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En marge des grands empires sahéliens : Djoutoubaya, un habitat du Bambouk médiéval (Sénégal oriental)
No full textLe site de Djoutoubaya consiste en un vaste habitat situé dans la vallée de la Falémé (Sénégal oriental) dont l’occupation est datée entre les 9e et 14e siècles de notre ère. En Afrique de l’Ouest, cette période est caractérisée par le développement d’entités politico-économiques et un commerce transsaharien florissant entre les populations ouest-africaines et les populations arabo-musulmanes au nord du désert. Initiées en 2016, les fouilles menées à Djoutoubaya ont révélé des vestiges singuliers qui questionnent l’insertion de cet habitat non seulement au sein de ces réseaux d’interaction transsahariens, mais aussi dans les réseaux d’échanges ouest-africains. L’un des principaux intérêts de cet habitat réside en effet dans la découverte de bâtiments en briques de terre crue, une architecture peu répandue dans le « Sahel médiéval », et la possibilité d’un travail in situ de métaux non-ferreux, comme l’or et/ou le cuivre. Si ces deux ressources ont particulièrement été prisées au sein du commerce transsaharien, les vestiges attestant de leur exploitation et/ou transformation en contexte ouest-africain sont en effet peu nombreux. Les recherches menées dans le cadre de ce travail de thèse avaient ainsi pour objectif de comprendre non seulement les modalités d’apparition de ces technologies au sein du site de Djoutoubaya, mais aussi l’insertion de ce dernier dans les réseaux d’interaction aux échelles locale, régionale et extra-régionale
Les métaphores dans les <i>Discours</i> de Cicéron
No full textFigure poétique entre toutes et ornement prisé des orateurs, la métaphore est une composante essentielle de la prose de Cicéron. Les discours et les ouvrages rhétoriques de l’Arpinate nous préservent encore cet éclat, et le lecteur se trouve sans cesse convié à admirer la richesse, la vivacité, la maîtrise et la subtilité qui se déploient dans ses ouvrages. Pourtant, certains éléments du style cicéronien, dont la métaphore, n’ont suscité que peu d’études d’ensemble. Afin de combler cette lacune, il a été procédé au repérage, au classement et à l’interprétation des métaphores des discours. En concomitance, des critères d’identification ont été élaborés ; des lectures ont été proposées qui mettent en évidence les liens entre la métaphore et son contexte et, à plus large échelle, entre les thèmes métaphoriques et l’argumentaire de chaque discours. Ce travail permet également de faire émerger des parallèles dans l’ensemble du corpus et de proposer ainsi une analyse nouvelle d’un grand nombre de passages. Fait rare dans la littérature ancienne, à côté des cinquante-huit orationes conservées de Cicéron, plusieurs ouvrages théoriques de sa main (De oratore, Orator) nous subsistent dans lesquels la métaphore se trouve définie ou décrite. La pratique oratoire cicéronienne a donc pu être examinée à l’aune de conceptions qu’il a lui-même formulées. Dans le cours de la recherche, il est apparu que ces ouvrages théoriques, parce qu’ils relèvent eux aussi d’un haut degré d’élaboration stylistique, méritaient d’être examinés avec la méthode établie pour les discours. Cette orientation du travail a ainsi permis d’éluder l’opposition frontale entre théorie et pratique. Il en est sorti une lecture métarhétorique centrée sur le De oratore. Celle-ci révèle les métaphores d’après lesquelles Cicéron appréhende son art, et comment il conçoit la notion même de métaphore. Elle offre en outre au lecteur une grille d’analyse valant pour l’ensemble du corpus examiné
GPCR localization and signaling at distinct subcellular sites
No full textG protein-coupled receptors (GPCRs) constitute the largest class of transmembrane receptors and regulate several key physiological processes, such as neurotransmission.
In addition to the plasma membrane (PM), GPCRs localize to various intracellular compartments, including nuclear membranes, endoplasmic reticulum (ER), the Golgi apparatus, endosomes, and mitochondria. Yet, GPCR function has been mainly studied with a focus on cell surface-localized receptors, not capturing the possible influence of subcellular GPCR localization on downstream signaling. As GPCRs are key therapeutic targets, deciphering their diverse signaling mechanisms within cells is crucial for the development of future drugs.
Activation of PM-localized GPCRs by ligands triggers the recruitment and activation of several transducers, including heterotrimeric G-proteins. Activated G-proteins then trigger downstream signaling cascades, that can involve changes in intracellular cyclic adenosine monophosphate (cAMP) concentration. Activated PM GPCRs also recruit members of the GPCR kinase (GRK) family, which phosphorylate the receptor at multiple sites. Phosphorylated GPCRs then bind to β-arrestins, which often induces their internalization. In contrast, the recruitment of transducers upon activation of Golgi-localized GPCRs remains largely uncharacterized.
i) Here, we investigated the dynamic recruitment of transducers to activated PM- and Golgi-localized opioid receptors (ORs) using a combination of fluorescence and luminescence-based assays. We revealed a location-dependent bias in transducer recruitment. More specifically, β-arrestins and a specific miniG probe selectively interacted with activated PM-localized ORs, directly demonstrating location bias in OR signal transduction. Further, through collaborative work using molecular dynamics simulation, we uncovered a likely role of the lipid environment in promoting the location-specific OR coupling. Finally, we observed distinct effects of activated PM- and Golgi-localized ORs on transcription and protein phosphorylation.
ii) Using phosphosite-specific antibodies, we also demonstrate that mu-OR (MOR) and delta-OR (DOR) are differentially regulated via phosphorylation at the Golgi apparatus. While both Golgi- and PM-localized MOR were phosphorylated upon agonist stimulation, DOR phosphorylation was restricted to the PM. We further utilized CRISPR knock-out cell lines lacking specific members of the GRK family and GRK inhibitors to dissect the specificity of MOR and DOR interactions with individual kinases and with β-arrestins.
iii) The subcellular localization of GPCRs in the Golgi apparatus has been extensively studied only for a small fraction of GPCRs. To expand the insights into subcellular GPCR distribution, we cloned 120 GPCRs mainly belonging to the class A family and profiled their cellular localizations via immunostaining, high throughput imaging, and automated image quantification. The approach revealed the intracellular retention and Golgi localization in a large subset of analyzed GPCRs.
Taken together, the thesis uncovers novel aspects of location bias between PM and Golgi-localized GPCRs, with a major focus on the clinically relevant ORs, and reveals that Golgi localization is a common feature of the GPCR family.</p
The theory of everything: A model that provides a unified solution for dealing with uncertainty in solving MCDM problems
No full textUncertainty is a fundamental aspect of the decision-making process, especially in Multi-Criteria Decision Making (MCDM) problems, where every stage of problem-solving involves some degree of uncertainty. MCDM problems are characterized by a framework of multiple criteria and alternatives, designed to achieve one or several objectives of the decision-making process. Ranging from everyday issues to highly complex industrial, military, and political challenges, MCDM problems have outcomes that can significantly impact many lives or incur substantial financial costs. Therefore, developing solutions that produce the least uncertain outputs is crucial.
Uncertainty in decision-making typically arises when decision-makers lack complete information about the elements of decision analysis or its outcomes. The primary aim of this paper-based doctoral dissertation is to offer a comprehensive solution, termed the 'theory of everything,' that addresses all sources of uncertainty in MCDM problems. Thirteen sources of uncertainty have been identified, including:
Decision-making goals
Decision-makers
Linguistic variables and scales
Conversion of uncertain to certain values
Weighting methods
MCDM method processes
Time
Missing information
Multi-layer problems
Philosophies and policies, encompassing the decision-making paradox
Validation
The Rank Reversal Paradox
To tackle each of these sources, various MCDM algorithms, statistical measures, novel scales, new numerical sets, a game, and a new theoretical framework were proposed. These solutions are detailed across eighteen scientific articles. In the final chapter, the unified model, including its components, properties, and limitations, is thoroughly discussed, offering a holistic approach to managing uncertainty in MCDM.</p
The Entanglement of Daily Fundraising Practices: The Perspective of Jordanian NGOs in the Aid Sector
No full textThe localization of aid has gained prominence since the World Humanitarian Summit in 2016, calling for a shift towards more localized aid interventions and increased decision-making power for local actors. Local NGOs, as the quintessential local actors in the aid sector, have been placed on a pedestal since the rise of neoliberal policies in the 1990s. The World Humanitarian Summit orchestrated this shift through changes in funding schemes, which play a crucial role in the dynamics of the aid sector and serve as the primary income source for local actors. However, the availability of international funding is intertwined with complex relationships, constraints, and norms.
This thesis explores how the localization of aid is implemented by examining how local NGOs in Jordan navigate the funding process and how it enables them to exercise agency and decision-making power. If local NGOs are among the ‘big winners’ of the Grand Bargain, how can their financial mechanisms provide them with the necessary means to take on more decision-making power? Drawing on a theoretical framework informed by the sociology of organizations and Science and Technology Studies (STS), I compare the strategies and practices of two local NGOs in their interactions with external actors and their day-to-day operations. Through participant observation, interviews, and document analysis, I investigate the techniques employed by these NGOs in developing project proposals and budgets, as well as the challenges they face in securing financial sustainability.</p
Bioengineering of Prevascularized Endocrine Constructs for the Treatment of Type 1 Diabetes
No full textIslet cell transplantation is a minimally invasive procedure that forms an integral part of the standard care for patients with complicated Type 1 Diabetes. Nonetheless, it is evident that the outcomes of islet transplantation, particularly in the long term, are far from optimal. Most patients require the transplantation of a substantial islet cell mass, which poses a significant problem due to the shortage of organs. The difficulty in achieving long-term function arises from several challenges that islets face during the islet isolation procedure and at the implantation site. These challenges include: (1) disruption of islet extra-cellular matrix (ECM), vasculature and innervation during the isolation process resulting in islet cell death both in the culture period and the early phases of the engraftment; (2) lack of prompt revascularization; (3) pro-inflammatory nature of the liver microenvironment; (4) immune attacks, including allo-rejection and auto-immunity recurrence. Thus, it is imperative to address the limitations of intraportal islet transplantation and identify alternative extra-hepatic transplantation sites.
This thesis seeks to advance the field by developing a functional prevascularized insulin-secreting construct toimprove islet engraftment, vascularization, survival and function while exploring alternative extra-hepatic transplantation sites such as epididymal fat pad -which is an environment similar to human omentum- and the subcutaneous space. To do so, several key strategies were developed: (1) Organoids generation with the formation of functional and uniformly sized insulin-secreting organoids; (2) Incorporation of human amniotic epithelial cells (AECs) as supporting cells due to their cytoprotective, low antigenicity, anti-fibrotic, anti-inflammatory and immunomodulatory properties; (3) Incorporation of blood outgrowth endothelial cells (BOECs) as a potential autologous endothelial cell source to improve graft revascularization; (4) Incorporation of insulin-secreting organoids into a bioengineered human amniotic membrane (hAM)-derived hydrogel scaffold, to provide an optimal microenvironment and structural support for the insulin-secreting cells.
The thesis adopts an article-based format and is composed of 2 main sections. The first section includes a chapter published in Type-1 Diabetes. Methods in Molecular Biology, which describes the protocol for generating insulin-secreting organoids and their in vitro assessment. The second section constitutes a manuscript, containing the results and discussion of the experiments of the main project conducted throughout my thesis. Altogether, our findings demonstrate that incorporating prevascularized organdies (PVOs), enriched with AECs and BOECs as supporting cells, in a BOEC-vascularized hAM-derived hydrogel, significantly improved engraftment and revascularization, leading to prompt diabetes reversal. Our strategy shows potential to pave the way for the engineering of a bioartificial pancreas.</p
Synthesis and Biological Evaluation of Probes Targeting the Primary Cilium and the Hedgehog Signaling Pathway
No full textLe cil primaire, un organite composé de microtubules, est une protrusion de la surface apicale des cellules mammifère. Cet organite fonctionne tel une « antenne » sensorielle pour la cellule, et ainsi réponds aux signaux environnementaux via des voies de signalisation complexes. Entre autres, la voie de signalisation Hedgehog (Hh) se base sur le cil primaire des cellules mammifères et est nécessaire au développement embryonnaire ainsi qu’à l’homéostasie tissulaire chez l’adulte. Les perturbations de la voie de signalisation Hh causent de nombreux cancers, notamment le carcinome des cellules basales. Des mutations génétiques conduisant à un dysfonctionnement du cil primaire conduisent à de nombreuses pathologies, appelées ciliopathies. L’importance du cil primaire dans les processus de développement et ses liens avec les maladies ont poussé la recherche à mieux comprendre les rôles complexes de l’organite.The primary cilium, a microtubule-based organelle, protrudes from the apical surface of mammalian cells. This organelle serves as a sensory ‘antenna’ for the cell and responds to environmental cues through complex signaling pathways. Among others, the Hedgehog signaling pathway heavily relies on the mammalian primary cilium and is necessary for embryonic development as well as tissue homeostasis. Dysregulations of the pathway have been linked to a variety of cancers, notably basal cell carcinoma and medulloblastoma. Genetic mutations leading to impaired functions of the primary cilium cause a number of diseases, termed ciliopathies. The importance of the primary cilium in developmental processes and its links to diseases propelled research to further understand the complex roles of the organelle.</p
Exploring the extrachromosomal circular DNA landscape and transposable element mobility in wheat
No full textThe study of genetics involves the exploration of hereditary traits and their transmission across generations through the conveyance of genetic information. On a parallel track, epigenetic research investigates modifications that modulate gene expression without altering the DNA sequence itself. Transposable elements (TEs), which are repetitive DNA segments, exhibit rigorous control by epigenetic mechanisms due to their propensity to trigger diverse genetic alterations upon activation. TEs play a dynamic role akin to a balancing act, bridging the realms of genetics, epigenetics, and environment. Throughout their life cycle, distinct classes of TEs exhibit varying molecular mechanisms that can lead to the generation of extrachromosomal circular DNA (eccDNA). These eccDNAs can constitute an integral component of a TE's replication process. Consequently, the emergence of eccDNA can often be attributed to TE activation. The rapid advancements in high-throughput sequencing technologies and computational pipelines have facilitated a comprehensive exploration of plant eccDNA landscapes. Recent discoveries highlight that various genomic regions, such as telomeres, centromere satellites, and even genic domains can contribute to the eccDNA pool. While progress has been made in identifying genomic regions producing eccDNA, the precise cellular functions of these elements remain elusive in plants. In his study, we present a comprehensive study of eccDNAs in wheat. First, we studied the regions of the genome that can contribute to eccDNA accumulation and then investigated if external stimuli can influence eccDNA quality and quantity. Our findings revealed that in wheat, eccDNAs largely originate from regions including plastid sequences, ribosomal DNA, and truncated TEs. Though their composition remained stable under single stress treatment in wheat, combining epigenetic stress with heat stress led to the emergence of full-length eccDNAs derived from a non-autonomous Helitron, suggesting we for the first time, observed an active TE in wheat. This finding prompted us to carry out a comprehensive global analysis of Helitrons with a particular focus on the family we found to be mobilizable in wheat. This family consists of 85 members, of which merely six were classified as autonomous copies as they potentially encoded full-length transposases. Remarkably, these autonomous Helitrons exhibited copy number variations across different wheat cultivars, suggesting a recent mobilization activity for this TE. Notably only a subset of cultivars showed a transcriptional response to our treatment. We found that transcriptional activation co-incited with reduced DNA methylation levels within the genomic Helitron sequence, particularly at an identified heat shock factor binding site. This further supports the notion that this TE family is restricted by DNA methylation. A inspection of the transposases encoded by the autonomous copies present in the wheat genome led to the identification of key distinctive domains suggesting that they contain all necessary functional domains required for Helitron mobility. Finally, we evaluated whether our treatment could lead to phenotypic diversity suitable for wheat breeding
Modelling handsome faces. Chitqua: A Chinese Artist & Chinese Art in Eighteenth Century London
No full textChitqua (also Chet-qua or Tan Chetqua) is the first Chinese artist to exhibit at the Royal Academy. He was listed as “sculptor” in the exhibition catalogue in London in 1770. Born around 1728 and died in 1796 in Canton (now: 廣州Guangzhou), he was a clay modeller who modelled unfired clay portrait figures for European people, he travelled from China via ships of the British East India Company. He left Canton for London in 1769, where he received a high reputation for his modelling technique. His success was not a coincidence but a consequence of the Chinese Taste— one of the art styles in eighteenth century London society following the British East India Company's significant expansions in Asia since its establishment in 1600. This dissertation starts from the overseas experiences of Chitqua to centre on two main strands. The first aims to establish a systematic catalogue of all the clay figures made by Chitqua and other Chinese modellers. Then, to review and clarify their techniques and objects systematically. The second is an investigation of the breadth and range of these figures related to Sino-European art, to rediscover the aesthetic value of Chitqua's works, and their social and economic value among eighteenth century global exchange, and stylistic transformations during the Early Modern Period