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Augmenter le potentiel thérapeutique du fébuxostat en développant de nouvelles formulations avec une solubilité et une biodisponibilité améliorée
No full textThe present doctoral thesis is organized into five core chapters, preceded by the definition of the research aims and objectives and followed by final reflections, supplementary information, and documentation of scientific dissemination. The work focuses on the rational design, preparation and characterization of innovative solid-state forms of febuxostat, aimed at enhancing its solubility, bioavailability and overall therapeutic potential. The structure of the thesis is described below: Chapter I - provides an overview of febuxostat, highlighting its physicochemical and pharmacological properties, therapeutic uses, and formulation challenges related to poor aqueous solubility and bioavailability. It reviews strategies such as salt formation, co-crystallization, and amorphous solid dispersions, alongside crystal engineering principles and multi-component systems. The chapter also outlines febuxostat's mechanism of action and clinical profile in comparison with allopurinol, establishing the scientific context for the research. Chapter II - reports the first structural elucidation of febuxostat Form A, the marketed polymorph, using 3D electron diffraction and single-crystal X-ray diffraction. It compares the crystallographic results from both techniques and includes thermal and lattice energy analyses, offering critical insight into the solid-state behavior of febuxostat and establishing a reference for developing new forms. Chapter III - describes the synthesis and solid-state characterization of a febuxostat-p-toluenesulfonic acid multi-component form (Tos1), using techniques such as XRPD, DSC, TGA, FT-IR and SC-XRD. The study clarifies the salt versus co-crystal nature of the system and highlights the Tos1 form's improved aqueous solubility and dissolution, supporting its potential as a superior alternative to crystalline febuxostat. Chapter IV - explored the development and characterization of novel febuxostat formulations, including salts, a co-crystal with acridine (Acd1) and amorphous solid dispersions with PEG6000. These systems were evaluated using solid-state analytical techniques and tested in vitro on HepG2 liver cells for cytotoxicity and on RAW 264.7 murine macrophages for anti-inflammatory effects under oxidative stress conditions. Chapter V - summarises the main findings and contributions of this thesis, offering an integrated perspective on the formulation strategies developed to enhance the solubility and therapeutic performance of febuxostat. This research provides structural and pharmaceutical insights into new salt, co-crystal and amorphous forms of the drug, demonstrating the potential of crystal engineering and solid dispersion approaches in overcoming solubility-related limitations. Notably, the structural elucidation of the marketed polymorph (Form A), the development of a febuxostat-acridine co-crystal with extended-release properties, and the generation of amorphous PEG6000-based systems represent key original outcomes of this work. These systems were evaluated using solid-state analytical techniques and tested in vitro on HepG2 liver cells for cytotoxicity and on RAW 264.7 murine macrophages for anti-inflammatory effects under oxidative stress conditions. A national patent has been granted for the co-crystal, highlighting its innovation potential.Looking forward, the findings of this thesis pave the way for broader application of these formulation strategies to other poorly soluble compounds and support future efforts toward preclinical evaluation and clinical translation of the most promising candidates.La présente thèse de doctorat est structurée en cinq chapitres principaux, précédés par la définition des objectifs et suivis de réflexions finales, d'annexes et de données sur la diffusion scientifique. Ce travail vise à concevoir, préparer et caractériser de nouvelles formes solides de febuxostat, afin d'en améliorer la solubilité, la biodisponibilité et le potentiel thérapeutique. Chapitre I présente une vue d'ensemble du febuxostat, ses propriétés physico-chimiques et pharmacologiques, ses usages thérapeutiques, ainsi que les limites liées à sa faible solubilité et biodisponibilité. Sont abordées diverses stratégies d'optimisation, notamment la formation de sels, la co-cristallisation et les dispersions solides amorphes, dans le cadre de l'ingénierie cristalline. Le mécanisme d'action et la comparaison clinique avec l'allopurinol complètent ce cadre. Chapitre II est consacré à la première élucidation structurale du polymorphe commercialisé du febuxostat (Forme A), par diffraction électronique 3D et diffraction des rayons X sur monocristal. Les analyses comparatives, thermiques et énergétiques, permettent une compréhension approfondie du comportement à l'état solide du composé. Chapitre III décrit la préparation et la caractérisation d'un système multi-composant febuxostat-acide p-toluène sulfonique (Tos1), via XRPD, DSC, TGA, FT-IR et SC-XRD. L'étude démontre la formation d'un sel, une amélioration significative de la solubilité aqueuse et du profil de dissolution, ce qui soutient son intérêt comme alternative améliorée au principe actif d'origine. Chapitre IV explore la formulation de nouvelles entités : sels, un co-cristal avec l'acridine (Acd1) et des dispersions solides amorphes avec le PEG6000. Leur caractérisation à l'état solide est suivie d'une évaluation biologique in vitro : tests de cytotoxicité sur cellules HepG2 et effets anti-inflammatoires sur macrophages RAW 264.7 exposés au stress oxydatif. Chapitre V résume les contributions majeures de cette recherche : l'élucidation structurale du polymorphe Forme A, le développement du co-cristal Acd1 à libération prolongée, la formulation de sels et de systèmes amorphes à base de PEG6000. L'ensemble des formulations a été évalué par des techniques analytiques et biologiques. Un brevet national a été déposé pour le co-cristal, soulignant son potentiel d'innovation. Les résultats de cette thèse ouvrent la voie à l'application de stratégies similaires à d'autres composés peu solubles, en soutenant leur évaluation préclinique et leur développement futur
Search for Diffuse Galactic Neutrinos with the Full ANTARES Telescope Dataset
No full textInternational audienceThe diffuse emission of gamma-rays and neutrinos, produced by interactions of cosmic rays with interstellar matter in the Milky Way, provides valuable insights into cosmic ray propagation and Galactic processes. Emission models incorporating different assumptions about cosmic ray diffusion, source distribution, and target gas density are tested using data from neutrino telescopes. In this study, the final all-flavor neutrino dataset, collected over 15 years (2007--2022) by the ANTARES neutrino telescope, is analyzed. A maximum likelihood ratio method built to handle templates of Galactic emission models is employed to evaluate the compatibility of these models with the observed spatial and energy distributions of neutrino events. The results do not yield stringent constraints on the tested models and upper limits on the diffuse neutrino flux are derived, which are compatible with the results obtained by other experiments
: Relationship between Organic Carbon Content and Land Use: application to soils in the Aix-Marseille Provence metropolitan area (TOODS)
No full textNational audienceTOODS est une contribution à mieux outiller la Métropole d’Aix-Marseille pour dialoguer avec l’État sur les choix stratégiques à opérer et aussi dans le but d’atteindre zéro émission nette d’ici 2050. Ce projet est en partenariat avec deux laboratoires, le laboratoire d’étude des Structures et des Processus d'Adaptation et des Changements de l'Espace (CNRS/UMR ESPACE 7300) et le Centre Européen de Recherche et d'Enseignement en Géosciences de l'Environnement (CEREGE UM 34). Il vise à évaluer l’effet de l'occupation du sol et du changement de la Couverture terrestre sur le stock de carbone organique du sol sur tout le territoire de la MAMP dans le but d’améliorer la capacité de ces sols à stocker plus de carbone. Un des principaux résultats du programme TOODS est la création et l'implémentation d'un modèle d’intelligence artificielle associant algorithmes d’apprentissage profond DNN, et d’apprentissage automatique non supervisés (Random Forest, GBM), supervisé (SVM) spatialisé d’estimation des teneurs en carbone organique des sols à partir de 50 mesures in-situ par carottage, des données de télédétection spatiale moyennes résolutions Sentinel 2 MSI et Landsat 5 TM, Landsat 8/9 OLI à partir desquelles sont produits une cartographie de l’occupation des sols et des changements, des indices spectraux (NDVI, NDBI, NDTI, BUI, SI), des structures paysagères, ainsi que les bases de données de terrain (MNT), géologiques, pédologiques, et de physiographiques
Myocardial Stiffness Quantification Using Ultrasound Shear Wave Elastography and Reduced Modeling for Subject-Specific Simulations
No full textNational audienceCardiac electromechanical models can significantly advance diagnosis, prognosis, and therapy planning. Despite their importance in evaluating myocardial function, key mechanical parameters such as myocardial stiffness (MS) are still missing in clinical practice. While ultrafast ultrasound imaging (UUI) provides reliable and reproducible data, its use in parameter estimation is still restricted, limiting the potential for comprehensive modeling. Integrating UUI data with reduced-order 0D models addresses these limitations by enabling more robust parameter estimation and improved data interpretation. The approach also significantly reduces computational costs compared to 3D simulations. This work presents a closed-loop 0D model calibrated using UUI-based shear wave elastography (SWE), a noninvasive technique providing detailed MS profiles across the cardiac cycle. By integrating MS, the model accounts for both active and passive contributions to myocardial function, with a primary focus on the active component. Modeled using the Bestel-Clement-Sorine (BCS) framework, it has been optimized with the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm and calibrated to healthy subject data. The aim is to develop a subject-specific tool for clinical studies supporting parameter calibration and integration into 3D simulations, while extending its application to pathological cases
Sphere of arbitrarily polarized exceptional points with a single planar metasurface
No full textInternational audienceExceptional points (EPs) are spectral singularities in non-Hermitian systems, where complex eigenvalues and eigenstates coalesce, reducing the Hilbert space dimension. Traditional photonic systems exhibit coalesced eigenstates corresponding to circular polarized light, restricting EPs to only two poles on the Poincaré sphere. Here, by combining optical anisotropy, chirality and non-Hermiticity in plasmonic metasurfaces we achieve a continuum of EPs, enabling coalesced eigenstates at any points on the Poincaré sphere. This breakthrough overcomes EPs' practical limitations, extending the associated topological phase to arbitrarily polarization. As a proof-of-concept, we construct topological metasurfaces tailored for linear, circular and elliptical polarized light. The emergence of these unconventional EPs not only promises disruptive</div
Effects of the built-in electric field on free and bound excitons in a polar GaN/AlGaN/GaN based heterostructure
No full textInternational audienceLow-temperature luminescence spectra reveal the presence of two independant populations of GaN excitons within a GaN/AlGaN/GaN/Al2O3 heterostructure in which a thick (1.5 µm) AlGaN layer separates a thin (150 nm) top GaN layer and a thick (3.5 µm) bottom GaN layer grown on sapphire. The presence of these two spectrally-distinct families of excitons in each GaN layer of the heterostructure is demonstrated using three different experimental methods: (i) low-power µ-photoluminescence (µPL) using laser excitation sources with wavelengths above and below the AlGaN bandgap, (ii) µPL as a function of optically injected free carrier density, and (iii) quantitative numerical simulation of the µ-Reflectivity (µR). One major impact of the built-in electric field is the reduction of the excitonic lifetime in the GaN surface layer, which transitions from less than 10 ps in the presence of the built-in electric field to the bulk lifetime (90 ps) when the field is screened. This increase in the excitonic lifetime is related to the modification of the band structure in the presence of optically injected free carriers. The effect of these lifetime variations on the luminescence spectra is analyzed. Lastly, we provide an estimate of the Mott density in GaN as nMott = 4 × 10 17 cm -3 at 130 K, consistent with values reported in the literature and accounting for the free carrier density required to screen the electric field
How do strategic and financial buyers affect post-acquisition performance?
No full textInternational audienceIn this paper, we investigate how the type of buyer can influence cross-border acquisition performance. We combine the resource-based view with the institutional change framework to provide a more comprehensive understanding of post-acquisition performance. We hypothesise that different types of buyers can lead to divergent performances of acquired firms and that this relationship can be shaped by changes in institutional environments. Using a multi-country and multi-industry dataset of 234 cross-border acquisitions, we find that both strategic and financial buyers have a positive effect on the performance of the target firm. Our findings show that strategic buyers positively affect innovative performance whereas financial buyers positively affect the economic performance of target firms. The observed effects are moderated by institutional changes
Physics-informed neural networks for multidisciplinary analysis and design
No full textInternational audienc
Enhancing Energy Efficient Task Caching and Offloading in Mobile Edge Computing
No full textInternational audienceMobile Edge Computing (MEC) enables both to prolong the battery life of mobile devices and support the execution of computationally intensive applications at the edge. This can be achieved by offloading these tasks to a server deployed near the base station and/or by directly caching them. Previous works focus on only one of these two strategies or formulate optimization problems that are hard to solve and propose a suboptimal solution. In this paper, we propose a linear model for the joint task caching and offloading optimization problem. Moreover, we present two efficient heuristics which provide close-to-optimal results in terms of energy efficiency with a low execution time. We further prove that the offloading subproblem can be solved with an optimal algorithm. Finally, we demonstrate the performance and scalability of our propositions by extensive simulations on a large number of 10^5 mobile devices
TELS1 stabilizes t-loops independently of TRF2 and controls telomere length in pluripotent cells
No full textInternational audienceTelomeric loops (t-loops) are thought to protect chromosome ends, with their stabilization generally requiring the shelterin protein TRF2. However, the mechanisms operating in pluripotent cells remain unknown. Here, we identify TELS1 as a TRF2-independent t-loop stabilizer in pluripotent cells. TELS1 binds single-stranded, G-rich telomeric DNA tracts likely present within duplex telomeric regions and promotes strand invasion in vitro, consistent with a direct role in t-loop formation. When targeted to telomeres in differentiated cells, TELS1 is able to substitute for TRF2 in making the t-loop, which partially protects from ATM activation. In TELS1-deficient pluripotent cells, telomeres lack t-loops but remain protected and become more accessible to telomerase, resulting in elongation. A genome-wide CRISPR screen identifies Ubr5 as essential for this tolerance. These findings validate the t-loop as an essential structure for end protection and uncover a telomere protection pathway unique to pluripotent cells that appears to function independently of shelterin