The current epidemic of obesity has been linked to an increase in fat intake associated with the Western diet. Nutrient-induced stimulation of enteroendocrine cells in the small intestine leads to the release of hormones that contribute to satiety and the control of food intake. In particular, ingested fat, specifically in the form of free fatty acids, is potent activator of enteroendocrine cells in the proximal small intestine. However, the underlying signaling cascade that free fatty acids initiate in these enteroendocrine cells, which leads to secretion of satiety hormones, is not known. In general, my research is focused on identifying nutrient-responsive pathways in enteroendocrine cells involved with the release of satiety signals and using this information to begin to develop novel drug delivery strategies to reduce food intake. In general, my results revealed that activation of the fatty acid receptor GPR120 was ecessary for the linoleic acid-induced intracellular calcium rise, a necessary precursor for hormone release. Using patch clamp recording, I discovered that linoleic acid activated enteroendocrine cells by inducing membrane depolarization, a process requiring the calcium-activated, monovalent cation permeable channel TRPM5, which is activated downstream of GPR120. To validate the unexpected finding that TRPM5 was involved in fattyacid signaling, I performed experiments using bitter compounds, whose transduction pathway is known to involve TRPM5. Enteroendocrine cells express the bitter taste receptors and release cholecystokinin in response to bitter stimuli, suggesting the probable role of gut in initiation of protective behavior against ingestion of potentially harmful substances. Armed with the data on the specifics of the fatty acid transduction, I performed experiments using nanoparticles to determine their utility for delivering pharmaceuticals specifically to the enteroendocrine cells. I fabricated and characterized PLGA nanoparticles and performed intracellular uptake studies in order to optimally delivery payloads inside cells. Finally, I validated their use by using cell-based assays to determine the effects of internalized PLGA nanoparticles on ion channels and signaling pathways involved in CCK release. Taken together, this dissertation research has identified the signaling pathways (pharmacological targets) involved in fatty acid-mediated satiety hormone release and validated the potential therapeutic use of nanoparticle-mediated drug delivery for the eventual control of food intake.

L’intérêt croissant pour les matériaux biosourcés dans le domaine de la construction se heurte à des difficultés quant à la simulation de leur comportement hygrothermique. En particulier, les matériaux isolants tels que les panneaux de fibres concentrent toutes les difficultés car ils sont peu conducteurs thermiquement, très hygroscopiques et très diffusifs à la vapeur d’eau. Conséquemment, en régime transitoire le couplage chaleur masse est exacerbé et les phases de l’eau ne sont pas à l’équilibre localement.Afin de mettre en évidence ce second phénomène, un nouveau dispositif expérimental a été développé. Il permet de soumettre un échantillon de quelques centimètres d’épaisseur à une perturbation de l’humidité relative sur sa face avant puis de mesurer simultanément l’évolution de l’humidité relative sur sa face arrière et de sa masse. En situation de non-équilibre, il existe un déphasage entre ces deux grandeurs que la formulation de transferts couplés classique n’arrive pas à prédire. Afin d’obtenir une prédiction correcte, une nouvelle formulation a été utilisée. Celle-ci se base sur l’emploi de fonctions mémoires caractérisant la diffusion microscopique. De manière à démontrer la capacité prédictive de la nouvelle formulation, ces fonctions ont été déterminées avec des essais gravimétriques réalisés sur de très petits échantillons à l’aide d’une balance à suspension magnétique. En parallèle, une analyse rigoureuse du couplage chaleur masse dans ces matériaux a permis de souligner l’impact sur leur caractérisation de différents paramètres macroscopiques.L’utilisation de la nouvelle formulation alimentée par les fonctions mémoires et les différents paramètres macroscopiques permet une excellente prédiction de l’humidité relative et de la masse. Cette nouvelle formulation validée expérimentalement est désormais utilisable dans des logiciels de simulation énergétique du bâtiment. / The growing interest in biosourced materials in the construction sector is confronted with difficulties in simulating their hygrothermal behavior. Insulating materials such as fiberboard concentrate all the difficulties because they are not very thermally conductive, very hygroscopic and very diffusive to water vapor. Consequently, in transient state, heat and mass coupling is exacerbated, and the phases of water are not in equilibrium locally.In order to highlight this second phenomenon, a new experimental device has been developed. It allows to subject a sample a few centimeters thick to a disturbance of relative humidity on its front face and then to simultaneously measure the evolution of relative humidity on its back face and its mass. In a situation of non-equilibrium, there is a phase shift between these two quantities that the classic coupled transfer formulation cannot predict. In order to obtain a correct prediction, a new formulation was used. It is based on the use of memory functions characterizing microscopic diffusion. In order to demonstrate the predictive capacity of the new formulation, these functions have been determined with gravimetric tests performed on very small samples using a magnetic suspension balance. In parallel, a rigorous analysis of the heat and mass coupling in these materials made it possible to highlight the impact of different macroscopic parameters on their characterization.The use of the new formulation fed by the identified memory functions and the various macroscopic parameters allows an excellent prediction of relative humidity and mass. This new formulation, experimentally validated, can now be used in energy simulation of the building.

Dark current is an unwanted source of noise in images produced by digital imagers, the de facto standard of imaging. The two most common types of digital imager architectures, Charged-Coupled Devices (CCDs) and Complementary Metal-Oxide-Semiconductor (CMOS), are both prone to this noise source. To accurately reflect the information from light signals this noise must be removed. This practice is especially vital for scientific purposes such as in astronomical observations. Presented in this dissertation are characterizations of dark current sources that present complications to the traditional methods of correction. In particular, it is observed that pixels in both CCDs and CMOS image sensors produce dark current that is affected by the presence of pre-illuminating the sensor and that these same pixels produce a nonlinear dark current with respect to exposure time. These two characteristics are not conventionally accounted for as it is assumed that the dark current produced will be unaffected by charge accumulated from either illumination or the dark current itself. Additionally, a model reproducing these dark current characteristics is presented. The model incorporates a moving edge of the depletion region, where charge is accumulated, as well as fixed recombination-generation locations. Recombination-generation sites in the form of heavy metal impurities, or lattice defects, are commonly the source of dark current especially in the highest producing pixels, commonly called "hot pixels." The model predicts that pixels with recombination-generation sites near the edge of an empty depletion region will produce less dark current after accumulation of charge, accurately modeling the behavior observed from empirical sources. Finally, it is shown that activation energy calculations will produce inconsistent results for pixels with the presence of recombination-generation sites near the edge of a moving depletion region. Activation energies, an energy associated with the temperature dependence of dark current, are often calculated to characterize aspects of the dark current including types of impurities and sources of dark current. The model is shown to generate data, including changing activation energy values, that correspond with changing activation energy calculations in those pixels observed to be affected by pre-illumination and that produce inconsistent dark current over long exposure times. Rather than only being a complication to dark current correction, the presence of such pixels, and the model explaining their behavior, presents an opportunity to obtain information, such as the depth of these recombination-generation sites, which will aid in refining manufacturing processes for digital imagers.

Les micro-résonateurs à modes de galerie, qu'ils soient déclinés sous forme de disques, anneaux ou hippodromes, sont devenus les éléments constitutifs clés de nombreux composants photoniques de haute performance. Les réalisations exploitant les semiconducteurs III-V sont particulièrement attrayantes car elles ouvrent la possibilité d'intégrer conjointement des sections actives et passives et donc de diversifier les fonctionnalités sur une même puce photonique. Au niveau technologique, l'intégration verticale du résonateur au-dessus de ses guides d'accès permet de distribuer les fonctions actives et passives sur des plans distincts et de faciliter la réalisation des composants grâce à des procédés mieux maitrisés. Une technique de fabrication récemment introduite dans l'équipe et basée sur la filière AlGaAs/AlOx a ainsi permis de réaliser, à l'aide d'étapes simples, des micro-disques couplés verticalement à leur guide d'accès. Les performances de ces composants restent toutefois limitées en raison de leur architecture, complexifiée par les empilements multicouches qui les constituent.Les travaux de recherche menés au cours de cette thèse ont porté sur la faisabilité d'émettre un peigne de fréquences optiques à partir de ces résonateurs. Pour cela, les composants doivent être conçus de manière à présenter un facteur de qualité suffisamment élevé tout en maximisant la puissance circulant dans la cavité, afin de pouvoir déclencher les processus non-linéaires à la base de la génération du peigne. Pour un composant monomode transverse, la puissance intracavité est maximale lorsque le système opère en régime de couplage critique, c'est-à-dire lorsque les pertes internes à la cavité sont égales aux pertes externes (ou pertes par couplage). Nous avons donc développé un outil semi-analytique basé sur une expansion modale afin de réaliser une modélisation paramétrique large bande des performances des systèmes couplés verticalement, encore peu étudiés, tant au plan théorique que pratique. Notre modèle générique exploite la théorie des modes couplés (CMT) et les relations universelles régissant les propriétés spectrales des micro-résonateurs couplés. Nous l'avons étendu en étudiant l'influence spectrale de différents paramètres opto-géométriques sur la fonction de transfert de la cavité couplée et avons, en particulier, mis en évidence par une approche variationnelle, deux conditions théoriques permettant d'obtenir un régime critique achromatique lorsque la cavité et son guide d'accès sont désaccordés en phase. Ce modèle à d'abord été appliqué à la simulation de résonateurs en hippodromes exploitant la filière Si3N4/SiO2 car plusieurs études ont déjà démontré la génération de peignes avec cette plateforme technologique. Ces travaux ont abouti au dessin de structures désaccordées en phase et technologiquement réalisables dont la bande passante critique est augmentée d'un ordre de grandeur par rapport au cas plus répandu de guides accordés en phase. Nous avons ensuite initié une évaluation numérique de la génération de peignes de fréquences, basée sur la résolution itérative de l'équation de Schrödinger non-linéaire prenant en compte les variations des propriétés spectrales et dispersives de ces hippodromes. Le modèle générique a enfin été appliqué aux micro-disques AlGaAs/AlOx. Pour cela, nous avons introduit un critère permettant d'utiliser la CMT dans le cas de coupleurs asymétriques présentant une zone de séparation multicouche. Les résultats, en bon accord avec l'expérience, nous ont permis de mieux appréhender les limitations des dispositifs réalisés et de proposer de nouvelles structures pour en améliorer les performances. Le dessin d'une nouvelle structure AlGaAs/AlOx multicouche permettant d'améliorer les facteurs de qualité des résonateurs jusqu'à deux ordres de grandeurs a ainsi été proposé. La validation expérimentale des dessins proposés tant pour la filière Si3N4/SiO2 que AlGaAs/AlOx est en cours. / Whispering-gallery -mode micro-resonators, whether in the form of disks, rings or racetracks, have become the key building blocks of many high-performance photonic components. The embodiments exploiting the III-V semiconductors are particularly attractive for they open the possibility of integrating active and passive sections together and therefore diversify the functionalities on the same photonic chip. Furthermore, the vertical integration of the resonator above its access waveguide(s) makes it possible to distribute the active and passive functions on distinct planes and makes the realization of the components easier by using better-controlled methods. A fabrication technique recently introduced in the team and based on the AlGaAs / AlOx technological platform, allowed us to realize, by means of simple steps, vertically-coupled microdisks. The performance of these components, however, is limited due to their architecture, complicated by their constitutive multilayer stack. The research carried out during this PhD thesis focused on the feasibility of emitting an optical frequency comb from these resonators. For this purpose, the components must be designed so as to present a sufficiently high quality factor while maximizing the power circulating in the cavity in order to be able to trigger the non-linear processes required for the comb generation. For a transverse single-mode component, the intracavity power is maximal when the system operates in critical coupling regime, i.e .when the losses inside the cavity are equal to external losses (or coupling losses). As a first step, we have developed a semi-analytical tool based on a modal expansion in order to carry out a broadband parametric study of the performances of vertically coupled systems. Up to now, this coupling layout has indeed been little studied, both theoretically and practically. Our generic model, based on the coupled mode theory (CMT) and the universal relations governing the spectral properties of coupled micro-resonators, reveals two theoretical conditions for obtaining an achromatic critical-coupling regime when the cavity and its access waveguide are phase-mismatched. We first applied it to the simulation of single- mode racetrack resonators made of Si3N4 / SiO2 since several studies have already demonstrated comb generation using this technological platform. Our work resulted in the design of phase-mismatched and technologically feasible structures with critical-copuling bandwidths being increased by one order of magnitude compared to the reference case of phase- matched waveguides. We subsequently initiated a numerical evaluation of frequency comb generation, based on the iterative resolution of the non-linear Schrödinger equation taking into account the variations of the spectral and dispersive properties of these racetracks. The generic model has finally been applied to AlGaAs / AlOx microdisks. For this purpose, we have introduced a criterion allowing an unambiguous implementation of CMT in the case of asymmetric couplers having a multi-layer separation zone. The results, in good agreement with experimental data, allowed us to better understand the limitations of the fabricated devices and to propose new structures AlGaAs / AlOx with improved performances. The experimental validation of the proposed designs for both the Si3N4 / SiO2 and AlGaAs / AlOx components is currently in progress.

This thesis studies novel and efficient computational sampling methods for appli- cations in three types of stochastic inversion problems: seismic waveform inversion, filtering problems, and static parameter estimation. A primary goal of a large class of seismic inverse problems is to detect parameters that characterize an earthquake. We are interested to solve this task by analyzing the full displacement time series at a given set of seismographs, but approaching the full waveform inversion with the standard Monte Carlo (MC) method is prohibitively expensive. So we study tools that can make this computation feasible. As part of the inversion problem, we must evaluate the misfit between recorded and synthetic seismograms efficiently. We employ as misfit function the Wasserstein metric origi- nally suggested to measure the distance between probability distributions, which is becoming increasingly popular in seismic inversion. To compute the expected values of the misfits, we use a sampling algorithm called Multi-Level Monte Carlo (MLMC). MLMC performs most of the sampling at a coarse space-time resolution, with only a few corrections at finer scales, without compromising the overall accuracy. We further investigate the Wasserstein metric and MLMC method in the context of filtering problems for partially observed diffusions with observations at periodic time intervals. Particle filters can be enhanced by considering hierarchies of discretizations to reduce the computational effort to achieve a given tolerance. This methodology is called Multi-Level Particle Filter (MLPF). However, particle filters, and consequently MLPFs, suffer from particle ensemble collapse, which requires the implementation of a resampling step. We suggest for one-dimensional processes a resampling procedure based on optimal Wasserstein coupling. We show that it is beneficial in terms of computational costs compared to standard resampling procedures. Finally, we consider static parameter estimation for a class of continuous-time state-space models. Unbiasedness of the gradient of the log-likelihood is an important property for gradient ascent (descent) methods to ensure their convergence. We propose a novel unbiased estimator of the gradient of the log-likelihood based on a double-randomization scheme. We use this estimator in the stochastic gradient ascent method to recover unknown parameters of the dynamics.

Indiana University-Purdue University Indianapolis (IUPUI) / Glaucoma is a multi-factorial ocular disease associated with death of retinal ganglion cells and irreversible vision loss. Many risk factors contribute to glaucomatous damage, including elevated intraocular pressure (IOP), age, genetics, and other diseases such as diabetes and systemic hypertension. Interestingly, alterations in retinal hemodynamics have also been associated with glaucoma. A better understanding of the factors that contribute to these hemodynamic alterations could lead to improved and more appropriate clinical approaches to manage and hopefully treat glaucoma patients. In this thesis, we develop several mathematical models aimed at describing ocular hemodynamics and oxygenation in health and disease. Precisely we describe: (i) a time-dependent mathematical model for the retinal circulation that includes macrocirculation, microcirculation, phenomenological vascular regulation, and the mechanical effect of IOP on the retinal vasculature; (ii) a steady-state mathematical model for the retinal circulation that includes macrocirculation, microcirculation, mechanistic vascular regulation, the effect of IOP on the central retinal artery and central retinal vein, and the transport of oxygen in the retinal tissue using a Krogh cylinder type model; (iii) a steady-state mathematical model for the transport of oxygen in the retinal microcirculation and tissue based on a realistic retinal anatomy; and (iv) a steady-state mathematical model for the production and drainage of aqueous humor (AH). The main objective of this work is to study the relationship between IOP, systemic blood pressure, and the functionality of vascular autoregulation; the transport and exchange of oxygen in the retinal vasculature and tissue; and the production and drainage of AH, that contributes to the level of IOP. The models developed in this thesis predict that (i) the autoregulation plateau occurs for different values of IOP in hypertensive and normotensive patients. Thus, the level of blood pressure and functionality of autoregulation affect the changes in retinal hemodynamics caused by IOP and might explain the inconsistent outcomes of clinical studies; (ii) the metabolic and carbon dioxide mechanisms play a major role in the vascular regulation of the retina. Thus, the impairment of either of these mechanisms could cause ischemic damage to the retinal tissue; (iii) the multi-layer description of transport of oxygen in the retinal tissue accounts for the effect of the inner and outer retina, thereby improving the predictive ability of the model; (iv) a greater reduction in IOP is obtained if topical medications target AH production rather that AH drainage and if IOP-lowering medications are administrated to patients that exhibit a high initial level of IOP. Thus, the effectiveness of IOP-lowering medications depend on a patient’s value of IOP. In conclusion, the results of this thesis demonstrate that the insight provided by mathematical modeling alongside clinical studies can improve the understanding of diseases and potentially contribute to the clinical development of new treatments.

Indiana University-Purdue University Indianapolis (IUPUI) / Metabolic survival mechanisms that defend body weight and conserve energy are currently at odds with modernized society which has a food supply that is ubiquitous, calorie dense, and highly palatable. Chronic overnutrition leads to a metabolic syndrome of obesity, insulin resistance, inflammation, and cardiovascular diseases that is increasingly prevalent and threatens health on a global scale. The brain is both a victim and culprit of metabolic diseases, and prolonged metabolic dysfunction can exacerbate the pathological mechanisms underlying both metabolic and neurodegenerative diseases. Since neuroendocrine pathways comprise an essential feedback mechanism that detects circulating hormones and nutrients in order to regulate satiety, energy expenditure, and glucose homeostasis, our research goals were to characterize molecular mechanisms within neuroendocrine pathways that could be leveraged for treating obesity, diabetes, and Alzheimer’s disease. First, we identified the expression of a G protein-coupled receptor, Gpr17, in POMC neurons and discovered that it protects aged mice from high-fat diet (HFD)-induced metabolic derangements. We examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, Pomc-Cre-driven Gpr17 knockout (PGKO) mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Second, we generated a highly insulin resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in muscle, adipose, and GLUT4-expressing neuronal subpopulations. This genetic approach recapitulates the primary defect preceding type 2 diabetes (T2D) and revealed additional factors/mechanisms that drive the ultimate progression of overt diabetes. Third, we used 5xFAD mice as a model of Alzheimer’s disease and showed that they were more susceptible to HFD-induced metabolic dysregulation and expression of AD pathological markers in the hippocampus. Our results helped elucidate the molecular and cellular mechanisms responsible for increased AD pathology in high-fat diet-fed 5xFAD mice and suggest that metabolic dysfunctions are a therapeutic target to ameliorate AD pathology. In conclusion, metabolic diseases are pervasive and require nuanced approaches that target the neuroendocrine system in order to restore metabolic homeostasis and protect the brain from neurodegenerative processes that are associated with obesity and diabetes.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18241号 / 工博第3833号 / 新制||工||1587(附属図書館) / 31099 / 京都大学大学院工学研究科社会基盤工学専攻 / (主査)教授 木村 亮, 教授 三村 衛, 准教授 木元 小百合 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18283号 / 工博第3875号 / 新制||工||1594(附属図書館) / 31141 / 京都大学大学院工学研究科電子工学専攻 / (主査)教授 野田 進, 教授 川上 養一, 教授 藤田 静雄 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18990号 / 工博第4032号 / 新制||工||1621(附属図書館) / 31941 / 京都大学大学院工学研究科電気工学専攻 / (主査)教授 引原 隆士, 教授 北野 正雄, 准教授 山田 啓文 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM