growth factor (TGF)-alpha, an epidermal growth factor family member, is frequently overexpressed in the early stages of glioma progression. We previously demonstrated that prolonged exposure of astrocytes to TGF-alpha is sufficient to trigger their reversion to a neural progenitor-like state. To determine whether TGF-alpha dedifferentiating effects are associated with cancerous transforming effects, we grafted intracerebrally dedifferentiated astrocytes. We show that these cells had the same cytogenomic profile as astrocytes, survived in vivo, and did not give birth to tumors. When astrocytes dedifferentiated with TGF-alpha were submitted to oncogenic stress using gamma irradiation, they acquired cancerous properties: they were immortalized, showed cytogenomic abnormalities, and formed high-grade glioma-like tumors after brain grafting. In contrast, irradiation did not modify the lifespan of astrocytes cultivated in serum-free medium. Addition of TGF-alpha after irradiation did not promote their transformation but decreased their lifespan. These results demonstrate that reversion of mature astrocytes to an embryonic state without genomic manipulation is sufficient to sensitize them to oncogenic stress

Genetic landscape of a large cohort of Primary Ovarian Insufficiency : New genes and pathways and implications for personalized medicine

Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Acquisition et didactique des langues

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Processus d’enseignement-apprentissage et processus d’acquisition

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Processus d’enseignement-apprentissage et processus d’acquisition

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Le projet européen Romtels (Roma translanguaging enquiry learning spaces). Un questionnement sur la médiation aux niveaux (inter)culturelle et identitaire

International audienceCette contribution liée au projet européen Romtels ERASMUS+ vise à problématiser les types de médiation à l’œuvre dans ce projet à partir de données collectées lors d’activités pédagogiques associant des élèves roms et leurs parents. L’expérience a été menée dans une démarche « d’enquête » qui permet l’utilisation des langues des élèves comme une ressource pour la résolution de tâches. L’approche linguistique retenue (« translanguaging »), les acteurs impliqués (élèves, enseignants et parents), les contextes d’élaboration et d’application (classe et musée) ainsi que les supports artistiques et numériques utilisés (tableaux et banque de données linguistiques) ont permis de faire émerger une réflexion sur les enjeux de la médiation notamment aux niveaux (inter)culturel et identitaire. Le présent article problématise, d’une part, le musée et l’œuvre d’art comme instruments de médiation (inter)culturelle et, d’autre part, le rôle d’(auto)médiation parentale dans la construction d’identité de parents d’élèves rom

Enfants gitans à l’école et en famille

Le public gitan est depuis longtemps montré du doigt comme étant un public à la marge, difficile à scolariser car souvent absent, évoluant dans un environnement multilingue (une langue à la maison différente de celle de l’école) et particulièrement paupérisé. L’enjeu d’un travail sur et avec ces enfants qui sont aussi des élèves, au-delà des bénéfices possibles pour leur réussite scolaire, est de mettre en lumière les approches linguistiques et didactiques qui permettraient à l’École d’inclure tous les enfants. À partir d’enquêtes conduites auprès de la population gitane de quartiers d’une grande ville du Sud de la France et dans les établissements scolaires de ces quartiers, et sur la base des apports de la recherche en sociolinguistique, sciences du langage et de la didactique, cet ouvrage aborde la question centrale de la difficulté scolaire par le biais des langues (familiales, scolaires) et de leur acquisition. Il interroge plus largement la capacité du système scolaire à aider ces élèves issus des communautés gitanes à réussir scolairement et au-delà, à relever le défi d’une école inclusive capable de prendre en compte la diversité et les singularités. À destination des chercheurs et des étudiants en sciences du langage, en didactique du français langue étrangère, en sciences de l’éducation et dans les disciplines connexes (sociologie, anthropologie, etc.), cet ouvrage intéressera également tous les enseignants quelle que soit leur spécialité, ainsi que les familles, associations et le grand public concernés par ces questions.This book aims to answer a controversial question in our society: how to help the children of gypsy communities to succeed in school? For a long time, the gypsy community has been singled out as being on the margins, difficult to educate because often absent, living in a multilingual environment (a home language different from school) and particularly impoverished. The challenge of working on and with these children who are also students, beyond the possible benefits for their academic success, is to highlight the linguistic and teaching approaches that would allow the school to include all children, whatever their real or imaged specificities might be, in order to teach all groups more effectively, including those who do not have any academic “problem” to start with. This book, intended for researchers and students of language sciences, didactics, education and related disciplines (sociology, anthropology, etc.), is also accessible to teachers regardless of their teaching subject, as well as to families and the general public. From the strict point of view of research, the original nature of the project is to rely on (socio)linguistics, development and didactics – fields rooted in language sciences. Our objective is to approach the phenomenon of academic difficulty through the medium of languages (in the family and at school) and their acquisition, while including the social dimensions and didactic implications of this reflection

Functional classification of ATM variants in ataxia-telangiectasia patients.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification

Diversité des prises en charge hospitalières de l'anorexie mentale en psychiatrie en France

International audienceBackground: Hospitalization is rare in anorexia nervosa (AN) and local application of indications is heterogeneous. However, no study has evaluated the effect of these different treatment modalities on the mean length of stay. Our objective was to describe the context and modalities of a wide range of hospital care programs offered to patients with anorexia nervosa in eleven specialized French psychiatric centers for patients from childhood to adulthood. This work was carried out within the framework of the EVHAN (Evaluation of Hospitalization for AN, Eudract number: 2007-A01110-53, registered in Clinical trials) research program. The EVHAN program comprises five main lines: weight objectives at discharge, the practice or not of a separation period, the use of clear nutritional dietary objectives (cognitive/behavioral), the intensity of family involvement in treatment, and the existence or absence of a stabilization phase before ending inpatient treatment. These main lines will make it possible to study the impact of treatment modalities on the future of patients in the short and medium term (at discharge and at 1-year follow-up). Methods: The eleven centers are located in France (Bordeaux, Nantes, Paris and Ile-de-France, Rouen and Saint-Étienne). Various staff members (psychiatrists, somatic doctors, nurses, dieticians, psychologists) from each center were interviewed using a semi-structured questionnaire. Data on operating modalities and context of care were collected and analyzed. Results: Four of the eleven centers were exclusively child/adolescent centers, and seven of 11 were adolescent (from 11, 13 or 16 years) and young adult centers. All centers offered a graduated approach from outpatient to full hospitalization. The majority had a number of beds allocated for patients with eating disorders. The criteria for hospitalization were homogeneous with respect to somatic and/or psychic severity prefiguring the consensus criteria defined by the French Health Authority (HAS) in 2010. Child/adolescent units used the weight curve to set weight objectives at discharge (between the 10th and 50th percentiles). Most adult units used weight objectives at discharge corresponding to a body mass index between 17 and 20 kg/m2. Nine centers used a written or oral care contract. One unit did not separate the patient from her/his usual environment, the others had a practice gradient of partial separation and total separation times. These were either short, lasting a maximum of 3 weeks, or long, lasting more than 3 weeks. Conversely, patients were not isolated within the unit, and benefited from a rich social life, depending on her/his physical condition. The patient's family was in contact with the team and fully supported. The longest periods of separation involved adolescents and adults. Nutritional support varied from a group approach (meals in the dining room, standardized meals of the care center) to very individualized approaches within a specific framework. All the units reported meeting with families at least once during the hospitalization; with the patient's parents for child/adolescent patients and/or unmarried patients and with the husband/wife for married patients. The majority of the centers requested a phase of weight stabilization, whatever the age before hospital discharge. Conclusion: There is international and national consensus regarding the indications for hospitalization, and the main lines of multidisciplinary care to be developed within this framework. However, local application of these indications was heterogeneous resulting in diverse modalities of hospital care for anorexia nervosa in France. Specialized teams have developed management strategies arising from their “team culture”. The complexity of the anorexic pathology, due to the psyche-soma intrication and the diversity of age groups, highlights the complexity of care available. The impact of this diversity of hospital care on patient outcomes will be studied as a result of this work