La péninsule tingitane, angle vif au nord-ouest du royaume, et ses capitales, Tanger et Tétouan, sont représentatives du Maroc en transition. Les recompositions territoriales du Nord marocain s'inscrivent dans l'histoire de deux villes, Tanger et Tétouan, où périodes d'ouverture ont alterné avec des temps de repli. Les principales activités et fonctions, ainsi que les grands projets d'infrastructure significatifs des dynamiques régionales, sont appréhendés comme des facteurs d'intégration pour le Maroc du Nord. La région Tanger-Tétouan est excentrée par rapport à l'axe urbain atlantique, mais sa situation stratégique en fait une locomotive pour le développement du royaume chérifien ; les processus d'intégration aux niveaux international et national semblent finalement se rejoindre. Du global au local, l'approche régionale conduit à l'échelle urbaine avec ses situations d'exclusion. La problématique porte sur les logiques inclusives des quartiers sous-équipés et de leurs populations pauvres. L'étalement des agglomérations de Tanger et de Tétouan pose avec acuité les questions de l'inclusion urbaine des périphéries irrégulières et plus largement de la cohésion sociale. La pauvreté structurelle du Maroc et le modèle social de protection par allégeance évoluent vers des formes d'exclusion : la population pauvre d'hier avait une place et un rôle dans une société hiérarchisée et inégalitaire qui maintenait des équilibres, alors qu'une partie des pauvres sont aujourd'hui des inutiles au monde. Dans la forme urbanistique particulière que représente l'habitat non réglementaire, les services essentiels et les équipements collectifs, et plus particulièrement l'accès aux services et infrastructures de base, notamment les transports collectifs et l'eau potable, constituent des indicateurs pour étudier les processus d'inclusion/exclusion dont les marges urbaines font l'objet. Ces outils d'analyse " transports et eau " permettent aussi d'appréhender les modes de gouvernance spécifiques aux villes de Tanger et de Tétouan. Enfin, au terme de cette thèse, plusieurs modèles d'inclusion urbaine sont identifiés.

La conception des filtres a réponse impulsionnelle finie (RIF) peut être formulée comme un problème d'optimisation non linéaire réputé pour être difficile sa résolution par les approches conventionnelles. Afin d'optimiser la conception des filtres RIF, nous explorons plusieurs méthodes stochastiques capables de traiter de grands espaces. Nous proposons un nouvel algorithme génétique dans lequel certains concepts innovants sont introduits pour améliorer la convergence et rendre son utilisation plus facile pour les praticiens. Le point clé de notre approche découle de la capacité de l'algorithme génétique (AG) pour adapter les opérateurs génétiques au cours de la vie génétique tout en restant simple et facile à mettre en oeuvre. Ensuite, l’optimisation par essaim de particules (PSO) est proposée pour la conception de filtres RIF. Finalement, un algorithme génétique hybride (HGA) est proposé pour la conception de filtres numériques. L'algorithme est composé d'un processus génétique pur et d’une approche locale dédiée. Notre contribution vise à relever le défi actuel de démocratisation de l'utilisation des AG’s pour les problèmes d’optimisation. Les expériences réalisées avec différents types de filtres mettent en évidence la contribution récurrente de l'hybridation dans l'amélioration des performances et montrent également les avantages de notre proposition par rapport à d'autres approches classiques de conception de filtres et d’autres AG’s de référence dans ce domaine d'application. / The design of finite impulse response (FIR) filters can be formulated as a non-linear optimization problem reputed to be difficult for conventional approaches. In order to optimize the design of FIR filters, we explore several stochastic methodologies capable of handling large spaces. We propose a new genetic algorithm in which some innovative concepts are introduced to improve the convergence and make its use easier for practitioners. The key point of our approach stems from the capacity of the genetic algorithm (GA) to adapt the genetic operators during the genetic life while remaining simple and easy to implement. Then, the Particle Swarm Optimization (PSO) is proposed for FIR filter design. Finally, a hybrid genetic algorithm (HGA) is proposed for the design of digital filters. The algorithm is composed of a pure genetic process and a dedicated local approach. Our contribution seeks to address the current challenge of democratizing the use of GAs for real optimization problems. Experiments performed with various types of filters highlight the recurrent contribution of hybridization in improving performance. The experiments also reveal the advantages of our proposal compared to more conventional filter design approaches and some reference GAs in this field of application.

De nombreuses méthodes de traitement du signal reposent sur des résultats puissants d'approximation numérique. Un exemple significatif en est l'utilisation de l'approximation de type Chebyshev pour l'élaboration de filtres numériques.En pratique, le caractère fini des formats numériques utilisés en machine entraîne des difficultés supplémentaires pour la conception de filtres numériques (le traitement audio et le traitement d'images sont deux domaines qui utilisent beaucoup le filtrage). La majorité des outils actuels de conception de filtres ne sont pas optimisés et ne certifient pas non plus la correction de leurs résultats. Notre travail se veut un premier pas vers un changement de cette situation.La première partie de la thèse traite de l'étude et du développement de méthodes relevant de la famille Remez/Parks-McClellan pour la résolution de problèmes d'approximation polynomiale de type Chebyshev, en utilisant l'arithmétique virgule-flottante.Ces approches sont très robustes, tant du point de vue du passage à l'échelle que de la qualité numérique, pour l'élaboration de filtres à réponse impulsionnelle finie (RIF).Cela dit, dans le cas des systèmes embarqués par exemple, le format des coefficients du filtre qu'on utilise en pratique est beaucoup plus petit que les formats virgule flottante standard et d'autres approches deviennent nécessaires.Nous proposons une méthode (quasi-)optimale pour traîter ce cas. Elle s'appuie sur l'algorithme LLL et permet de traiter des problèmes de taille bien supérieure à ceux que peuvent traiter les approches exactes. Le résultat est ensuite utilisé dans une couche logicielle qui permet la synthèse de filtres RIF pour des circuits de type FPGA.Les résultats que nous obtenons en sortie sont efficaces en termes de consommation d'énergie et précis. Nous terminons en présentant une étude en cours sur les algorithmes de type Remez pour l'approximation rationnelle. Ce type d'approches peut être utilisé pour construire des filtres à réponse impulsionnelle infinie (RII) par exemple. Nous examinons les difficultés qui limitent leur utilisation en pratique. / The field of signal processing methods and applications frequentlyrelies on powerful results from numerical approximation. One suchexample, at the core of this thesis, is the use of Chebyshev approximationmethods for designing digital filters.In practice, the finite nature of numerical representations adds an extralayer of difficulty to the design problems we wish to address using digitalfilters (audio and image processing being two domains which rely heavilyon filtering operations). Most of the current mainstream tools for thisjob are neither optimized, nor do they provide certificates of correctness.We wish to change this, with some of the groundwork being laid by thepresent work.The first part of the thesis deals with the study and development ofRemez/Parks-McClellan-type methods for solving weighted polynomialapproximation problems in floating-point arithmetic. They are veryscalable and numerically accurate in addressing finite impulse response(FIR) design problems. However, in embedded and power hungry settings,the format of the filter coefficients uses a small number of bits andother methods are needed. We propose a (quasi-)optimal approach basedon the LLL algorithm which is more tractable than exact approaches.We then proceed to integrate these aforementioned tools in a softwarestack for FIR filter synthesis on FPGA targets. The results obtainedare both resource consumption efficient and possess guaranteed accuracyproperties. In the end, we present an ongoing study on Remez-type algorithmsfor rational approximation problems (which can be used for infinite impulseresponse (IIR) filter design) and the difficulties hindering their robustness.

Tee PhD thesis presents the study of the response of Mycobacterium tuberculosis, the causative agent of tuberculosis, upon prolonged exposure to lethal concentrations of the first line anti-tuberculosis drug, rifampicin. The study shows that prolonged exposure to lethal concentration of rifampicin causes cell death initially by several log orders of cells, followed by a persistence phase, from where rifampicin resisters emerge carrying mutation in the RRDR locus of the rpoB gene. This phenomenon was found to occur even when the drug concentration is well above MBC levels. Luria-Delbruck experiment, in a modified format, showed that the resisters emerged as fresh mutants, and not due to the growth of pre-existing natural resisters to rifampicin. The per sister cells, which showed high levels of hydroxyl radical generation, were found to have thickened outer layer, unlike the mid-log phase cells, which restricts the permeability of a fluorescent-conjugate of rifampicin, 5-FAM-rifampicin, 10-fold less in per sister cells, as compared to mid-log phase cells. The thickened outer layer has high negative surface charge and is hydrophilic in nature. It is proposed that the hydrophilic-natured thickened outer layer might have restricted the permeability of lethal concentrations of hydrophobic-natured rifampicin. This, in turn, might have ensured the presence of sub-lethal concentration rifampicin inside the per sisters, which in turn might have generated the hydroxyl radical that caused mutagenesis to generate rifampicin resisters. The Chapter 1 is the Introduction to the thesis presented in 4 parts – Part 1.1, 1.2, 1.3 and 1.4, introducing briefly the history of antibiotics, antibiotic resistance, antibiotic persistence and a brief history of tuberculosis respectively. It is concluded with a rationale behind the present study. The Chapter 2 presents the entire Materials and Methods used in the experiments described in the thesis. The Chapter 3 presents the data on the response of M. tuberculosis to rifampicin upon extended exposure. Rifampicin exposure of susceptible M. tuberculosis H37Ra cells showed a decrease in their CFU/ml followed by a persistence phase wherein the CFU/ml remained constant. However, prolonged exposure of rifampicin even at higher concentrations showed regrowth in the culture, which was found to be due to the emergence of rifampicin-resistant bacteria. Screening of rifampicin-resistant mutants showed point mutations in the rifampicin resistance determining region (RRDR) of the rpoB gene in all the mutants. In parallel, using trans formants of M. tuberculosis expressing unstable GFP under the respective native ribosomal RNA promoter, the metabolic status of the per sister cells was determined. When actively growing highly fluorescing cells were exposed to lethal concentration of rifampicin, their metabolism diminished, as illustrated by the decrease in their fluorescence during persistence phase, followed by the emergence of a sub-population of bacteria which were again metabolically active. In order to verify whether the rifampicin resisters are freshly formed mutants or have come from the naturally existing resisters, Luria-Delbruck fluctuation test was performed in a modified manner. The number of rifampicin resisters that emerged from the persistent phase was found to vary amongst different cultures from different days and different times of exposure, showing fluctuation. However, the addition of theorem before persistence phase almost abolished the generation of the rifampicin-resistant bacilli, indicating the role of hydroxyl radical in the emergence of rifampicin resisters. The generation of hydroxyl radical in mycobacteria exposed to rifampicin was confirmed using electron para-magnetic resonance spectrometry (EPR), with the spin trap agent, 5,5- Dimethyl-1-pyrroline N-oxide (DMPO) specific for hydroxyl radical. An increase in the formation DMPO-OH adduct in the persistence phase cells was observed, in comparison to mid-log phase cells. Exposure to theorem significantly diminished the adduct formation. The persistence phase cells also showed significantly high levels of signal specific to the hydroxyl-specific fluorescent dye, hydroxyphenyl fluorescein (HPF), as compared to the mid-log phase cells. In addition we have determined the oxidative stress in the bacilli upon rifampicin exposure using a redox biosensor (Mrx1-roGFP) which also showed high oxidative stress in the persistent phase. These observations confirmed the presence of high levels of oxidative stress and hydroxyl radical in the rifampicin persistent cells, in comparison with mid-log phase cells. Whole genome sequencing of the four independently isolated rifampicin resistant M. tuberculosis showed genome wide mutations having less common mutations with respect to the wild type genome, indicative of the occurrence of random mutagenesis. In addition mutation frequencies were comparable between the samples with respect to the wild type sample. About 69% of the mutations were A-C or T-G, followed by A-T or T-A, which is known to be due to oxidative stress in the cells. Variations in the colony morphology were also observed on the persistent phase cells, indicating the occurrence of mutagenesis in the bacterial genome during rifampicin treatment. The Chapter 4 is on the morphological and ultrastructural studies on rifampicin-exposed M. tuberculosis cells. Transmission electron micrographs of rifampicin per sisters showed significant thickening of the outermost capsular layer (OL), as compared to the mid-log phase cells. This observation was verified by staining the cells with ruthenium red, which specifically stains anionic polysaccharide of the OL. Zeta potential (ZP) measurement of the surface charge of the persistent cells showed high negative ZP, as compared to the mid-log phase cells. The negative ZP value was found to gradually increase during the course of rifampicin treatment and to decrease during the regrowth phase. Hexadecane assay showed larger proportion of per sister cells being retained in the aqueous phase, as compared to the mid-log phase cells. This indicated the higher hydrophilicity of the per sister cells, which was in agreement with the higher surface negative charge of the cells. The permeability of rifampicin per sister cells to 5-FAM-rifampicin (rifampicin conjugated to 5-carboxy fluorescein, which is as hydrophobic as rifampicin) was found to be 10-fold less than that of the mid-log phase cells. However, removal of the thick OL by bead beating (BB) with 4 mm glass beads significantly improved the permeability of per sister cells to 5-FAM-rifampicin. On the contrary, no difference in the 5-FAM-rifampicin uptake was observed in mid-log phase cells, with or without BB. These observations implied that the thick hydrophilic-natured OL with high negative surface charge may be playing a significant role in limiting the permeability of hydrophobic-natured rifampicin entry into the persisted cells. This in turn may ensure the presence of sub-lethal concentration of rifampicin inside the persisted cells that are exposed to lethal concentration of the antibiotic. Exposure of bacteria to sub-lethal concentration of antibiotics has been reported to generate oxidative stress in the bacteria, leading to mutagenesis. A model has been proposed based on these observations in which the persistent mycobacteria are protected from lethal concentrations of the rifampicin by the thick OL which in turn ensures sub-lethal intracellular antibiotic concentration, leading to the generation of hydroxyl radical mediated mutagenesis and thereby emergence of rifampicin resisters. This thesis is concluded with the list of salient findings, publications and references.

Yes / Background: Tuberculosis (TB) is the highest-mortality infectious disease in the world and the main cause of death related to antimicrobial resistance, yet its surveillance is still paper-based. Rifampicin-resistant TB (RR-TB) is an urgent public health crisis. The World Health Organization has, since 2010, endorsed a series of rapid diagnostic tests (RDTs) that enable rapid detection of drug-resistant strains and produce large volumes of data. In parallel, most high-burden countries have adopted connectivity solutions that allow linking of diagnostics, real-time capture, and shared repository of these test results. However, these connected diagnostics and readily available test results are not used to their full capacity, as we have yet to capitalize on fully understanding the relationship between test results and specific rpoB mutations to elucidate its potential application to real-time surveillance. Objective: We aimed to validate and analyze RDT data in detail, and propose the potential use of connected diagnostics and associated test results for real-time evaluation of RR-TB transmission. Methods: We selected 107 RR-TB strains harboring 34 unique rpoB mutations, including 30 within the rifampicin resistance–determining region (RRDR), from the Belgian Coordinated Collections of Microorganisms, Antwerp, Belgium. We subjected these strains to Xpert MTB/RIF, GenoType MTBDRplus v2.0, and Genoscholar NTM + MDRTB II, the results of which were validated against the strains’ available rpoB gene sequences. We determined the reproducibility of the results, analyzed and visualized the probe reactions, and proposed these for potential use in evaluating transmission. Results: The RDT probe reactions detected most RRDR mutations tested, although we found a few critical discrepancies between observed results and manufacturers’ claims. Based on published frequencies of probe reactions and RRDR mutations, we found specific probe reactions with high potential use in transmission studies: Xpert MTB/RIF probes A, Bdelayed, C, and Edelayed; Genotype MTBDRplus v2.0 WT2, WT5, and WT6; and Genoscholar NTM + MDRTB II S1 and S3. Inspection of probe reactions of disputed mutations may potentially resolve discordance between genotypic and phenotypic test results. Conclusions: We propose a novel approach for potential real-time detection of RR-TB transmission through fully using digitally linked TB diagnostics and shared repository of test results. To our knowledge, this is the first pragmatic and scalable work in response to the consensus of world-renowned TB experts in 2016 on the potential of diagnostic connectivity to accelerate efforts to eliminate TB. This is evidenced by the ability of our proposed approach to facilitate comparison of probe reactions between different RDTs used in the same setting. Integrating this proposed approach as a plug-in module to a connectivity platform will increase usefulness of connected TB diagnostics for RR-TB outbreak detection through real-time investigation of suspected RR-TB transmission cases based on epidemiologic linking. / KCN was supported by Erasmus Mundus Joint Doctorate Fellowship grant 2016-1346, and BCdJ, LR, and CJM were supported by European Research Council-INTERRUPTB starting grant 311725.