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‘‘La nation, frontière du libéralisme’’ ? La conservation des savoir-faire manufacturiers français au début du XIXe siècle
No full textInternational audienc
MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination
No full textInternational audienceMuscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of myotonic dystrophy type 1. In myotonic dystrophy type 1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. Although attention on MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double-knockout (dKO) mice, in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis. In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in myotonic dystrophy type 1 and in a range of diseases associated with RNA dysregulation
FAP-CAR-T cells reduce dystrophic muscle fibrosis, improving adeno-associated virus gene transfer efficacy
No full textInternational audienceTissue fibrosis is a pathological feature of many diseases including muscular dystrophies such as Duchenne muscular dystrophy (DMD). Fibrosis may limit the effectiveness of gene therapy in muscle impacting on viral dosing but direct evidence is lacking. Strategies to reduce skeletal muscle fibrosis are limited. The fibrosis Fap gene is over-expressed in the skeletal muscles of a severe mouse model of DMD, suggesting that cells expressing membrane fibroblast activation protein (FAP) could be targeted by chimeric antigen receptor (CAR)-T cells. Two consecutive administrations of FAP-specific CAR-T cells in the severe DMD model reduced collagen deposits and fibrotic biomarkers and also reduced the number of FAP-positive cells in muscle. Single cell transcriptomics revealed that FAP-CAR-T cells triggered cellular interactions with otherwise inactive muscle resident macrophages and depleted specific subsets of FAP-highly-expressing fibro-adipogenic progenitor cells, pointing to their importance in the fibrosis process. Reducing fibrosis with FAP-CAR-T cells enhanced adeno-associated virus (AAV) microdystrophin gene transfer in the model by increasing vector copies, demonstrating that fibrosis is a restriction factor for AAV gene delivery in skeletal muscle. These results provide novel insights into therapeutic strategies for DMD or other fibrotic diseases
Les longs ARN non codants dans la régulation de l'épissage alternatif
No full textEukaryotes genomes encode thousands of long non-coding RNAs (lncRNAs). The majority of them have unknown functions, but it is widely accepted that they can be important regulators of gene expression and development. In this PhD thesis, we study lncRNAs involved in alternative splicing (AS) regulation in the context of root development in Arabidopsis thaliana. In the first chapter, we collaborated with a system biology team to assess lncRNA regulatory networks based on expression data and transcription factor binding sites. I experimentally confirmed the predicted regulation of the transcription factors KAN1, MYB44, and PIF4 on root-specific lncRNA expression. We then exploited a detailed transcriptomic time course analysis to define the AS landscape associated with lateral root initiation and organogenesis. An isoform switching splicing event of the cell cycle-related AURORA2 protein kinase mRNA was characterized further. Rescue experiments in aur1/2 mutants show that AURORA2 mRNA isoforms have distinct functions during lateral root formation. In the second chapter, the central aim of this PhD project is presented, the identification of new lncRNAs involved in AS regulation. Therefore, we initially performed a bioinformatic screen identifying lncRNA that interact with the splicing factors NSRa (for nuclear speckle RNA-binding protein a) or GRP7 (glycine-rich RNA binding protein 7) and being regulated during lateral root development. Subsequently, an in planta transient expression screen combined with RNA-seq was used to select the most promising candidates. We isolated four lncRNAs that modulate more than 250 AS events in these conditions. Knockdown (KD) or overexpression (OE) of one of them, we named ACHLYS, results in the modulation of AS and impaired root development. In parallel, in collaboration with Pr. D. Staiger, we identified in vivo NSRa RNA binding sites genome-wide using iCLIP. This confirmed the direct interaction between ACHLYS and NSRa and revealed local enrichment of NSRa at ACHLYS-dependent intron retention events. A second lncRNA transiently regulating splicing was named RHAPSO. In chapter 3, we show that RHAPSO encodes a 69 amino acid peptide with an unknown N-terminal signal peptide. RHAPSO is expressed in lateral root and leaf primordia. Its overexpression or knockdown results in impaired shoot and root development and slower lateral root emergence. These phenotypes are absent in OE-RHAPSO lines with a mutated start codon. The peptide presumably localizes in the cytoplasm and nucleus and affects the transcription of hypoxia and ethylene signaling related genes. This PhD thesis contributed to our understanding of the regulation and the action of lncRNAs and their potential encoded peptides in AS during lateral root organogenesis.Les génomes des eucaryotes codent pour des milliers d'ARN longs non codants (ARNlnc). La plupart ont des fonctions inconnues, mais il est largement admis qu'ils sont des rǵulateurs importants pour l'expression génétique et du développement. Dans cette thèse de doctorat, nous étudions les ARNlnc impliqués dans la régulation de l'épissage alternatif (EA) dans le contexte du développement racinaire chez Arabidopsis thaliana. Dans le premier chapitre, nous avons collaboré avec une équipe de biologie systémique pour évaluer les réseaux de régulation des ARNlnc à partir des données d'expression et des sites de liaison des facteurs de transcription. J'ai confirmé expérimentalement la régulation prédite des facteurs de transcription KAN1, MYB44 et PIF4 sur l'expression des ARNlnc spécifiques aux racines. Nous avons ensuite exploité une analyse transcriptomique détaillée pour définir le paysage de l'EA associé à l'initiation des racines latérales et à l'organogenèse. Un événement d'épissage avec changement d'isoforme de l'ARNm de la protéine kinase AURORA2, liée au cycle cellulaire, a été caractérisé plus en détail. Des expériences de sauvetage chez des mutants aur1/2 montrent que les isoformes de l'ARNm de AURORA2 ont des fonctions distinctes pendant la formation des racines latérales. Dans le deuxième chapitre, l'objectif central de ce projet a été présenté, à savoir l'identification de nouveaux lncRNA impliqués dans la régulation de l'EA. Pour cela, nous avons d'abord effectué un criblage bioinformatique afin d'identifier les ARNlnc interagissant avec les facteurs d'épissage NSRa ou GRP7 qui sont régulés pendant le développement des racines latérales. Après, on a utilisé un criblage d'expression transitoire in planta combiné avec ARN-seq pour sélectionner les candidats les plus prometteurs. Nous avons isolé quatre ARNlnc qui modulent plus de 250 événements d'EA dans ces conditions. Le knockdown (KD) ou la surexpression (SE) de l'un d'entre eux, que nous avons nommé ACHLYS, entraîne la modulation de l'EA et une altération du développement racinaire. En parallèle, en collaboration avec Pr. D. Staiger, nous avons identifié in vivo les sites de liaison de l'ARN NSRa à l'échelle du génome à l'aide de la technique iCLIP. Cela a confirmé l'interaction directe entre ACHLYS et NSRa et a révélé un enrichissement local de NSRa lors des événements de rétention d'introns dépendants d'ACHLYS. Un deuxième ARNlnc régulant temporairement l'épissage a été nommé RHAPSO. Au chapitre 3, nous montrons que RHAPSO code pour un peptide de 69 acides aminés avec un peptide signal N-terminal inconnu. RHAPSO est exprimé dans les racines latérales et les primordia foliaires. Sa SE ou son KD entraîne une altération du développement des pousses et des racines et un ralentissement de l'émergence des racines latérales. Ces phénotypes sont absents dans les lignées OE-RHAPSO avec un codon d'initiation muté. Le peptide se localise vraisemblablement dans le cytoplasme et le noyau et affecte la transcription des gènes liés à l'hypoxie et à la signalisation de l'éthylène. Cette thèse de doctorat a contribué à notre compréhension de la régulation et de l'action des ARNlnc et de leurs peptides codés potentiels dans l'EA pendant l'organogenèse des racines latérales
Étude expérimentale de la rupture de joints en T surmoulés sur composites avec une maîtrise fine des conditions aux limites
No full textInternational audienceÉtude expérimentale de la rupture de joints en T surmoulés sur composites avec une maîtrise fine des conditions aux limite
Entry and exit of Fragilariopsis cylindrus diatoms from the polar night: evidence for chromatin-mediated genome control
No full textAbstract Regulation of the epigenome landscape plays a crucial role in adaptation to environmental changes. However, the molecular mechanisms by which epigenome landscapes are established and tuned to adjust the cellular status to environmental cues remain poorly understood, especially in unicellular photosynthetic eukaryotes. Polar microalgae must adapt to extreme variations in light and temperature for survival and therefore represent excellent models to understand the diversity of gene regulatory mechanisms, yet chromatin-based mechanisms have never been explored in these organisms. In this study, we combined genome-wide profiling of histone and DNA modifications with transcriptomic analyses of the marine polar diatom Fragilariopsis cylindrus upon entry and exit of a 3-month-long polar night. We show that, in agreement with its established role in transcription facilitation, histone H2B monobiquitination (H2Bub) is modulated at active genes upon prolonged darkness to light re-exposure. In contrast, histone H3 lysine 27 trimethylation (H3K27me3) and DNA cytosine methylation (CG methylation), two modifications typically associated with the silencing of genes or transposable elements (TEs), remained stable throughout the transitions, reinforcing their role in transcriptional repression, particularly at TEs but also at a few genes. We further demonstrate that H3K27me3 and DNA methylation are physically associated at TEs, probably reflecting a dual locking system enabling F.cylindrus cells to cope with the invasive nature of these genetic elements under extreme environmental conditions. These findings enhance our understanding of genome and epigenome regulation in diatoms in response to environmental variability and open new avenues for exploring the role played by chromatin-level regulation in the unique evolutionary history of polar unicellular eukaryotes
Size of chaos for Gibbs measures of mean field interacting diffusions
No full textInternational audienceWe investigate Gibbs measures for diffusive particles interacting through a two-body mean field energy. By identifying a gradient structure for the conditional law, we derive sharp bounds on the size of chaos, providing a quantitative characterization of particle independence. To handle interaction forces that are unbounded at infinity, we study the concentration of measure phenomenon for Gibbs measures via a defective Talagrand inequality, which may hold independent interest. Our approach provides a unified framework for both the flat semi-convex and displacement convex cases. Additionally, we establish sharp chaos bounds for the quartic Curie-Weiss model in the sub-critical regime, demonstrating the generality of this method
Risk-averse Dynamic Bayesian Network for Supply Chain Risk Evaluation under Ripple Effects and Risk Dispersion
No full textInternational audienceSevere disruptions in the supply chain (SC) trigger a ripple effect, leading to significant temporal and structural propagation with lasting impacts. Mitigating these effects requires a thorough SC risk assessment, focusing on performance fluctuations to inform long-term crisis strategies. Although prior studies often overlook dispersion characteristics, particularly from a risk-averse perspective, this research introduces a novel approach to evaluate multi-echelon SC risk under data scarcity. The proposed method: (i) models temporal and structural propagation using a risk-averse dynamic Bayesian network (RA-DBN) and probability interval method (PIM); (ii) formulates the problem with a risk-averse nonlinear programming (RA-NLP) model; and (iii) employs a quadratically constrained quadratic program (QCQP) technique for efficient resolution
An optimal transport approach for the multiple quantile hedging problem
No full textWe consider the multiple quantile hedging problem, which is a class of partial hedging problems containing as special examples the quantile hedging problem (Föllmer & Leukert 1999) and the PnL matching problem (introduced in Bouchard & Vu 2012). In complete non-linear markets, we show that the problem can be reformulated as a kind of Monge optimal transport problem. Using this observation, we introduce a Kantorovitch version of the problem and prove that the value of both problems coincide. In the linear case, we thus obtain that the multiple quantile hedging problem can be seen as a semi-discrete optimal transport problem, for which we further introduce the dual problem. We then prove that there is no duality gap, allowing us to design a numerical method based on SGA algorithms to compute the multiple quantile hedging price
The busy beaver game for reaction systems
No full textInternational audienceThe busy beaver game was introduced by Tibor Radó in 1962 and consists in finding the longest halting run that can be achieved by a Turing machine with a given number of states n . The function BB ( n ) measuring this length is a well-studied example of an uncomputable function. In this work, we transpose the concept of the busy beaver game to reaction systems—a set rewriting-based model of computing inspired by biochemical reactions. We give a generalized framework for defining various busy beaver challenges and give concrete instantiations for longest runs, periods, preperiods, etc. We further list several busy beaver champions and bounds, depending on what is optimized and what is measured as the size of a reaction system. Finally, we discuss possible implications of our work to thinking about theoretical biology