Les opioïdes restent encore à l’heure actuelle les composés pharmacologiques les plus efficaces pour traiter les différentes formes de douleurs, et donc fournir une analgésie thérapeutique. Cependant, l’administration répétée de ces composés entraîne des effets secondaires majeurs comme la dépression respiratoire, la tolérance, mais également, il a été montré que certains de ces opioïdes pouvaient engendrer des états proépileptiques. D’un point de vue thérapeutique, il existe donc un réel besoin pour de nouveaux et meilleurs traitements analgésiques, n’élicitant pas ces effets secondaires. Notre laboratoire étudie la signalétique des récepteurs couplés aux protéines G comme les récepteurs opioïdes et leur capacité de sélectivité fonctionnelle depuis des années, et en particulier celle du récepteur delta opioïde (DOP). En effet, celui-ci présenterait moins d’effets indésirables que le récepteur mu opioïde (MOP) qui est la cible principale des opioïdes classiques comme la morphine. Cependant, il semblerait que le DOP justement soit à l’origine des états proépileptiques précédemment décrits. Ainsi malgré la promesse initiale des agonistes delta par rapport à la diminution des effets secondaires, les effets proépileptiques de certains ont notamment contribué à une baisse d’intérêt vers le DOP et aucun de ses agonistes n’a pu passer les phases de tests cliniques. Cependant, il a été démontré que certains agonistes delta n’entraînaient pas d’effet proépileptique; tandis que d’autres oui. Comment expliquer un tel phénomène ? Ceci est la question que pose la présente recherche. Ainsi notre objectif sera d’obtenir et de comparer les signatures pharmacologiques des agonistes connus pour être proépileptiques versus ceux qui ne le sont pas ; par rapport à la transduction de signal via le récepteur delta opioïde et sa protéine G hétérotrimérique ; et par rapport à un de ses effecteurs principaux pour l’analgésie, un canal potassique rectifiant entrant. Cette comparaison se fera selon les paramètres du modèle classique de la pharmacologie, comme l’efficacité et la puissance ; mais également avec un outil plus récent appelé modèle opérationnel, utilisant des paramètres comme l’affinité et le coefficient de transduction. Pour se faire, le transfert d'énergie par résonance de bioluminescence ou BRET sera utilisé afin de caractériser les différentes voies signalétiques impliquées. Cette recherche s’inscrit dans un vaste contexte de collaboration entre différents laboratoires, et au sein de chacun d’entre eux, dans l’espoir de pouvoir synthétiser un jour, de meilleurs composés pharmacologiques, capables de cibler uniquement les voies médiatrices des effets thérapeutiques voulus, ici l’analgésie ; sans éliciter celles entraînant les effets secondaires associés, ici, les états proconvulsifs. L’aboutissement de cette recherche permettrait donc d’impacter la vie de millions de gens en souffrance, et c’est pourquoi il nous semble plus qu’important de continuer à l’entreprendre. / Opioids are still nowadays the most efficacious pharmacological compounds available to treat the different types of pain, and therefore provide a therapeutic analgesia. However, repeated administration of those compounds lead to major secondary effects like respiratory depression, tolerance, but also it was shown that some opioid compounds could induce seizures. From a therapeutical point of view, there is a serious need for new and better analgesic treatments that do not elicit such adverse effects. Our lab has been studying for years the signaletics of G-protein coupled receptors like the opioid receptors, and their capacity for functional selectivity, especially more recently the one of the delta opioid receptor (DOP). Indeed, this receptor elicits fewer adverse effects compared to the mu opioid receptor (MOP) that is the main target of all clinically used opioids such as morphine. However, it seems like the DOP itself would be responsible for the pro-epileptic states previously described. Thus, despite initial promises of the delta agonists towards reducing adverse effects whilst providing analgesia, the pro-convulsive effects that some seem to elicit have induced a loss of interest towards the DOP, and so far none of its agonists have gone further than pre-clinical trials. However, it has been shown that not all of those DOP agonists had those pro-convulsive adverse effects. How to explain such a phenomenon? This is the question which the present research will be asking. Thus our goal is to obtain and compare pharmacological signatures of the agonists known for being pro-convulsive versus those that are not ; regarding the transduction of signals through the delta opioid receptor and its heterotrimeric G-Protein ; and also regarding one of its main effectors to induce analgesia, an inwardly rectifying potassium channel. This comparison will be done according to the classical parameters of pharmacology, such as efficacy and potency ; but also according to the newest operational model, with parameters such as affinity and transduction coefficients. In order to do so, bioluminescence resonance energy transfer or BRET, will be used in order to characterize and quantify the signalling pathways there implicated. This research is embedded in a vast collaboration context, in between laboratories around the world, and within those laboratories as well, in hope to be able to one day synthesize, better pharmacological compounds, capable of targeting only the pathways responsible for the desired effects, here analgesia ; without triggering the associated adverse effects, here pro-convulsive states. The culmination of this research could allow to impact the lives of millions of people throughout the world, and this is why it is more than important for us to keep on pursuing it.

A substantial number of works have aimed at modeling the receptive field properties of the primary visual cortex (V1). Their evaluation criterion is usually the similarity of the model response properties to the recorded responses from biological organisms. However, as several algorithms were able to demonstrate some degree of similarity to biological data based on the existing criteria, we focus on the robustness against loss of information in the form of occlusions as an additional constraint for better understanding the algorithmic level of early vision in the brain. We try to investigate the influence of competition mechanisms on the robustness. Therefore, we compared four methods employing different competition mechanisms, namely, independent component analysis, non-negative matrix factorization with sparseness constraint, predictive coding/biased competition, and a Hebbian neural network with lateral inhibitory connections. Each of those methods is known to be capable of developing receptive fields comparable to those of V1 simple-cells. Since measuring the robustness of methods having simple-cell like receptive fields against occlusion is difficult, we measure the robustness using the classification accuracy on the MNIST hand written digit dataset. For this we trained all methods on the training set of the MNIST hand written digits dataset and tested them on a MNIST test set with different levels of occlusions. We observe that methods which employ competitive mechanisms have higher robustness against loss of information. Also the kind of the competition mechanisms plays an important role in robustness. Global feedback inhibition as employed in predictive coding/biased competition has an advantage compared to local lateral inhibition learned by an anti-Hebb rule.

Informações sobre as características funcionais e estruturais da unidade motora (UM) são altamente relevantes em investigações fisiológicas e nos estudos clínicos das disfunções neuromusculares. A eletromiografia (EMG) é um método adequado para obtenção dessas informações. Entretanto, devido à dificuldade na separação da atividade individual de uma unidade motora das outras que estão simultaneamente ativas, seu uso em clínica prática se dá comumente através de métodos invasivos, empregando eletrodos de agulha ou fios implantados. Apesar da EMG de superfície ser não-invasiva e, portanto mais apropriada para aplicações clínicas, não é usada em clínica porque não há até o presente um método satisfatório para decomposição do sinal EMG de superfície. Um EMG de superfície é muito mais difícil de decompor devido a significante superposição dos Potenciais de Ação das UMs (MUAPs) e a relação sinal-ruído relativamente baixa, se comparada aos métodos invasivos. Defendemos que a separação da atividade individual das UMs pode ser feita de modo não-invasivo aliando-se técnicas de aquisição altamente especializadas com técnicas usadas em reconhecimento de padrões. Desenvolvemos um método para decomposição de EMGs de superfície, a partir do qual foi possível extrair características relevantes das UMs, que permitem seu uso em avaliação e diagnóstico de desordens neuromusculares. Em nossa abordagem, o sinal EMG é inicialmente captado sob contração isométrica fraca usando eletrodos desuperfície. O sinal EMG bruto passa em seguida por um filtro Diferencial Passa-Baixas Ponderado (DPBP) em série com um detector de picos, que detecta os picos de MUAPs e extrai suas formas de onda. Na sequência, o conjunto de MUAPs extraído é classificado por uma rede neural SOM, e os MUAPs agrupados pela similaridade de suas formas de onda. No próximo passo a informação temporal dos disparos é checada, eliminando possíveis erros de classificação, e finalmente os Trens de MUAPs (MUAPTs) das UMs individuais são reconstituídos do EMG original. As estatísticas de disparos (IPI) bem como as formas de ondas dos MUAPs das respectivas UMs são então extraídas e armazenadas para estudos posteriores. Resultados preliminares obtidos com EMGs normais e patológicos, extraídos de membros superiores sob contração fraca, indicam que, o método mostrou-se apto a decompor EMGs de superfícies, além de potencial para aplicações em estudos clínicos não-invasivos de disfunções neuromusculares.Informações sobre as características funcionais e estruturais da unidade motora (UM) são altamente relevantes em investigações fisiológicas e nos estudos clínicos das disfunções neuromusculares. A eletromiografia (EMG) é um método adequado para obtenção dessas informações. Entretanto, devido à dificuldade na separação da atividade individual de uma unidade motora das outras que estão simultaneamente ativas, seu uso em clínica prática se dá comumente através de métodos invasivos, empregando eletrodos de agulha ou fios implantados. Apesar da EMG de superfície ser não-invasiva e, portanto mais apropriada para aplicações clínicas, não é usada em clínica porque não há até o presente um método satisfatório para decomposição do sinal EMG de superfície. Um EMG de superfície é muito mais difícil de decompor devido a significante superposição dos Potenciais de Ação das UMs (MUAPs) e a relação sinal-ruído relativamente baixa, se comparada aos métodos invasivos. Defendemos que a separação da atividade individual das UMs pode ser feita de modo não-invasivo aliando-se técnicas de aquisição altamente especializadas com técnicas usadas em reconhecimento de padrões. Desenvolvemos um método para decomposição de EMGs de superfície, a partir do qual foi possível extrair características relevantes das UMs, que permitem seu uso em avaliação e diagnóstico de desordens neuromusculares. Em nossa abordagem, o sinal EMG é inicialmente captado sob contração isométrica fraca usando eletrodos desuperfície. O sinal EMG bruto passa em seguida por um filtro Diferencial Passa-Baixas Ponderado (DPBP) em série com um detector de picos, que detecta os picos de MUAPs e extrai suas formas de onda. Na sequência, o conjunto de MUAPs extraído é classificado por uma rede neural SOM, e os MUAPs agrupados pela similaridade de suas formas de onda. No próximo passo a informação temporal dos disparos é checada, eliminando possíveis erros de classificação, e finalmente os Trens de MUAPs (MUAPTs) das UMs individuais são reconstituídos do EMG original. As estatísticas de disparos (IPI) bem como as formas de ondas dos MUAPs das respectivas UMs são então extraídas e armazenadas para estudos posteriores. Resultados preliminares obtidos com EMGs normais e patológicos, extraídos de membros superiores sob contração fraca, indicam que, o método mostrou-se apto a decompor EMGs de superfícies, além de potencial para aplicações em estudos clínicos não-invasivos de disfunções neuromusculares. / Information on the functional and structural characteristics of the motor unit (MU) they are highly important in physiologic investigations and in the clinical studies of the neuromuscular dysfunctions. The electromyography (EMG) it is an appropriate method for obtaining of that information. However, due to the difficulty in the separation of the individual activity of a motor unit of the another that are simultaneously active, your use in practical clinic happen commonly through methods invasive, employing needle electrodes or implanted threads. In spite of surface EMG to be non-invasive and, therefore more appropriate for clinical applications, it is not used at clinic because there is not until the present a satisfactory method for decomposition of the surface EMG sign. A surface EMG is much more difficult of decomposing due to significant overlap of the Motor Unit Action Potentials (MUAPs) and the relationship sign-noise relatively low, if compared to the invasive methods. We defended that the separation of the individual activity of MUs can be made in way non-invasive allying highly specialized acquisition techniques with techniques used in recognition of patterns. We developed a method for decomposition of surface EMGs, starting from which was possible to extract important characteristics of MUs, which allow your use in evaluation and diagnosis of neuromuscular disorders. In our approach, the sign EMG is captured initially under weak isometriccontraction using surface electrodes. The sign EMG raw raisin soon after for a Biased Low-Pass Differential filter (BLPD) in series with a detector of peaks, that detects the peaks of MUAPs and it extracts your wave forms. In the sequence, a SOM neural network classifies the set of extracted MUAPs, and MUAPs are clustered by the similarity in your wave shape. In the next step the temporal information of the discharges is checked, eliminating possible classification mistakes, and finally the MUAPs Trains (MUAPTs) of individual MUs they are reconstituted of original EMG. The statistics of discharges (IPI) as well as the forms of waves of MUAPs of respective MUs are then extracted and stored for subsequent studies. Results preliminaries obtained with normal and pathological EMGs, extracted of superior members under weak contraction, they indicate that, the method was shown capable to decompose surfaces EMGs, besides potential for applications in clinical studies non-invasive of neuromuscular dysfunctions.

The numerics of hyperbolic conservation laws, e.g., the Euler equations of gas dynamics, shallow water equations and MHD equations, is non-trivial due to the convective terms being highly non-linear and equations being coupled. Many numerical methods have been developed to solve these equations, out of which central schemes and upwind schemes (such as Flux Vector Splitting methods, Riemann solvers, Kinetic Theory based Schemes, Relaxation Schemes etc.) are well known. The majority of the above mentioned schemes give rise to very dissipative solutions. In this thesis, we propose novel low dissipative numerical algorithms for some hyperbolic conservation laws representing fluid flows. Four different and independent numerical methods which give low diffusive solutions are developed and demonstrated. The first idea is to regulate the numerical diffusion in the existing dissipative schemes so that the smearing of solution is reduced. A diffusion regulator model is developed and used along with the existing methods, resulting in crisper shock solutions at almost no added computational cost. The diffusion regulator is a function of jump in Mach number across the interface of the finite volume and the average Mach number across the surface. The introduction of the diffusion regulator makes the diffusive parent schemes to be very accurate and the steady contact discontinuities are captured exactly. The model is demonstrated in improving the diffusive Local Lax-Friedrichs (LLF) (or Rusanov) method and a Kinetic Scheme. Even when employed together with accurate methods of Roe and Osher, improvement in solutions is demonstrated for multidimensional problems. The second method, a Central Upwind-Biased Scheme (CUBS), attempts to reorganize a central scheme such that information from irrelevant directions is largely reduced and the upwind biased information is retained. The diffusion co-efficient follows a new format unlike the use of maximum characteristic speed in the Local Lax-Friedrichs method and the scheme results in improved solutions of the flow features. The grid-aligned steady contacts are captured exactly with the reorganized format of diffusion co-efficient. The stability and positivity of the scheme are discussed and the procedure is demonstrated for its ability to capture all the features of solution for different flow problems. Another method proposed in this thesis, a Central Rankine-Hugoniot Solver, attempts to integrate more physics into the discretization procedure by enforcing a simplified Rankine-Hugoniot condition which describes the jumps and hence resolves steady discontinuities very accurately. Three different variants of the scheme, termed as the Method of Optimal Viscosity for Enhanced Resolution of Shocks (MOVERS), based on a single wave (MOVERS-1), multiple waves (MOVERS-n) and limiter based diffusion (MOVERS-L) are presented. The scheme is demonstrated for scalar Burgers equation and systems of conservation laws like Euler equations, ideal Magneto-hydrodynamics equations and shallow water equations. The new scheme uniformly improves the solutions of the Local Lax-Friedrichs scheme on which it is based and captures steady discontinuities either exactly or very accurately. A Grid-Free Central Solver, which does not require a grid structure but operates on any random distribution of points, is presented. The grid-free scheme is generic in discretization of spatial derivatives with the location of the mid-point between a point and its neighbor being used to define a relevant coefficient of numerical dissipation. A new central scheme based on convective-pressure splitting to solve for mid-point flux is proposed and many test problems are solved effectively. The Rankine-Hugoniot Solver, which is developed in this thesis, is also implemented in the grid-free framework and its utility is demonstrated. The numerical methods presented are solved in a finite volume framework, except for the Grid-Free Central Solver which is a generalized finite difference method. The algorithms developed are tested on problems represented by different systems of equations and for a wide variety of flow features. The methods presented in this thesis do not need any eigen-structure and complicated flux splittings, but can still capture discontinuities very accurately (sometimes exactly, when aligned with the grid lines), yielding low dissipative solutions. The thesis ends with a highlight on the importance of developing genuinely multidimensional schemes to obtain accurate solutions for multidimensional flows. The requirement of simpler discretization framework for such schemes is emphasized in order to match the efficacy of the popular dimensional splitting schemes.

Biological signal processing can help us gain knowledge about biological complexity, as well as using this knowledge to engineer better systems. Three areas are identified as critical to understanding biology: 1) understanding DNA, 2) examining the overall biological function and 3) evaluating these systems in environmental (ie: turbulent) conditions. DNA is investigated for coding structure and redundancy, and a new tandem repeat region, an indicator of a neurodegenerative disease, is discovered. The linear algebraic framework can be used for further analysis and techniques. The work illustrates how signal processing is a tool to reverse engineer biological systems, and how our better understanding of biology can improve engineering designs. Then, the way a single-cell mobilizes in response to a chemical gradient, known as chemotaxis, is examined. Inspiration from receptor clustering in chemotaxis combined with a Hebbian learning method is shown to improve a gradient-source (chemical/thermal) localization algorithm. The algorithm is implemented, and its performance is evaluated in diffusive and turbulent environments. We then show that sensor cross-correlation can be used in solving chemical localization in difficult turbulent scenarios. This leads into future techniques which can be designed for gradient source tracking. These techniques pave the way for use of biologically-inspired sensor networks in chemical localization.

No description available.

Esta tesis doctoral es una colección de tres artículos. Los capítulos 1 y 2, co-autorados con Joachim Voth, investigan por qué Europa en 1700 ya era más rico que el resto del mundo y por qué Inglaterra fue el primer país en industrializarse. Encontramos que las dinámicas de la población, en lugar del crecimiento de la productividad, fueron los promotores más importantes del desarrollo económico de Europa Occidental durante la temprana edad moderna (1450-1700). Calibramos un modelo probabilístico para representar Inglaterra en 1700 y encontramos que ingresos iniciales más altos unidos a limitaciones de fertilidad aumentaron la probabilidad de industrialización. En el tercer capítulo, presento un nuevo hecho estilizado y analizo su contribución al sesgo del cambio tecnológico hacia los trabajadores más cualificados: El porcentaje de trabajadores cualificados en la producción intermedia está altamente correlacionado con la proporción de trabajo cualificado en la producción final. Esto genera un efecto multiplicador que refuerza la demanda de trabajo cualificado a lo largo de la cadena de producción. El efecto es importante, explica más de un tercio del aumento de la demanda de trabajadores cualificados en la industria manufacturera de EE.UU. / This dissertation is a collection of three essays. Chapters 1 and 2, co-authored with Joachim Voth, investigate the question why Europe in 1700 was ahead of the rest of the world and why England was the first country to industrialize. We find that population dynamics, rather than productivity growth, were the most important drivers for Western Europe to overtake China in the early modern period (1450-1700). We calibrate a probabilistic model to match England in 1700 and find that higher initial per capita incomes together with fertility limitation increased its industrialization probabilities. In the third chapter, I present a novel stylized fact and analyze its contribution to the skill bias of technical change: The share of skilled labor embedded in intermediate inputs correlates strongly with the skill share employed in final production. This delivers a multiplier that reinforces skill demand along the production chain. The effect is large, accounting for more than one third of the observed skill upgrading in U.S. manufacturing.

Parmi plus de 20000 espèces de trématodes hermaphrodites, les Schistosomatidae ont un statut particulier car ils sont gonochoriques (i.e. deux sexes séparés). Le gonochorisme chez ces espèces, et leur dimorphisme sexuel, seraient en fait une stratégie d’adaptation à leur habitat : le système veineux des vertébrés à sang chaud, dont l’Homme. Malgré un mode chromosomique de déterminisme du sexe (i.e. hétérogamétie femelle ZW), les individus mâles et femelles demeurent phénotypiquement identiques durant tous les stades larvaires de leur cycle de vie hétéroxène. La différenciation sexuelle n’a lieu qu’après l’infestation de leur hôte définitif. Dans ce travail, nous nous sommes intéressés aux facteurs moléculaires déclenchant cette différenciation chez Schistosoma mansoni. Nous avons établi le profil d’expression sexe-dépendant de gènes conservés de la cascade de détermination/différenciation chez les animaux : les DMRT (Double-sex and Male-abnormal-3 Related Transcription Factors). Nous avons par ailleurs généré un transcriptome comparatif mâle/femelle (RNA-seq) sur 5 stades de développement in vivo, dont 3 stades « schistosomules » inédits. Cela nous a permis d’identifier de potentiels gènes « clés » de la différenciation sexuelle et de souligner l’importance de l’interaction hôte-parasite. Enfin, par la combinaison de cette approche transcriptomique et d’une analyse épigénomique (ChIP-seq), nous avons montré une dynamique de la compensation de dose génique au cours du cycle de vie chez les femelles ainsi que la mise en place d’une stratégie transcriptionnelle particulière chez les mâles, optimisant leur développement dans l’hôte et ainsi, leur succès reproducteur. / Parasitic flatworms include more than 20.000 species that are mainly hermaphrodites. Among them, the hundred species of Schistosomatidae are intriguing because they are gonochoric. The acquisition of gonochorism in these species is supposed to provide genetic and functional advantages to adapt to their hosts: warm-blooded animals. Sex of schistosomes is genetically determined at the time of fertilization (i.e. ZW female heterogametic system). However, there is no phenotypic dimorphism through all the larval stages of its complex lifecycle: sexual dimorphism appears only in the definitive host. The molecular mechanisms triggering this late sexual differentiation remain unclear, and this is precisely the topic of our present work. We performed transcriptomic (RNA-Sequencing and quantitative-PCRs) and structural (ChIP-Sequencing) analyses at different stages of Schistosoma mansoni development. Here, we present data suggesting that the sexual differentiation relies on a combination of genetic and epigenetic factors. In a genetic point of view, we show a sex-associated expression of the DMRT genes (Double-sex and Mab-3 Related Transcription Factors) that are known to be involved in sex determination/differentiation through all the animal kingdom. In addition, we propose new potential sex-determining key genes and a pivotal role of host-pathogen interaction at the time of development. In a structural point of view, we highlight a dynamic status of dosage compensation in females and chromatin modifications in males. This intense remodeling reveals a specific transcriptomic strategy which optimizes male development and beyond that, schistosomes reproductive success.

Solar energy conversion, miniaturization of semiconductor devices and associated lifetime, reliability and efficiency of devices are the basic premise of this work. This work is focused on the study of optoelectronic devices especially solar cells and its nondestructive diagnostic. Solar cells are advantageous for study mainly because the pn junction is located near the surface and contains a lot of inhomogeneities. It has been difficult until recently to investigate their local physical (electrical and optical) parameters due to the size of inhomogeneities. Behavior of inhomogeneities can be well understood with knowledge of its local properties. Establishment of measurement workplace, that satisfies requirements for measurement of local emission and optically induced current measurement, allows us detection and localization of inhomogeneities with spatial resolution more or less 100 nm. The core of thesis is characterization of imperfection using nondestructive techniques in the macroscopic region but primarily in microscopic region using scanning probe microscopy. Integral parts of the work are characterization techniques for photoelectrical devices, microscopic techniques and data processing. Scanning near-field optical microscope is used for the purpose of microscopic characterization such as topography, local optical, photoelectrical and electrooptical properties of structures in high spatial resolution. Locally induced current technique, current voltage characteristics, emission from reversed bias pn junction measurement including its thermal dependence are used for samples investigation in macroscopical region. It is possible to localize defects and structure inhomogeneity using mentioned techniques. Localised defects are consequently analyzed for composition and measured using electron microscopy. Specific outputs of work are classification of photoelectric devices defects and specification of nondestructive characterization techniques used for defect detection. Experimental characterization techniques are described together with defects measurement procedures. The key output is the catalog of serious defects which was detected. Particular defects of samples are shown including describe of its properties and physical meaning.

La leucémie myéloïde aiguë (LMA) est causée par une prolifération anormale de cellules souches sanguines immatures. Notre laboratoire se concentre sur un sous-groupe de la LMA représentant près de 30% de la LAM pédiatrique et caractérisé par la translocation chromosomique KMT2A-MLLT3. L'analyse par séquençage de l’ARN (RNA-seq) dans notre modèle de LMA médiée par la fusion KMT2A-MLLT3 et des échantillons de patients leucémiques a révélé que les gènes codant la chimiokine CCL23 et son récepteur correspondant CCR1 sont surexprimés dans cette maladie. Bien qu'il ait été rapporté que CCL23 et CCR1 sont impliqués dans le trafic de leucocytes et le développement de l'inflammation, les rôles exacts de ces deux protéines dans la leucémogenèse sont inconnus. Pour illustrer les effets de la signalisation CCL23/CCR1 dans la leucémie causée par la fusion KMT2A-MLLT3, nous avons utilisé la technique de transfert d'énergie de résonance de bioluminescence 2 améliorée (ebBRET2) avec des tests d'immuno-empreintes. Nos résultats ont révélé que la signalisation de l'axe CCL23/CCR1 active plusieurs effecteurs de signalisation intermoléculaire, y compris Gi2, G12/13 et β-arrestine 1/2, mais avec un biais vers le recrutement de la β-arrestine. Nous avons également montré que le récepteur CCR1 présente une activité constitutive qui peut se coupler à une voie médiée par la protéine G et activer la voie impliquant les MAP kinases. Enfin, nous avons montré que la signalisation de l'axe CCL23/CCR1 provoque une activation de ERK1/2 dans les lignées cellulaires LMA potentiellement par une voie médiée par la β-arrestine. Ces résultats indiquent que la signalisation de l'axe CCL23/CCR1 active plusieurs voies biologiques pouvant fournir des avantages majeurs pour le développement et la progression de la LMA et présentent ainsi CCL23 et CCR1 comme deux candidats intéressants pour une thérapie ciblée contre la LMA de type KMT2A-MLLT3. / Acute Myeloid Leukemia (AML) is caused by abnormal proliferation of immature blood stem cells. Our lab focuses on an AML subgroup accounting for almost 20% of pediatric AML and characterized by a chromosomal translocation that generates the gene fusion: KMT2A-MLLT3 (KM3). Interestingly, RNA-seq analysis of our KM3 AML model and AML patient samples has revealed that the chemokine CCL23 and its corresponding receptor CCR1 are highly upregulated in this disease. Although it has been reported that CCL23 and CCR1 are implicated in leukocyte trafficking and development of inflammation, the exact roles of these two proteins in leukemia are unknown. To illustrate the effects of CCL23/CCR1 signaling in the KMT2A-MLLT3 rearranged leukemia we employed the enhanced bystander bioluminescence resonance energy transfer 2 (ebBRET2) technique along with phospho-immunoblots assays. Our results revealed that CCL23/CCR1 axis signaling activates multiple intermolecular signaling effectors, including Gi2, G12/13, and β-arrestin1/2 albeit with a bias towards β-arrestin recruitment. We also showed that the CCR1 receptor exhibits a constitutive activity which can couple to a G-protein mediated pathway to activate the MAPK cascade. Finally, we showed that CCL23/CCR1 axis signaling causes an activation of ERK1/2 in AML cell lines potentially through a β-arrestin-mediated pathway. These results indicate that the CCL23/CCR1 axis signaling activates several biological pathways than can provide major advantages for the AML disease development and progression thus presenting both CCL23 and CCR1 as interesting candidates for targeted therapy against KMT2A-MLLT3 AML.