ED Mathématiques et Informatique
Study of quantum LDPC codes and their decoding
by Wouter ROZENDAAL (IMB - Institut de Mathématiques de Bordeaux)
The defense will take place at 14h30 - Salle 1 Institut de Mathématiques de Bordeaux Université de Bordeaux, Bâtiment A33 351, cours de la Libération F-33405 Talence, France
in front of the jury composed of
- Gilles ZéMOR - Professeur des universités - Université de Bordeaux - Directeur de these
- Valentin SAVIN - Directeur de recherche - CEA-Léti - Rapporteur
- Jean-Pierre TILLICH - Directeur de recherche - Inria de Paris - Rapporteur
- Benjamin AUDOUX - Professeur des universités - Aix-Marseille Université - Examinateur
- Elena BERARDINI - Chaire de professeur junior - Université de Bordeaux - Examinateur
- Cyril GAVOILLE - Professeur des universités - Université de Bordeaux - Examinateur
Quantum Low-Density Parity-Check (LDPC) codes provide a promising solution to protect quantum information from errors, and are therefore considered an important step in the realisation of a full-scale fault-tolerant quantum computer. In this thesis, we study quantum LDPC codes under three different approaches, providing insights in renormalisation decoding for Kitaev's toric code, establishing bounds on the minimum distance of geometrically-local codes, and constructing small instances of quantum Tanner codes. Kitaev's toric code is a prominent quantum LDPC code that is currently the most widely pursued for experimental implementation. We focus on the probabilistic renormalisation decoders introduced by Duclos-Cianci and Poulin, a family of decoders that exhibit one of the best trade-offs between accuracy and efficiency. We study how they handle adversarial errors by introducing a deterministic renormalisation decoder that does not use a priori probabilities of the error model. We find that this renormalisation decoder allows for fractal-like uncorrectable error patterns, and we obtain a lower bound on the weight of such errors. Due to physical constraints, a lot of attention has gone into quantum LDPC codes whose stabilisers act only on a limited number of nearby qubits. We extend the well known Bravyi-Terhal bound to quantum codes defined by local constraints on a lattice quotient, providing a crucial insight into the limitations of geometrically-local stabiliser codes. As an application, we provide upper bounds on the minimum distance of Abelian Two-Block Group Algebra codes, a family of quantum LDPC codes for which the minimum distance is currently unknown. In recent years, asymptotically good quantum LDPC codes were constructed, but provable results on their minimum distances only apply to impractically long codes. Following the effort in the design of near-term implementable codes, we construct short instances of quantum Tanner codes using square complexes obtained from lifted products of regular graphs. Several explicit instances of these codes exhibit minimum distances surpassing the square root of the code length.
ED Sciences Chimiques
Chemically modified oligonucleotides to fight against resistance to anti-infective drugs
by Henri BARRY (Acides nucléiques : Régulations Naturelles et Artificielles)
The defense will take place at 14h30 - BBS Amphithéâtre, rez de chaussé 2 Rue Dr Hoffmann Martinot, Bâtiment "Bordeaux Biologie Santé", 33000 Bordeaux
in front of the jury composed of
- Tina KAUSS - Professeure des universités - Université de Bordeaux - Directeur de these
- Isabelle BESTEL - Professeure des universités - Université de Bordeaux - Examinateur
- Monique MATHE - Chargée de recherche - Nantes Université - Rapporteur
- Sébastien BENIZRI - Docteur - Evotec - Examinateur
- Frédéric TEWES - Professeur des universités - Université de Poitiers - Rapporteur
Bacterial resistance to antibiotics is a major public health issue, largely fueled by the acquisition and spread of resistance genes. In enterobacteria such as Escherichia coli (E. coli), the production of extended-spectrum β-lactamases (ESBLs), encoded by genes such as blaCTX-M-15, compromises the efficacy of cephalosporins. Given the difficulty of designing new conventional molecules and the challenges of transmembrane penetration in Gram-negative bacteria, antisense oligonucleotides (ONs) represent a promising alternative strategy for targeting the expression of resistance genes. However, their application is limited by their stability, target affinity, and, most importantly, intracellular delivery barriers. The objective of this thesis was to evaluate the feasibility and therapeutic potential of chemically modified and/or vectorized antisense oligonucleotides, primarily directed against the blaCTX-M-15 mRNA in E. coli. Complementary targets (efflux genes, toxin-antitoxin systems) were also explored. The approach was resolutely interdisciplinary, combining the chemical synthesis of oligonucleotides, their in-depth physicochemical characterization, and in vitro biological evaluation on resistant strains. A series of ONs was designed, incorporating modifications (2′-O-methyl/2′-O-methoxyethyl, LNA) and architectures (gapmer) to improve stability and target affinity. The major innovation lies in the use of oligonucleotide-conjugated nucleolipids (LON), a technology patented by the ARNA laboratory. Their characterization (ITC, DLS, TEM) confirmed their ability to self-assemble into stable nanomicelles under physiological conditions. In vitro biological evaluation provided proof of concept: the best-performing ONs, particularly the LONs, induced a significant reduction in the expression of the β-lactamase CTX-M-15 (confirmed by Western blotting) and resulted in a notable decrease in the Minimum Inhibitory Concentration (MIC) to β-lactams, reaching up to a 32-fold reduction. This proof of concept demonstrates measurable modulation of resistance. Efficacy was also improved by formulation in fusogenic liposomes. In addition, super-resolution imaging (STORM) and confocal microscopy studies allowed the study of the interaction of LONs with bacteria. The low cytotoxicity on the HepG2 cell line at active concentrations reinforces their safety profile. This thesis makes a solid experimental contribution to the fight against antibiotic resistance. By combining the chemical innovation of nucleolipids with optimized vectorization strategies, the feasibility of targeting major resistance genes in E. coli has been demonstrated. These results open the way to preclinical developments, now requiring sequence optimization and validation of the most promising vector systems (nucleolipids and fusogenic liposomes) in in vivo infection models, to fulfill the therapeutic potential of this approach.
ED Sciences de la Vie et de la Santé
Contribution of multiplex microscopic imaging and bioinformatics study in the phenotypic and functional analysis of the tissue macrophage efferocytosis process during systemic sclerosis, an inflammatory disease
by Damien BRISOU (Immunologie Conceptuelle, Expérimentale et Translationnelle)
The defense will take place at 14h00 - Salles Nord et Sud du Hall du bâtiment BBS UNIVERSITE DE BORDEAUX Bâtiment BBS - 3e étage - Equipe Blanco 2 rue du Dr Hoffmann Martinot 33000 Bordeaux - FRANCE
in front of the jury composed of
- Cécile CONTIN-BORDES - Maîtresse de conférences - praticienne hospitalière - Université de Bordeaux - Directeur de these
- Divi CORNEC - Professeur des universités - praticien hospitalier - Université de Brest - Rapporteur
- Vincent VUIBLET - Professeur des universités - praticien hospitalier - CHU de Reims - Rapporteur
- Florence APPARAILLY - Directrice de recherche - Institut de médecine régénératrice et biothérapies (IRMB) de Montpellier - Examinateur
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by progressive skin fibrosis and vascular manifestations. When fibrosis affects vital organs (heart, lungs), the prognosis can be fatal. Despite advances, treatment options remain limited, and once fibrosis has developed, it becomes irreversible. Its pathophysiology, which is still poorly understood, involves complex interactions between the immune system, the vascular system, and fibroblasts in their tissue microenvironment. Under physiological conditions, tissues protect themselves from apoptosis, or programmed cell death, through efferocytosis. This mechanism, mediated by macrophages, not only eliminates apoptotic bodies before they become toxic, but also contributes to the resolution of inflammation and the tissue repair process. Growing evidence suggests that alteration of the efferocytosis mechanism contributes to the progression of fibrosis. My host team is studying how interactions between macrophages and endothelial cells in the vascular niche, particularly under the effect of IL-1β secreted by activated platelets, induce a pathophysiological loop promoting inflammation and fibrosis in SSc (P Laurent, AR 2022). We aim now at better understanding macrophage's efferocytosis defects in the sclerodemra vascular niche. To identify direct evidence of efferocytosis dysregulation in sclerodermic skin tissues, we combined innovative spatial analysis techniques, the results of which reveal dysregulation of endothelial apoptosis and efferocytosis, which is more pronounced in patients with clinical manifestations of vasculopathy. Tyramide signal amplification (TSA) immunofluorescence targeting cleaved Caspase-3 (cCasp-3) and CD31 revealed significantly increased endothelial apoptosis in a subgroup of scleroderma patients compared to controls. TSA staining (cCasp-3, MerTK, CD68+) showed a decrease in MerTK expression in perivascular macrophages, as well as a loss of their ability to modulate this expression according to the vascular apoptotic load. This defect is accompanied by a significantly increased ratio of apoptotic vascular cells to merMacs in patients with digital ulcers. We also observed persistent expression of CD31, which is normally reduced on the surface of apoptotic endothelial cells, in a subgroup of patients. Highly multiplex analysis (37 proteins, MACSima system, Miltenyi), conducted on seven ScS patients, corroborated these observations and revealed a tendency toward an increase in the ratio of apoptotic vascular cells to merMacs. It showed that merMacs adopt an M2-type phenotype (overexpression of CD14, CD209, and CD163) with changes in efferocytosis markers (a tendency toward a decrease in MerTK and ANXA1 in particular) and paradoxical overexpression of GLUT-1, which is necessary for aerobic glycolysis in the efferocytosis process. Finally, another TSA staining revealed signs of deep endothelial-mesenchymal transition (co-expression of CD31 and αSMA) and signs of vascular alteration on the surface with loss of CD31 expression by endothelial cells. These data paint a picture of a vicious circle in which unresolved apoptosis, macrophage dysfunction, and endothelial plasticity fuel fibrosis and inflammation. They thus pave the way for therapeutic strategies targeting efferocytosis and macrophages.
PREFRONTAL NEURONAL POPULATIONS IN THREAT REPRESENTATIONS AND THE ORCHESTRATION OF DEFENSIVE BEHAVIORS
by Guillem LOPEZ-FERNANDEZ (Neurocentre Magendie)
The defense will take place at 14h00 - CARF/CGFB Building - Salle de Conférence 146 Rue Léo Saignat - CARF/CGFB - 33000 Bordeaux, France
in front of the jury composed of
- Cyril HERRY - Directeur de recherche - Université de Bordeaux - Directeur de these
- Jan GRüNDEMANN - Professor - Université de Bonn - Rapporteur
- Letzkus JOHANNES - Professor - Université de Fribourg - Rapporteur
- Daniela POPA - Directrice de recherche - Institut de Biologie de l'École normale supérieure (IBENS) - Examinateur
- Nikolas KARALIS - Chargé de recherche - Institut du Cerveau - Examinateur
- Lisa ROUX - Directrice de recherche - Université de Bordeaux - Examinateur
Behavior originates from the interaction between brain function, internal motivational demands, and environmental signals. Within this interplay, a crucial part of an animal's behavior is driven by the need to anticipate, detect and respond to environmental challenges such as danger. Responses to threat emerge from the organization of multiple interconnected brain regions into what is known as survival circuits of defense, among which the medial prefrontal cortex (mPFC) is a central regulator of defensive behavior. Most of the research on defensive systems over the last decades rely on classical conditioning paradigms, which, while providing immense insight into the neurobiology of aversive memories, are limited by their reductionist design. By studying a single threat and defensive response, these frameworks cannot model the complexity of behavior in more naturalistic settings, where organisms must dynamically evaluate multiple threats and integrate both aversive and rewarding signals to flexibly execute appropriate behaviors. Consequently, while the mPFC is known to integrate multimodal stimuli and exert precise control over complex behavior, its role in the flexible expression of context-appropriate coping strategies has been rarely addressed. Moreover, the literature has largely centered on the function of pyramidal neurons or mixed populations, whereas the less abundant yet functionally crucial GABAergic interneurons (INs) have received relatively little attention. To address these gaps, we used a recently introduced behavioral paradigm that exposes mice to distinct threats requiring specific defensive responses. By combining this task with electrophysiology, calcium imaging, optogenetic manipulations, and neuronal population and behavioral analyses, we examined the contribution of the dorsomedial PFC (dmPFC) and its distinct neuronal populations in the representation of threat-related information and the orchestration of defensive coping strategies. Our results demonstrate that the dmPFC encodes both general and specific representations of danger, and that its major inhibitory neuronal populations—namely somatostatin (SST) and parvalbumin (PV)-expressing interneurons—have different, yet complementary, roles in the representation of threatening and non-threatening conditions and the execution of defensive behaviors. While SST-INs contribute to the refinement of threat discrimination and to resolving stimulus uncertainty, PV-INs convey the general detection of emotionally-salient stimuli to mediate transitions from basal to aversive states. In addition, by using behavioral segmentation onto defensive responses, we show that distinct defensive strategies arise from sequences of discrete behavioral motifs that are distinctly and dynamically encoded in the dmPFC. Our findings elucidate that appropriate coping strategies depend on specific, non-stationary dmPFC activity patterns that promote the flexible arrangement of these motifs into context-adapted behavioral sequences, whereas stationary activity patterns are associated with rigid behavioral patterns and inappropriate coping strategies. This underscores a key computational process by which altered dmPFC activity may underlie core features of cognitive and behavioral inflexibility observed across multiple fear- and anxiety-related disorders.
Study of dentate gyrus astrocytes and associated adult-born neurons during cognitive ageing in rats
by Justine PALHOL (Neurocentre Magendie)
The defense will take place at 14h30 - Auditorium Centre Broca Nouvelle Aquitaine 146 rue Léo-Saignat 33076 Bordeaux Cedex
in front of the jury composed of
- Stéphane OLIET - Directeur de recherche - Inserm - Université de Bordeaux - Directeur de these
- Ruth BECKERVORDERSANDFORTH - Professeure - Friedrich-Alexander-Universität Erlangen-Nürnberg - Rapporteur
- Nicolas TONI - Professeur - Université de Lausanne - Rapporteur
- Gwenaëlle CATHELINE - Directrice d'études - CNRS - Université de Bordeaux - Examinateur
Normal ageing is accompanied by a progressive cognitive decline, which is nonetheless highly variable among individuals: some are resilient to age-related alterations and maintain excellent faculties throughout life, whereas others are more vulnerable and experience significant ability impairments. Investigating these interindividual differences is essential to unravel the mechanisms of cognitive ageing and identify potential strategies to mitigate its effect. Memory is one of the cognitive functions most affected by age, and relies on the hippocampus, a brain region undergoing substantial changes in ageing. At the cellular and molecular levels, ageing alters not only neuronal long-term synaptic plasticity, regarded as the cellular basis of memory, but also the astrocytes, which closely regulate this process. However, astrocyte ageing has mainly been studied by comparing old animals to younger ones, and whether interindividual variability in cognitive ageing is associated to differences in astrocyte characteristics and functions is still largely unexplored. To start addressing this question, we took advantage of a peculiar type of plasticity that has been linked to resilience to cognitive ageing and in which astrocytes play a major role: adult neurogenesis in the dentate gyrus. It has indeed been shown that successful ageing of spatial memory depends not only on the production of new dentate granule neurons, but also on old adult-born neurons (Adu-DGNs), particularly on their recruitment during learning and on the preservation of their glutamatergic inputs. In this context, we investigated the properties of Adu-DGN-associated astrocytes in the dentate gyrus inner molecular layer (IML) of vulnerable and resilient rats during ageing. Our approach consisted in identifying resilient and vulnerable animals in cohorts of 8-, 12- and 18-month-old male rats based on their performance in the Morris water maze test, before studying different parameters of astrocytes and Adu-DGNs using immunohistochemistry and ex vivo patch-clamp experiments. Firstly, we showed that the complexity of astrocyte GFAP labelling is higher in vulnerable animals compared to resilient, suggesting a change in astrocyte functional state. Yet, no difference was found in astrocyte electrophysiological properties or gap junction coupling between the two groups. We next assessed glutamatergic transmission at IML-Adu-DGN synapses and its regulation by D-serine, a co-agonist of synaptic NMDA receptors specifically released by astrocytes. While D-serine synaptic availability was similar in both conditions, differences in the NMDA/AMPA ratio of Adu-DGNs hinted towards potential synaptic maturation deficits in middle-age vulnerable rats. Lastly, we did not observe any difference in Adu-DGN excitability between experimental groups. In conclusion, this study revealed that ageing differentially alters the functional state of dentate gyrus astrocytes in animals that are resilient or vulnerable to the age-related decline of spatial memory. Moreover, we demonstrated that these astrocytic differences do not impact the synaptic availability of D-serine, and therefore the co-agonist binding site occupancy of Adu-DGN synaptic NMDA receptors. This PhD work paves the way for the exploration of other astrocyte-dependent mechanisms that may contribute to spatial learning impairment in vulnerable animals, such as deficits in Adu-DGN long-term synaptic plasticity or synaptic integration, and highlights the importance of considering interindividual variability to uncover the mechanisms underlying cognitive ageing.
ED Sciences Physiques et de l'Ingénieur
Development of Organic Electrochemical Transistors (OECTs) for Biological Applications
by Reem EL ATTAR (Laboratoire de l'Intégration du Matériau au Système)
The defense will take place at 9h30 - Amphithéâtre Jean Paul DOM A0.85 351 Cours de la Libération, Bâtiment A31 (IMS) 33405 Talence Cedex, France
in front of the jury composed of
- Mamatimin ABBAS - Chargé de recherche - Université de Bordeaux - Directeur de these
- Damien THUAU - Maître de conférences - Bordeaux INP - CoDirecteur de these
- Fabio BISCARINI - Professeur - Università degli Studi di Modena e Reggio Emilia - Rapporteur
- Sylvie RENAUD - Professeure - IMS laboratory - Examinateur
- Esma ISMAILOVA - Maîtresse de conférences - Ecole Nationale Supérieure des Mines de Saint Etienne - Rapporteur
- Vincent NOEL - Professeur des universités - Université Paris cité - Examinateur
The evolution of bioelectronic devices based on organic materials is bridging the gap between organic semiconductor-based electronics and the ionic nature of biological systems. Among these devices, Organic Electrochemical Transistors (OECTs) have emerged as particularly promising due to their high transconductance and excellent signal-to-noise ratio, making them suitable for detecting weak biological signals. This PhD thesis focuses on the fabrication and characterization of OECTs for biological applications. Devices were microfabricated in the cleanroom by photolithography process, and the conducting polymer channel was deposited using electropolymerization, a technique chosen for its advantages in localized deposition, dopant incorporation, and tunability of film properties. Several functional monomers were electropolymerized and their performance as organic mixed ionic electronic conductor in OECT were investigated: After an initial effort of establishing electro-polymerization setup, EDOT (3,4-ethylenedioxythiophene) was electropolymerized. The resulting PEDOT-based OECTs exhibited high transconductance (gm max ~ 12 mS), and remained stable in biological medium over several days. Cardiomyocyte-like (HL-1) cells were grown on the OECT channel to validate the performance of the OECTs and the experimental setup for monitoring cellular electrical activity. In parallel, a zinc-selective thiophene based trimer with a Dipicolylamine (Tri-DPA), was used to fabricate Zn²⁺-specific sensors, for the detection of zinc ion flux during insulin secretion from pancreatic β-cells in pancreatic islets. OECTs specific to Zinc ion were obtained, with a limit of detection (LoD) of about 1.5 µM, showing promising results for extracellular electrical activity recording of β-cells. Moreover, electropolymerization of an n-type monomer was performed, with the aim of fabricating and characterizing n-type OECTs, eventually to integrate these n-type devices with p-type OECTs to create complementary circuits, which are promising for biological applications. This monomer bares a naphthalene diimide core with thiophene functional group, destined to do anodic electropolymerization to facilitate the deposition process. Despite the challenges usually associated with n-type polymers, successful electropolymerization in OECT channels was achieved. Experiments were conducted to enhance the properties of the polymer film by studying the effect of the solvents, the monomer concentration, and the size of working electrode. Although no gate modulation has been observed, extensive insights have been gained to guide the future development of n-type electropolymerized OECTs. This thesis work aimed to advance the development of functional OECT-based sensors for applications in both electrophysiological recording and ion detection, while also laying the groundwork for the integration of complementary circuits in future bioelectronic systems.
Nonlinear optical process in THz waveguides
by Ilyes BETKA (Laboratoire de l'Intégration du Matériau au Système)
The defense will take place at 14h00 - Amphi de l'IMS 351 Cours de la Libération, 33405 Talence Cedex, France
in front of the jury composed of
- Damien BIGOURD - Chargé de recherche - Université de Bordeaux - Directeur de these
- Patricia SEGONDS - Professeure des universités - Université Grenoble-Alpes - Rapporteur
- Patrick MOUNAIX - Directeur de recherche - CNRS/Université de Bordeaux - CoDirecteur de these
- Sukhdeep DHILLON - Directeur de recherche - CNRS/Sorbonne Université - Rapporteur
- Mathieu CHAUVET - Professeur des universités - Université Marie-et-Louis-Pasteur - Examinateur
- Eric CORMIER - Professeur des universités - Université de Bordeaux - Examinateur
The objective of this thesis is to investigate the generation of terahertz waves in lithium niobate (LiNbO3) and periodically poled lithium niobate (PPLN) waveguides via χ(2) processes, pumped by a high repetition rate Ytterbium-based laser operating at a wavelength around 1 μm. In a LiNbO3 waveguide with a cross-section of 500×500 μm2, broadband THz radiation spanning 4 THz and centered at 3.1 THz was generated through polariton parametric scattering. The measured optical spectrum at the waveguide output showed good agreement with the theoretically calculated gain spectrum and the experimental results. In a PPLN waveguide of the same size, narrowband THz radiation centered at 0.48 THz with a bandwidth of 180 GHz was achieved using chirped and delayed laser pulse technique, in excellent agreement with simulations. The pulses were stretched using a parallel grating-pair pulse stretcher and delayed with a Michelson interferometer. As a potential application derived from the latter work, the selective excitation of specific spatial mode profiles in the PPLN waveguide, achieved by adjusting the delay between the two pulses, was numerically demonstrated by solving the depleted nonlinear optical coupling-wave equations. For chirped pulses with a duration of 100 ps, a relative delay of 41.9 ps enabled efficient generation of the TE10 mode, while delays of 42 ps and 43.9 ps selectively generated the TE20 and the TE30 respectively, with high efficiency compared to other modes.