Sustainable livelihoods to adaptive capabilities: a global learning journey in a small state, Zanzibar

This thesis takes global learning out of the formal setting of a Northern classroom to a rural community setting in the Global South as a social learning process. It begins with a critical reflection of a large EU project to develop a global learning programme as a Global North South initiative. The focus narrows to Zanzibar, a small island state, to critically reflect on the delivery of the programme. And then further to focus on the global social learning and change that occurred in a rural community setting in the north of the island. Through participatory action research, I investigate the relevance of global learning as a social learning process, how norms and rules are shaped within a community setting and how these enable social change towards sustainable livelihoods. The thesis splices the intersection between critical and social theories of learning and engagement, to include critical social theories of Habermas (1984) and Wals (2007); critical race theories of Giroux (1997) and Said (1994) and distributive justice and entitlements theories of Sen (1997) and Moser (1998). It demonstrates the importance of dissonance and a safe space for deliberative dialogue, to be able to consider the global pressures and forces on local realities as the precursor to social change towards sustainability. I conclude by relating the learning from this small island state to the wider world and the current discourse on quality of education in a community development context

Analyse de réarrangements génomiques chez des patients atteints d'anomalies du développement embryonnaire : retard mental et malformations multiples congénitales; spectre oculo-auriculo-vertébral

Notre travail s’est intéressé aux anomalies du développement embryonnaire d’origine génétique en étudiant : -d’une part des patients associant des malformations congénitales multiples plus ou moins associées à un retard mental et à un syndrome dysmorphique, -et d’autre part des patients présentant un phénotype particulier : le spectre oculo-auriculo-vertébral (OAVS) incluant le syndrome de Goldenhar. L’analyse a consisté en l’étude pangénomique de ces patients au moyen de puces à ADN (CGH-array), dans le but d’identifier de nouveaux remaniements chromosomiques avec anomalie du nombre de copies. Nous avons identifié différentes régions variantes et analysé pour chacune leur caractère pathogène potentiel en fonction de leur nature, de leur taille, de leur caractère hérité ou de novo, de leur contenu en gènes et en polymorphismes du nombre de copies, des éléments déjà décrits dans les bases de données et la littérature. Les régions variantes identifiées ont été vérifiées par d’autres techniques de recherche d’anomalies de dosage génique. L’ensemble de ces résultats permet de formuler des hypothèses quant à de nouveaux gènes candidats pour plusieurs symptômes observés, et pour l’OAVS. Ils permettent d’ajouter de nouvelles données à l’ensemble des anomalies décrites depuis quelques années grâce à ces techniques innovantes.Our work focused on embryonic development abnormalities of genetic origin by studying: - patients with multiple congenital malformations associated or not associated with mental retardation and a dysmorphic syndrome; - patients presenting with the oculo-auriculo-vertebral spectrum (OAVS) that includes the Goldenhar syndrome. Patients were analysed by array-CGH in order to identifying novel chromosomal rearrangements with copy number abnormalities. We have identified several chromosomal regions with copy number variations and analysed for each of those their pathogenic potential, according to their nature, size, either inherited or de novo status, genes and copy number polymorphisms content, and data already reported both in databases and in the literature. The existence of a copy number variation was confirmed by other experimental approaches able to detect gene dosage abnormalities. Our results allowed discussing the possible involvement of candidate genes with respect to the symptoms observed in the patients and to OAVS. They also allowed to add new data to the growing field of copy number variations gathered over the recent years

Analyse de réarrangements génomiques chez des patients atteints d'anomalies du développement embryonnaire : retard mental et malformations multiples congénitales; spectre oculo-auriculo-vertébral

Notre travail s’est intéressé aux anomalies du développement embryonnaire d’origine génétique en étudiant : -d’une part des patients associant des malformations congénitales multiples plus ou moins associées à un retard mental et à un syndrome dysmorphique, -et d’autre part des patients présentant un phénotype particulier : le spectre oculo-auriculo-vertébral (OAVS) incluant le syndrome de Goldenhar. L’analyse a consisté en l’étude pangénomique de ces patients au moyen de puces à ADN (CGH-array), dans le but d’identifier de nouveaux remaniements chromosomiques avec anomalie du nombre de copies. Nous avons identifié différentes régions variantes et analysé pour chacune leur caractère pathogène potentiel en fonction de leur nature, de leur taille, de leur caractère hérité ou de novo, de leur contenu en gènes et en polymorphismes du nombre de copies, des éléments déjà décrits dans les bases de données et la littérature. Les régions variantes identifiées ont été vérifiées par d’autres techniques de recherche d’anomalies de dosage génique. L’ensemble de ces résultats permet de formuler des hypothèses quant à de nouveaux gènes candidats pour plusieurs symptômes observés, et pour l’OAVS. Ils permettent d’ajouter de nouvelles données à l’ensemble des anomalies décrites depuis quelques années grâce à ces techniques innovantes.Our work focused on embryonic development abnormalities of genetic origin by studying: - patients with multiple congenital malformations associated or not associated with mental retardation and a dysmorphic syndrome; - patients presenting with the oculo-auriculo-vertebral spectrum (OAVS) that includes the Goldenhar syndrome. Patients were analysed by array-CGH in order to identifying novel chromosomal rearrangements with copy number abnormalities. We have identified several chromosomal regions with copy number variations and analysed for each of those their pathogenic potential, according to their nature, size, either inherited or de novo status, genes and copy number polymorphisms content, and data already reported both in databases and in the literature. The existence of a copy number variation was confirmed by other experimental approaches able to detect gene dosage abnormalities. Our results allowed discussing the possible involvement of candidate genes with respect to the symptoms observed in the patients and to OAVS. They also allowed to add new data to the growing field of copy number variations gathered over the recent years

A recurrent missense variant in EYA3 gene is associated with oculo-auriculo-vertebral spectrum

Goldenhar syndrome or oculo-auriculo-vertebral spectrum (OAVS) is a complex developmental disorder characterized by asymmetric ear anomalies, hemifacial microsomia, ocular and vertebral defects. We aimed at identifying and characterizing a new gene associated with OAVS. Two affected brothers with OAVS were analyzed by exome sequencing that revealed a missense variant (p.(Asn358Ser)) in the EYA3 gene. EYA3 screening was then performed in 122 OAVS patients that identified the same variant in one individual from an unrelated family. Segregation assessment in both families showed incomplete penetrance and variable expressivity. We investigated this variant in cellular models to determine its pathogenicity and demonstrated an increased half-life of the mutated protein without impact on its ability to dephosphorylate H2AFX following DNA repair pathway induction. Proteomics performed on this cellular model revealed four significantly predicted upstream regulators which are PPARGC1B, YAP1, NFE2L2 and MYC. Moreover, eya3 knocked-down zebrafish embryos developed specific craniofacial abnormalities corroborating previous animal models and supporting its involvement in the OAVS. Additionally, EYA3 gene expression was deregulated in vitro by retinoic acid exposure. EYA3 is the second recurrent gene identified to be associated with OAVS. Moreover, based on protein interactions and related diseases, we suggest the DNA repair as a key molecular pathway involved in craniofacial development

0305 : Heterogeneous conduction properties in the pig right ventricle

The right ventricular outflow tract (RVOT) has a distinct embryological origin and is a common anatomical source of arrhythmias in the healthy and diseased myocardium. We hypothesised that specific RVOT activation and conduction properties may underlie the preferential RVOT origin of arrhythmias. Pig right ventricular (RV) wedge preparations were perfused via the left anterior descending and right coronary arteries. Electrical activation and conduction properties were obtained by optical mapping of the epicardial surface (di-4- ANEPPS 10μM) upon electrical stimulation of the preparation. Transmural needles were inserted in the RV free wall and RVOT and unipolar electrograms (EGMs) were recorded. Fiber orientation was obtained by diffusion tensor MRI. Regional mRNA expression was determined by RT-PCR and fibrosis was assessed histologically. Longitudinal and transverse conduction velocities were significantly reduced in RVOT compared to RV free wall (P<0.01). A different direction of propagation was observed in the RVOT compared to the RV free wall and a line of slowed propagation was found at the interface between the 2 regions. This was consistent with a 135±2° change in fiber orientation observed between the 2 regions within a restricted distance (<6cm). The RVOT showed more sites with fractionated EGMs (P<0.01) and more deflections per electrode (P<0.001) than the RV free wall. In line with these findings, a decreased expression of Scna5 and Gja1 was found in the RVOT compared to the RV free wall (P<0.001). Moreover, the RVOT was characterized by an upregulation of type I collagen mRNA, a higher collagen content (P<0.05) and the presence of fat infiltrations which were absent in the free wall.Conduction is slower in the pig RVOT and is associated with fractionated unipolar electrograms. Conduction slowing was related to (i) reduced connexin and sodium channel expression and (ii) region-specific structural properties which may generate a substrate for RVOT arrhythmias

Arrhythmogenic Remodeling of the Left Ventricle in a Porcine Model of Repaired Tetralogy of Fallot

International audienc

Evidence of mosaicism in SPAST variant carriers in four French families

International audienceHereditary spastic paraplegias (HSP) are heterogeneous disorders, with more than 70 causative genes. Variants in SPAST are the most frequent genetic etiology and are responsible for spastic paraplegia type 4 (SPG4). Age at onset can vary, even between patients from the same family, and incomplete penetrance is described. Somatic mosaicism is extremely rare with only three patients reported in the literature. We report here SPAST mosaic variants in four unrelated patients. We confirm that mosaicism in SPAST is a very rare event with only four identified cases on more than 300 patients with a SPAST variant previously described by our clinical diagnostic laboratory