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Accompagnement des étudiants à besoins spécifiques, sensibilisation de l’entourage aux situations de handicap
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Approches microfluidiques pour le tri et la caractérisation morpho-mécanique d’agrégats cellulaires
No full textCell aggregates, such as spheroids and organoids, are increasingly used in laboratories to replicate biological tissues. Typically comprising a few thousand cells, they exhibit an intermediate level of complexity between conventional cell cultures and animal models, and offer promising perspectives for both fundamental and applied research, particularly in the field of personalised medicine. However, their use remains limited by high experimental variability and by the lack of standardised analysis methods. In this context, this doctoral work aimed to develop automated approaches for the characterisation of large populations of cell aggregates. First, I adapted the principles of flow cytometry to the sorting of cell aggregates, based on real-time image analysis and encapsulation in millimetric droplets manipulated by acoustic radiation force. The cytometer thus designed is capable of measuring morphological and phenotypic properties within populations of several hundred aggregates, and of isolating subpopulations with homogeneous properties. This approach paves the way for more reproducible and statistically robust characterisation protocols for the study of spheroids and organoids. I then investigated the mechanisms of self-organisation of human induced pluripotent stem cell (hiPSC) cysts. These aggregates consist of a spherical epithelial cell monolayer enclosing a central cavity called a lumen, and are considered as models of embryos at the epiblast stage. Since these fragile samples cannot be imaged over long periods, I developed an on-chip cytometry method using automated confocal imaging, which enabled the analysis of hundreds of cysts at different stages of growth, from lumen formation to epithelial stratification. This revealed scaling laws of the self-organisation of hiPSC cysts and highlighted the key stages of their development, interpreted from a geometric and mechanical perspective. Finally, I characterised the mechanical properties of cysts through micropipette aspiration experiments, a technique historically dedicated to single cells and more recently adapted to cellular aggregates. In particular, I studied cyst rupture under extreme deformations and explored the possibility of extending these analyses towards high-throughput deformability cytometry, in order to generalise the measurement of their mechanical properties. In this thesis, I thus introduced new methods dedicated to the manipulation and characterisation of cellular aggregates, hence contributing to the standardisation of their large-scale study.Les agrégats cellulaires, tels que les sphéroïdes et les organoïdes, sont de plus en plus utilisés en laboratoire pour répliquer les tissus biologiques. Comprenant typiquement quelques milliers de cellules, ils présentent un niveau de complexité intermédiaire entre les cultures cellulaires classiques et les modèles animaux, et offrent des perspectives prometteuses pour la recherche fondamentale et appliquée, notamment dans le domaine de la médecine personnalisée. Toutefois, leur utilisation reste limitée par une forte variabilité expérimentale et par le manque de méthodes d’analyse standardisées. Dans ce contexte, ce travail de thèse visait à développer des approches automatisées pour la caractérisation de grandes populations d’agrégats cellulaires. Dans un premier temps, j’ai adapté les principes de la cytométrie en flux au tri d’agrégats cellulaires basé sur l’analyse d’images en temps réel et l’encapsulation dans des gouttes millimétriques manipulées par force de radiation acoustique. Le cytomètre ainsi conçu est capable de mesurer des propriétés morphologiques et phénotypiques dans des populations de plusieurs centaines d’agrégats, et d’en isoler des sous-populations aux propriétés homogènes. Cette approche ouvre la voie à des protocoles de caractérisation plus reproductibles et statistiquement robustes pour l’étude des sphéroïdes et des organoïdes. J’ai ensuite étudié les mécanismes d’auto-organisation de cystes de cellules souches pluripotentes induites humaines (hiPSC). Ces agrégats sont constitués d’une monocouche cellulaire épithéliale sphérique enveloppant une cavité centrale appelée lumen, et sont considérés comme des modèles d’embryons au stade d’épiblastes. Ces échantillons fragiles ne pouvant être imagés sur de longues périodes, j’ai développé une méthode de cytométrie sur puce par imagerie confocale automatisée, permettant l’analyse de centaines de cystes à différents stades de croissance, de la formation du lumen à la stratification de l’épithélium. Cette approche a révélé des lois d’échelle de l’auto-organisation de cystes de hiPSC et mis en évidence les étapes clés de leur développement, interprétées dans une perspective géométrique et mécanique. Enfin, j’ai caractérisé les propriétés mécaniques des cystes par des expériences d’aspiration en micropipette, une technique historiquement dédiée aux cellules uniques et récemment adaptée aux agrégats cellulaires. J’ai notamment étudié la rupture des cystes lors de déformations extrêmes et exploré la possibilité de transposer ces analyses vers une cytométrie de déformabilité à haut débit, afin de généraliser la mesure de leurs propriétés mécaniques. Dans cette thèse, j’ai ainsi introduit de nouvelles méthodes pour la manipulation et la caractérisation des agrégats cellulaires, contribuant à la standardisation de leur étude à grande échelle
Structuring, Sequencing, Staging, Selecting: the 4S method for the longitudinal analysis of multidimensional questionnaires in chronic diseases
No full textInternational audienceIn clinical studies, questionnaires are often used to report disease-related manifestations from clinician and/or patient perspectives. Their analysis can help identify relevant manifestations throughout the disease course, enhancing knowledge of disease progression and guiding clinicians in appropriate care provision. However, the analysis of questionnaires in health studies is not straightforward as made of repeated, ordinal, and potentially multidimensional item data. Sum-score summaries may considerably reduce information and hamper interpretation; items’ changes over time occur along clinical progression; and as many other longitudinal processes, observations may be truncated by events. This work establishes a comprehensive strategy in four consecutive steps to leverage repeated ordinal data from multidimensional questionnaires. The 4S method successively (1) identifies the questionnaire structure into dimensions satisfying three calibration assumptions (unidimensionality, conditional independence, increasing monotonicity), (2) describes each dimension progression using a joint latent process model which includes a continuous-time item response theory model for the longitudinal subpart, (3) aligns each dimension progression with disease stages through a projection approach, and (4) identifies the most informative items across disease stages using the Fisher information. The method is applied to multiple system atrophy (MSA), a rare neurodegenerative disease, with the analysis of daily activity and motor impairments over disease progression. The 4S method provides an effective and complete analytical strategy for questionnaires repeatedly collected in health studies
José M. Menudo, The Entrepreneur in the History of Political Economy. The Hunting for Heffalumps in the Early Economic Analysis
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Whole-genome sequencing of 1,060 Brettanomyces bruxellensis isolates reveals significant phenotypic impact of acquired subgenomes in allopolyploids
No full textInternational audienceGenomic architecture changes can significantly influence genome evolution and phenotypic variation within a species. Polyploidization events are thought to be one of the important catalysts for adaptation, speciation and tumorigenesis. However, little is known about the overall impact of such events on the phenotypic landscape at a population level. Here, we completely sequenced and phenotyped a large population of 1060 Brettanomyces bruxellensis yeast isolates, punctuated by multiple independent polyploidization events, notably allopolyploidization, giving rise to a highly structured population related to various anthropized ecological niches. A subgenome-aware population analysis revealed differential genome evolution between the primary and acquired genomes, with the latter showing a higher degree of conservation between isolates. Distinct phenotypic signatures were identified across major populations, with allopolyploid isolates showing an enrichment of extreme phenotypes. Genome-wide association analysis consistently revealed the substantial influence of the acquired genome of allopolyploids, with associated variants exhibiting significantly larger effect sizes than those from the primary genome. Overall, our study illustrates the profound and species-wide impact of polyploidization events on genome evolution and phenotypic diversity. It also provides a useful resource to explore the impact of allopolyploidy on adaptation
Genetic Assignment at Different Geographical Levels: A Case Study in a Forest Tree Species ( <i>Pinus pinaster</i> Ait.) Using SNP Markers
No full textInternational audienceGenetic markers can assist in the identification of the stock origin in different organisms. Comparative studies of forest tree provenances have demonstrated that forest tree populations differ in performance across environments and at multiple geographic levels: populations nested within regions nested within gene pools. These levels are critical for conservation and sustainable use of genetic resources: regions of provenance are key units for seed marketing, while populations guide reproductive material collection under most seed regulations. Despite their potential, genetic methods have rarely been applied to identify forest tree origins due to methodological (sufficient number of highly discriminatory markers) and practical (construction of a baseline composed of a representative selection of samples) challenges. In our study, we analyzed a genomic dataset comprising 10,185 SNPs from 1579 samples of Pinus pinaster, a species with strong population structure, across 86 populations, 45 regions of provenance, and 10 gene pools, to discriminate among these hierarchical levels and assign individuals to them. We used two software packages to evaluate the reliability of our baseline dataset (i.e., reference data) for genetic discrimination and assignment: RUBIAS, which performs genetic stock identification and associated tasks, and assignPOP, implementing a supervised machine-learning genetic-assignment framework. Using numerical validation analyses, we assessed their suitability and limitations for origin inference at each geographical level. Our results indicate that origin assignment is reliable in P. pinaster at the gene pool and region of provenance levels, but less so at the population level, provided that the 10 K SNP markers and a comprehensive genetic baseline are used. Incomplete baselines may result in wrong assignments at any hierarchical level, irrespective of sampling intensity for sampled candidate origins. We provide an extensive and publicly available baseline for P. pinaster, offering a useful tool for the management of forest genetic resources of this economically and ecologically important tree species. | IntroductionGenetic assignment methods can be employed to ascertain population membership of individuals or groups of individuals (Manel et al. 2005), based on the genotypes of the target sample to be identified and those of the candidate sources in a baseline that could contribute to the target sample. Although genetic assignment methods have been most successfully applied to fishery and marine organisms (e.g., Moran and Anderson 2019), most of the studies on forest trees are related to the identification.</div
Elaboration de cadres chronologiques des différents groupes humains pendant la transition Pléistocène-Holocène entre le sud du Brésil et le nord de l'Uruguay : l'apport de la datation par la luminescence.
No full textThis PhD studies the chronological and archaeological data from prehistoric sites in South America with levels attributed to the Pleistocene-Holocene transition (between 14 and 8 ka for this study): three in Brazil (Toca dos Coqueiros, Piauí; Linha Policial 7, Santa Catarina; Ilha Redonda, Rio Grande do Sul) and five surveys in Uruguay (Paso Catalán Chico A and B; Triunfo 1, 2, and 3, Artigas). Toca dos Coqueiros illustrates, in particular, an in situ technical evolution of the fossil director lesmas of the Itaparica phenomenon, while the other sites further south generally share the presence of tools on large flakes, usually produced using distinct flake support methods. This work has enabled a geochronological study of the different archaeological levels using optically stimulated luminescence (OSL) dating in single-grain and multi-grain analysis on quartz. This method makes it possible to determine the last exposure to light of the sediments covering the remains, thus revealing, using single-grain analysis, complex deposition phenomena that remained undetected with the radiocarbon (14C) dating already available for some sites in the corpus. This work provides new geochronological data for the Catalán Chico area in Uruguay and demonstrates the major chronological interest of using dating methods complementary to radiocarbon in order to refine the geochronological understanding of sedimentary deposits at archaeological sites in South America, both for the Late Pleistocene and the Holocene.Cette thèse analyse les données chronologiques et archéologiques de sites préhistoriques en Amérique du Sud présentant des niveaux attribués à la transition Pléistocène-Holocène (entre 14 et 8 ka pour cette étude) : trois au Brésil (Toca dos Coqueiros, Piauí ; Linha Policial 7, Santa Catarina ; Ilha Redonda, Rio Grande do Sul) et cinq sondages en Uruguay (Paso Catalán Chico A et B ; Triunfo 1, 2 et 3, Artigas). Toca dos Coqueiros illustre, notamment, une évolution technique in situ du fossile directeur lesmas du phénomène Itaparica, tandis que les autres sites plus au sud partagent globalement la présence d’outils sur grands éclats, produits généralement selon des méthodes d’obtention du support éclats distinctes. Ce travail a permis la réalisation d’une étude géochronologique des différents niveaux archéologiques, en recourant à la datation par luminescence stimulée optiquement (OSL) en analyse mono-grain et multi-grain sur quartz. Cette méthode permet de déterminer la dernière exposition à la lumière des sédiments recouvrant les vestiges, révélant ainsi, grâce au mono-grain, des phénomènes de dépôts complexes restés indétectés avec les datations radiocarbone (14C) déjà disponibles pour certains sites du corpus. Ce travail apporte notamment des données géochronologiques inédites pour la zone de Catalán Chico en Uruguay et démontre globalement l’intérêt chronologique majeur d’utiliser des méthodes de datations complémentaires au radiocarbone afin d’affiner les compréhensions géochronologiques des dépôts sédimentaires des sites archéologiques en Amérique du Sud, tant pour le Pléistocène final que pour l’Holocène
Cutaneous T-cell lymphomas and dupilumab use for atopic dermatitis: a systematic review and recommendations
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Devenir professionnel en 2025 des anciens internes de médecine générale de Bordeaux des promotions ECN 2017 à 2019
No full textIntroduction: in response to the shortage of general practitioners (GPs), one of the strategies proposed to encourage practice establishment is the strengthening of GP training. The 2017 reform of the third cycle of medical studies introduced major structural changes, such as the establishment of the « Diplôme d’Études Spécialisées » as the required and sufficient degree to practice a specialty, and the implementation of a competency-based approach. Objective: to determine the type of professional activity among former GP trainees in Bordeaux since the 2017 reform, two to four years after the end of residency, and to identify the factors influencing their career paths. Method: a cross-sectional, descriptive, observational study was conducted using an electronic questionnaire sent to 506 former GP residents in Bordeaux from the 2017–2019 French National Ranking Examination (ECN) cohorts. Results: the response rate was 48% (n=243). Women accounted for 67.5% of respondents. Overall, 73.7% were practicing ambulatory general medicine, including 30.9% in established practice (private practice, collaboration, salaried positions in health centers) and 42.8% working as replacements. Among the 25.9% not practicing ambulatory general medicine, 74.6% were working in hospitals or clinics, 38.1% of them in general medicine or emergency departments. One respondent (0.4%) reported a non-medical activity. Factors associated with ambulatory GP practice included not enrolling in training programs such as university diplomas (DU) or inter-university diplomas (DIU) and having had a positive professional experience during professionalizing internships. Factors influencing establishment in practice were being male, having initially entered medical school with the intention of becoming a GP, and having had a positive professional experience during professionalizing internships. Conclusion: the 2017 reform appears to promote ambulatory GP practice. Enhancing the visibility of general practice as early as middle and high school and strengthening the pedagogical quality of ambulatory internships may further encourage careers in ambulatory general medicine. Longitudinal cohort studies are needed for the development of future health policies.Introduction : face à la pénurie de médecins généralistes (MG), un des leviers proposés pour encourager l’installation est la formation des MG. La réforme du 3e cycle des études médicales de 2017 est source de changements structurels majeurs tels que l’institution du diplôme d’études spécialisées comme le diplôme nécessaire et suffisant à l’exercice d’une spécialité, et l’approche par compétences. Objectif : déterminer le type d’activité professionnelle des anciens internes de médecine générale bordelais, depuis la réforme de 2017, deux à quatre ans après la fin de l’internat, et les facteurs l’influençant. Méthode : une étude observationnelle, descriptive, transversale a été réalisée via un questionnaire électronique, envoyé aux 506 anciens internes de MG issus des promotions ECN 2017 à 2019. Résultats : le taux de réponse est de 48% (n=243). 67,5% étaient des femmes. 73,7% exerçaient la médecine générale ambulatoire dont 30,9% étaient installés (installation, collaboration, salariat en centre de santé) et 42,8% effectuaient des remplacements. Parmi les 25,9% qui n’exerçaient pas la médecine ambulatoire, 74,6% travaillaient à l’hôpital ou en clinique dont 38,1% dans un service de médecine polyvalente ou d’urgences. 0,4% exerçait une activité non médicale. Les facteurs influençant la pratique de la MG ambulatoire étaient la non inscription à des formations type DU/DIU, le fait d’avoir eu une bonne expérience professionnelle dans les stages de niveau 1 et lors du SASPAS. Les facteurs influençant l’installation étaient le genre masculin, le fait de débuter médecine en voulant être MG et l’expérience professionnelle ressentie lors du stage de niveau 1 et du SASPAS. Conclusion : la réforme de 2017 semble favoriser l’exercice de MG ambulatoire. La promotion de la MG dès le collège ou le lycée et le renforcement de la qualité pédagogique des stages ambulatoires permettraient de favoriser également son exercice. Des études de cohortes sont indispensables pour l’élaboration des politiques de santé futures