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Detection of enzyme activity has gained popularity in molecular imaging because increased activity of enzymes such as urokinase plasminogen activator (uPA) can serve as biomarkers and assist in cancer diagnosis. Chemical exchange saturation transfer (CEST) Magnetic Resonance Imaging (MRI) is a non-invasive technique that can be utilized to detect enzyme activity; however, CEST MRI is not the only technique that can assess enzyme activity. Chapter 1 provides an overview of various imaging modalities that have been used to detect enzyme activity in vivo. Advances made in probe-design are discussed, in addition to advantages and disadvantages of each technique. Chapter 2 focuses on detection of uPA activity in a pancreatic cancer tumor model using a catalyCEST MRI contrast agent. Chapter 2 also discusses the importance of uPA in tumor biology, addresses the synthesis of the contrast agent, and evaluates the results of in vivo detection and ex vivo validation of uPA activity in response to therapy of pancreatic tumor models of Capan-2. The in vivo and ex vivo results showed no significant difference in uPA activity between chemotherapy-treated and non-treated mice. Additionally, no significant difference was observed between before and after chemotherapy-treated groups. Chapter 3 addresses some of the limitations of the study detailed in Chapter 2 and proposes improvements.

We propose a novel 3D navigation system for autonomous vehicle path-planning. The system processes a point-cloud data from an rgb-d camera and creates a 3D occupancy grid with adaptable cell size. Occupied grid cells contain normal distribution characterizing the data measured in the area of the cell. The normal distributions are then used for cell classification, traversability and collision checking. The space of traversable cells is then used for path-planning. The ability to work in three-dimensional space allows the usage of autonomous robots in highly structured environments with multiple levels, uneven surface or various elevated and underground crossings. That is important for the usage of robots in real- world scenarios, in urban areas or for disaster rescue missions. Powered by TCPDF (www.tcpdf.org)

MRI is a powerful imaging method that offers several advantages including non-ionizing radiation, significant depth of penetration, and great spatial resolution. Current demand for precision medicine and the movement toward personalized medicine have encouraged researchers in the field of medical imaging to develop MRI-based techniques. Various techniques are now available for molecular imaging by MRI. MRI started by utilizing T1 relaxation properties of molecules but soon after other relaxation mechanisms such as T2 and recently Chemical Exchange Saturation Transfer (CEST) were developed. Each of those MRI techniques offers advantages and disadvantages such as differences in experimental procedures, complexity of the method, selectivity and specificity of signals, and translation into clinical applications. We have been developing MRI techniques and responsive contrast agents for CEST MRI in the Pagel laboratory (Contrast Agent and Molecular Imaging Laboratory, also called CAMEL) for the past decade. We have mainly utilized MRI techniques and responsive contrast agents to detect and measure cancer biomarkers. Detection of the activity of enzymes and measurement of pH have been our main focus, and we have developed catalyCEST MRI probes and techniques for the detection of the activity of enzymes and acidoCEST for the measurement of pH. My research started with investigation on paramagnetic agents as potential CEST MRI probes (paraCEST) and continued with an investigation on diamagnetic agents (diaCEST). I completed several projects in which I prepared and evaluated paraCEST and diaCEST contrast agents for the detection of DT-diaphorase, and alkaline phosphatase enzymes, respectively. Although CEST MRI was my main activity in CAMEL, I started a new direction in CAMEL after encountering a series of observations that were unexplainable with CEST MRI. Through my research, I introduced a new class of responsive contrast agents based on the T2-Exchange (T2-Ex) relaxation mechanism. I employed the T2-Ex mechanism to evaluate responsive contrast agents for the detection of nitric oxide biomolecule and nitroreductase enzyme. My research activities in the CAMEL group resulted in one review paper, one book chapter, two published research articles, and two submitted research manuscripts at the time of preparing my PhD dissertation. In addition to my projects, I was involved in another project that focused on nanocapsule drug delivery, which resulted in a second author publication.

This thesis is concerned with the problem of planning paths for autonomous cars through a smart traffic intersection. In this thesis, we describe existing concepts for solving this problem and discuss the possibilities of approaching intersection problems theoretically. Then, we choose one specific approach and design a declarative model for solving the problem. We use that model to perform a series of theoretical experiments to test the throughput and the quality of intersection paths described by different graphs. After that, we translate theoretical plans to actions for real robots and run it. In these experiments, we measure the degree of robots desynchronization and performance success of the plans based on the collision rate. We also describe how to improve action translation to achieve better performance than that for real robots following the straightforward plans.

Cuba’s government has set a goal to generate 24 percent of the country’s electricity from renewable sources by 2030. The country’s many sugar mills have been identified as key contributors to reach this goal as their cogeneration units have the potential to significantly increase Cuba’s electricity production from biomass by upgrading them to bioelectric plants. This study evaluates the feasibility of upgrading the cogeneration unit of George Washington sugar mill in the province of Villa Clara, Cuba. An energy balance of the proposed upgraded scheme is done to deduce its feasibility from an energy perspective. To deduce the project’s feasibility from a financial standpoint its net present value (NPV), internal rate of return (IRR), discounted payback period (DPP) and levelized cost of energy (LCOE) are calculated. The spared CO2 emissions by integrating more biopower in the Cuban electricity system are calculated from the avoided burning of diesel for electricity production. The impact on Cuba’s energy independence is quantified by calculating the avoided diesel imports. The NPV of the proposed scheme is 64.9 MUSD, the IRR is 25.6 percent which is significantly higher than the set discount rate of 6.5 percent, the DPP is 5.3 years and the LCOE is 0.0533 USD/kWh which is lower than the maximum LCOE set by AZCUBA to 0.14 USD/kWh. The avoided CO2 emissions and imported diesel are estimated to be 110,173 tonnes CO2 and 36,724 tonnes diesel each year, respectively. These indicators suggest that the upgrade of George Washington’s cogeneration unit is feasible.​ / Kubas regering har satt som mål att generera 24 procent av landets elektricitet från förnyelsebara källor till år 2030. Landets många sockerbruk har identifierats som nyckelaktörer för att nå detta mål då sockerbrukens kraftvärmeenhet har potential att öka Kubas elproduktion från biomassa genom att uppgradera dem till bioelektriska kraftverk. Denna studie utvärderar möjligheten att uppgradera kraftvärmeenheten på sockerbruket George Washington i provinsen Villa Clara, Kuba. Först görs en energibalans på det föreslagna uppgraderade systemet för att utläsa dess genomförbarhet ur ett energiperspektiv. För att utvärdera projektets genomförbarhet ur ett finansiellt perspektiv beräknas investeringens nettonuvärde (NPV), interna avkastningsgrad (IRR), diskonterade återbetalningstid (DPP) och energiproduktionskostnad (LCOE). De undvikta CO2 utsläppen genom integrering av mer biokraft i det kubanska elsystemet beräknas från den uteblivna förbränningen av diesel för elproduktion i landet. Effekterna på Kubas energioberoende kvantifieras genom att man beräknar den minskade dieselimporten. NPV i det föreslagna uppgraderade systemet är 64,9 MUSD, IRR är 25,6 procent vilket är betydligt högre än den fastställda diskonteringsräntan på 6,5 procent, DPP är 5,3 år och LCOE är 0,0533 USD/kWh vilket är lägre än det maximala LCOE som fastställts av AZCUBA till 0,14 USD/kWh. De uteblivna CO2-utsläppen och minskningen av importerad diesel beräknas uppgå till 110 173 ton CO2 respektive 36 724 ton diesel varje år. Dessa indikatorer tyder på att uppgraderingen av George Washingtons kraftvärmeenhet är genomförbar.​

L’effet des composés paramagnétiques sur le déplacement chimique des protons, c’est-à-dire sur leur fréquence de résonance propre, beaucoup utilisé en RMN conventionnelle, peut également être un outil de contraste en Imagerie par Résonance Magnétique (IRM) pour réaliser des images encodées en fréquence et donc sélectives selon la nature ou l’environnement de l’entité que l’on cherche à révéler. Cette approche fait intervenir le transfert d’aimantation par échange chimique de protons mobiles, en anglais « Chemical Exchange Saturation Transfer » (CEST). Le principe consiste à saturer sélectivement un signal donné de protons labiles appartenant à la structure-même de l’agent de contraste ou aux molécules d’eau qui lui sont transitoirement liées, à l’aide d’une impulsion radiofréquence bien choisie. L’image résulte alors de l’altération du signal des protons échangés. Le fonctionnement de la méthode repose sur l’existence effective de deux ensembles ou réservoirs de protons, celui correspondant aux protons associés à l’agent de contraste et celui représenté par le milieu environnant, autrement dit l’eau des tissus, ces deux réservoirs présentant une fréquence de résonance bien distincte. Les systèmes LipoCEST, liposomes encapsulant un complexe paramagnétique de lanthanide, permettent une telle différenciation de deux réservoirs de protons constitutifs d’une part de l’eau contenue dans la cavité interne des liposomes (dont la fréquence de résonance est modifiée par l’agent paramagnétique) et d’autre part de l’eau présente à l’extérieur de la structure. La sensibilité de tels systèmes est principalement due au grand nombre de protons contenus dans le réservoir interne. La nature de l’agent paramagnétique joue un rôle déterminant dans la sélectivité de l’effet CEST et la nature de la membrane des liposomes dont la perméabilité permet un échange plus ou moins rapide entre les deux réservoirs d’eau doit être sélectionnée de manière à conduire à une réponse CEST efficace.Les travaux réalisés au cours de cette thèse portent sur une telle mise au point avec pour objectif l’optimisation de systèmes destinés à une IRM-CEST après administration par voie intraveineuse. De ce fait, le diamètre des liposomes a été fixé inférieur à 200 nm et leur surface recouverte de chaînes de poly(éthylène glycol) pour assurer leur future stabilité dans le compartiment sanguin. Le choix des agents de déplacement chimique à centre lanthanide, principalement des complexes de thulium, a été fixé à partir de leurs propriétés structurales et magnétiques. La méthodologie spécialement développée pour encapsuler ces entités au sein de liposomes de compositions lipidiques induisant des perméabilités membranaires distinctes a permis la mise au point d’un nouvel agent de contraste LipoCEST. / The effect of paramagnetic compounds in the chemical shift of endogenous protons, i.e., their resonance frequency, widely used in conventional NMR, can also be a tool to modulate the contrast in magnetic resonance imaging (MRI) by achieving frequency-encoded images depending on the nature or the environment of the entity or tissue to be revealed. This approach involves the transfer of magnetization by chemical exchange of protons also referred to as "Chemical Exchange Saturation Transfer" (CEST). The principle consists in selectively saturate by applying a radio frequency pulse, the signal of labile protons transiently belonging to the structure of the contrast agent or to the water molecules which are associated transiently to it. The image then results from the alteration of the signal of the exchanged protons. The method is based on the actual existence of two sets of protons or pools with two distinct resonance frequencies, one corresponding to the protons associated with the contrast agent and the other represented by the surrounding bulk water.LipoCEST systems, liposomes encapsulating a paramagnetic lanthanide complex, allows such a differentiation of two proton pools constituted on one hand by the water molecules contained in the inner cavity of the liposomes (with a resonance frequency changed by the paramagnetic agent ) and on the other hand by the water present outside the vesicle structure. The sensitivity of such systems is mainly due to the large number of protons in the inner pool. The nature of the paramagnetic agent plays a role in the selectivity of the CEST effect while the nature of the liposome membrane and related permeability behavior controls the proton exchange kinetics between the two water pools. These two parameters must be selected and adjusted to provide effective CEST contrast.The work in this thesis aimed at such a development by optimizing liposome systems for MRI-CEST after intravenous administration. Therefore, the diameter of the liposomes was set below 200 nm and their surface covered by chains of poly (ethylene glycol) to ensure stability in the blood compartment. The choice of chemical shift agents based on lanthanide complexes, mainly thulium-based derivatives, was established from their structural and magnetic properties. The methodology specially developed to encapsulate these entities into vesicles of different membrane composition and permeability to water allowed to generate a new LipoCEST contrast agent.

L’objectif de cette thèse est de développer l’imagerie de transfert de saturation des agents de contraste lipoCEST pour la détection de l’angiogenèse dans un modèle souris de tumeur cérébrale U87. Un lipoCEST offrant un seuil de sensibilité in vitro de 100 pM est optimisé afin de répondre aux contraintes de l’imagerie CEST in vivo. Grâce à la mise en place d’un dispositif expérimental dédié à l’imagerie CEST, nous évaluons les performances des lipoCEST pour détecter de façon spécifique l’angiogenèse tumorale. Nous montrons pour la première fois qu’il est possible de détecter un lipoCEST in vivo dans un cerveau de souris suite à une injection intraveineuse. De plus, l’utilisation d’un lipoCEST fonctionnalisé avec un peptide RGD permet de cibler spécifiquement l’intégrine ανβ3 surexprimée lors de l’angiogenèse tumorale. L’association spécifique du RGD-lipoCEST est confirmée grâce à des données d’immunohistochimie et de microscopie de fluorescence. Enfin, dans le but de tendre vers un protocole d’imagerie moléculaire par IRM-CEST, nous mettons en place un outil de quantification des lipoCEST. Cet outil repose sur la modélisation des processus d’échange de protons in vivo. Grâce à la prise en compte des inhomogénéités de champs B0 et B1 qui peuvent se révélées être délétères pour le contraste CEST, nous démontrons que la précision de notre outil de quantification est de 300 pM in vitro. La quantification des données CEST acquises chez la souris U87 permet d’estimer à 1,8 nM la concentration maximale en RGD-lipoCEST liés à leur cible moléculaire. / The study aimed at developing saturation transfer imaging of lipoCEST contrast agents for the detection of angiogenesis in a U87 mouse brain tumor model. A lipoCEST with a sensitivity threshold of 100 pM in vitro was optimized in order to make it compatible with CEST imaging in vivo. Thanks to the development of an experimental setup dedicated to CEST imaging, we evaluated lipoCEST to detect specifically tumor angiogenesis. We demonstrated for the first time that lipoCEST visualization was feasible in vivo in a mouse brain after intravenous injection. Moreover, the integrin ανβ3 overexpressed during tumor angiogenesis can be specifically targeted using a functionalized lipoCEST with RGD peptide. The specific association between the RGD-lipoCEST and its target ανβ3 was confirmed by immunohistochemical data and fluorescence microscopy. Finally, in order to tend to a molecular imaging protocol by CEST-MRI, we developed a quantification tool of lipoCEST contrast agents. This tool is based on modeling of proton exchange processes in vivo. By taking into account both B0 and B1 fields inhomogeneities which can dramatically alter CEST contrast, we showed that the accuracy of our quantification tool was 300 pM in vitro. The tool was applied on in vivo data acquired on the U87 mouse model and the maximum concentration of RGD-lipoCEST linked to their molecular targets was evaluated to 1.8 nM.

Presented master thesis defines and investigates Adversarial Cooperative Path-finding problem (ACPF), a generalization of standard Cooperative Path-finding. In addition to the Cooperative path- finding where non-colliding paths for multiple agents connecting their initial positions and destinations are searched, consideration of agents controlled by the adversary is included in ACPF. This work is focused on both theoretical properties and practical solving techniques of the considered problem. ACPF is introduced formally using terms from graph theory. We study computational complexity of the problem where we show that the problem is PSPACE-hard and belongs to EXPTIME complexity class. We introduce and discuss possible methods suitable for practical solving of the problem. Considered solving approaches include greedy algorithms, minimax methods, Monte Carlo Tree Search and adaptation of algorithm for the cooperative version of the problem. Surprisingly frequent success rate of greedy methods and rather weaker results of Monte Carlo Tree Search are indicated by the conducted experimental evaluation. Powered by TCPDF (www.tcpdf.org)