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"This thesis presents technologies that integrate field programmable gate arrays (FPGAs), model-driven design tools, and software-defined radios (SDRs). Specifically, an assessment of current state-of-the-art practices applying model-driven development techniques targeting SDR systems is conducted. FPGAs have become increasingly versatile computing devices due to their size and resource enhancements, advanced core generation, partial reconfigurability, and system-on-a-chip (SoC) implementations. Although FPGAs possess relatively better performance per watt when compared to central processing units (CPUs) or graphics processing units (GPUs), FPGAs have been avoided due to long development cycles and higher implementation costs due to significant learning curves and low levels of abstraction associated with the hardware description languages (HDLs). This thesis conducts a performance assessment of SDR designs using both a model-driven design approach developed with Mathworks HDL Coder and a hand-optimized design approach created from the model-driven VHDL. Each design was implemented on the FPGA fabric of a Zynq-7000 SoC, using a Zedboard evaluation platform for hardware verification. Furthermore, a set of guidelines and best practices for applying model-driven design techniques toward the development of SDR systems using HDL Coder is presented."

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Prevention of macrophage apoptosis in advanced atherosclerotic lesions can help stop atherosclerosis progression to vulnerable plaques. High density lipoprotein (HDL) can protect macrophages from apoptosis that has been induced by a variety of agents. We hypothesize that this is the consequence of the sphingolipid, sphingosine-1-phosphate (S1P), specifically carried by HDL, and transferred to S1P receptor 1 (S1P1) on the cells via the HDL receptor, scavenger receptor class B type 1 (SR-B1). Apoptosis was induced in murine peritoneal macrophages from wild type and different knockout mice with, tunicamycin, thapsigargin, staurosporine, or UV irradiation. Apoptosis was measured by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) or with cleaved caspase-3 (CC3) staining. Treatment of cells with HDL or S1P protected them against apoptosis induced by a variety of stimuli. In contrast, pre-treatment of HDL with S1P lyase, which irreversibly cleaves S1P, eliminated the ability of HDL to protect macrophages. Inhibition of SR-B1’s lipid transport activity reduced HDL dependant protection against apoptosis. Furthermore, HDL dependent protection against apoptosis induced by tunicamycin was prevented when the S1P receptor S1P1 was knocked out. However, this protection was not prevented when apoptosis was induced by staurosporine. These results suggest that the HDL mediated protection of macrophages against apoptosis is multi-faceted and one approach may involve SR-B1 mediated delivery of S1P from HDL to the S1P1. Understanding the mechanisms by which HDL elicits atheroprotective signalling in macrophages will provide insight into new targets for therapeutic intervention in atherosclerotic disease. / Thesis / Master of Science in Medical Sciences (MSMS) / Atherosclerosis, is a disease where in the artery walls thicken due to cholesterol build-up, is the major underlying cause for cardiovascular diseases, which is currently a leading cause of death in many populations. We believe that HDL, the “good” cholesterol and S1P, a small molecule carried by HDL, can help prevent the progress of atherosclerosis by preventing macrophages, cells that absorb the cholesterol, from dying. We attempt to prove this by providing S1P or HDL to macrophages that are made to undergo cell death. Results show that both HDL and S1P can protect cells against cell death induced by many factors. However, HDL can protect against certain cell death inducing stimuli without the need for S1P and more research is required to fully understand HDL’s protective role in atherosclerosis. Understanding how HDL elicits atheroprotective signalling in macrophages will help in finding new drugs and therapies to reduce atherosclerosis-based deaths across the world.

Para que un fármaco ejerza un efecto clínico, debe actuar dentro de un margen terapéutico. Existen muchos fármacos que, por sus características químicas, poseen propiedades biofarmacéuticas inadecuadas, como baja solubilidad y permeabilidad. Para mejorar estas características y controlar que se mantengan dentro de los límites terapéuticos pueden utilizarse nanotransportadores. Los hidróxidos dobles laminares (HDL) son materiales prometedores para este tipo de aplicaciones. Su estructura deriva de la sustitución isomórfica de la brucita (Mg(OH)2), donde cierta cantidad de Mg es reemplazado por un metal trivalente, generando una carga estructural positiva en la lámina del HDL. Para mantener la neutralidad, estas cargas positivas son neutralizadas con aniones que se ubican entre las láminas de la estructura. Los HDL son representados por la siguiente fórmula: [M1-x2+ Mx3+ (OH)2] Ax/nn-.mH2O donde M2+ y M3+ son los iones divalentes y trivalentes respectivamente y An- es el anión interlaminar. Éste, puede ser un fármaco, el cual es intercalado en la estructura del HDL para neutralizar las cargas. Los HDL pueden sintetizarse por diferentes métodos: coprecipitación, reconstrucción e intercambio iónico. En este trabajo de tesis se sintetizaron complejos de diferentes fármacos como vancomicina, ciprofloxacina y valproato de sodio con un HDL a través de diferentes métodos. Las muestras sintetizadas fueron caracterizadas por diferentes técnicas para tener un abordaje integral, como difracción de rayos X, espectroscopia IR, microscopia electrónica de barrido y de transmisión, movilidad electroforética, entre otras. Los análisis demostraron la formación de la estructura del HDL en todos los casos, pero con algunas consideraciones en cuanto a la disposición de cada fármaco en esa estructura: la vancomicina y parte de la ciprofloxacina quedaron adsorbidas en la superficie externa y la parte restante de ciprofloxacina y el valproato de sodio lograron intercalarse dentro del HDL, ocupando las superficies internas de las partículas. Para la vancomicina se observan diferentes comportamientos cinéticos según el método de síntesis, donde la liberación del principio activo en la muestra obtenida por coprecipitación ocurre principalmente como consecuencia de la disolución de la estructura del HDL, fenómeno que no se observa en la muestra obtenida por reconstrucción. Para la muestra con ciprofloxacina se observa que a pH ácidos la liberación del fármaco se da por la disolución del HDL mientras que a valores de pH neutros-básicos depende del intercambio iónico o desorción de la droga del HDL. Y para el caso del sólido con valproato, la liberación del mismo depende exclusivamente del intercambio que se produce con los aniones presentes en la solución. Debido a la sensibilidad de los HDL en medios ácidos sería necesario algún tipo de recubrimiento entérico que los proteja de esa degradación. Es importante destacar algunas consideraciones respecto a las características fisicoquímicas que deben poseer los fármacos a la hora de seleccionarlos para su estudio con un HDL: • Deben ionizarse negativamente a los valores de pH de síntesis; • Deben ser estables y evitar su degradación en las condiciones de síntesis; • Mientras mayor sea la relación carga/tamaño de la molécula se lograrán mejores resultados con respecto al intercalado del fármaco. / Drugs must act within a therapeutic framework in order to exert a clinical effect. Many drugs possess inadequate biopharmaceutical properties, such as low solubility and permeability, due to their chemical characteristics. Nanocarriers can be employed to improve these characteristics and ensure that the drugs remain within therapeutic limits. Layered double hydroxides (LDHs) are promising materials for such applications. Their structure derives from the isomorphic substitution of brucite (Mg(OH)2), where a certain amount of Mg(II) is replaced by a trivalent metal, generating a positive structural charge in the LDH layer. To maintain neutrality, these positive charges are neutralized with anions located between the layers of the structure. LDHs can be represented by the following formula: [M1-x2+ Mx3+ (OH)2] Ax/nn-.mH2O where M2+ and M3+ are divalent and trivalent ions respectively and An- is the interlayer anion. The interlayer anion can be a drug, which is intercalated into the LDH structure to neutralize the positive charges. LDHs can be synthesized through different methods: coprecipitation, reconstruction, and ion exchange. In this thesis, complexes of different drugs such as vancomycin, ciprofloxacin, and sodium valproate were synthesized with an LDH using various methods. All synthesized samples were characterized using different techniques to obtain a comprehensive approach, including X-ray diffraction, IR spectroscopy, scanning electron microscopy, transmission electron microscopy, and electrophoretic mobility, among others. The analyses demonstrated the formation of the LDH structure in all cases, but with some differences regarding the arrangement of each drug within that structure: vancomycin and a portion of ciprofloxacin were adsorbed on the external surface, while the remaining part of ciprofloxacin and sodium valproate were successfully intercalated into the LDH, occupying the internal surfaces of the crystallites. Different kinetic behaviors were observed for vancomycin depending on the synthesis method, where the release of the active principle in the coprecipitation sample occurred mainly due to the dissolution of the LDH structure, a phenomenon not observed in the reconstruction sample. For the ciprofloxacin sample, drug release at acid pH was due to LDH dissolution, while at neutral to basic pH values, it depended on ion exchange or desorption of the drug from the LDH. In the case of the solid with valproate, its release depended exclusively on the exchange with the anions present in the solution. Due to the sensitivity of LDHs to acidic environments, some enteric coating would be necessary to protect them from degradation. It is important to highlight some considerations regarding the physicochemical characteristics that drugs must possess when selecting them for study with LDHs: • Drugs should ionize negatively at the pH values of synthesis. • They should be stable and avoid degradation under synthesis conditions. • Better results in terms of drug intercalation can be achieved with a higher charge-to-size ratio of the molecule of interest.

Conventional cancer therapies such as chemotherapy and radiation often lead to severe side effects since they are unable to specifically target the tumor. Additionally, they do not guarantee the prevention of metastasis or recurrence. Recent developments on small-molecule inhibitors, such as kinase inhibitors that target cellular pathways characteristically upregulated in cancer cells, show promise. However, significant challenges such as tolerance and mutations causing drug resistance need to be overcome. Immunotherapy, wherein the host's immune system is leveraged to recognize and target cancer cells, is a better alternative that shows reduced toxicity. Macrophages are an attractive target for immunotherapy seeing as they constitute 50% of the infiltrating leukocytes in the tumor microenvironment. Their plastic nature allows them to be modulated from pro-tumor to anti-tumor phenotype. Although, it does not work for everyone, necessitating a need to monitor response to medication at earlier time points. In this thesis, I have designed an HDL mimicking nanoparticle system to target tumor associated M2 macrophages through the SRB1 receptor. The nanoparticle was optimized for better stability, better loading of the targeting peptide, and the drug as well. It was used to deliver a CSF1R inhibitor drug to successfully repolarize pro-tumor M2 macrophages to anti-tumor M1 phenotype. In addition to that, it was also used to deliver an Arginase-responsive probe that only fluoresces when engulfed by arginase-producing M2 macrophages, differentiating them from arginase non-producing M1 phenotype. Through this study, the SRB1 receptor was successfully targeted to effectively deliver small molecules. This can be used to target and modulate tumor-associated macrophages.

Estudos clínicos e epidemiológicos indicam que baixas concentrações plasmáticas da lipoproteína de alta densidade (HDL) estão forte e independentemente associadas a uma maior incidência de doença arterial coronária (DAC). Entretanto, o insucesso dos agentes que são capazes de aumentar a concentração de HDL-C sugere que a funcionalidade da HDL pode representar um alvo terapêutico mais apropriado. Para a avaliação de um dos aspectos funcionais da HDL, o presente trabalho descreve o desenvolvimento de um método de grande praticidade que permite uma visão integrada de uma etapa fundamental do metabolismo que é a transferência de lípides entre as diferentes classes de lipoproteínas. A avaliação deste fenômeno nas subfrações de HDL, aspecto ainda não explorado, poderá fornecer novas informações a respeito da fisiopatologia da DAC. O método descrito no presente trabalho permite a avaliação da transferência simultânea das quatro principais classes lipídicas doadas por uma nanoemulsão semelhante à LDL para a HDL3. Foi realizada análise dos possíveis interferentes neste método. Verificou-se que a elevação da temperatura de 0 a 40 °C resultou em aumento progressivo na transferência de todos os lipídeos para a HDL3. A variação de pH entre 6,5 e 8,5 e o aumento na concentração de albumina não alteraram os valores de transferência. O aumento no tempo de incubação acima de 60 minutos promoveu diminuição na transferência de colesterol esterificado para a HDL3 e aumento na transferência de fosfolipídeos. O método apresentou boa precisão intra e inter-ensaio, sendo o coeficiente de variação menor que 5% para todos os lipídeos. A porcentagem média de transferência de colesterol livre, fosfolipídeos, triacilglicerol e colesterol em 45 invíduos saudáveis foi de respectivamente de 1,1±0,06; 13,5±0,15; 2±0,05 e 0,84±0,04% e em 45 portadores de doença arterial coronária foi respectimente 1,0±0,04; 15,8±0,44; 1,77±0,04 e 1,0±0,06%. Não houve diferença nos valores de idade, IMC, colesterol total, HDL-C, LDL-C, triacilglicerol, apo A-1, apo B, CETP, PLTP e LCAT, mas os indivíduos portadores de doença arterial coronária apresentaram valores maiores de colesterol livre e colesterol total em relação aos indivíduos saudáveis. O método desenvolvido no presente estudo é prático, preciso e de potencial relevância como ferramenta no estudo dos distúrbios de função da HDL.. / Clinical and epidemiological studies show that low concentrations of high density lipoproteins (HDL) are strongly and independently associated to an increased incidence of coronary artery disease (CAD). However, the lack of success of some drugs developed to increase HDL cholesterol concentrations (HDL-C) suggests that the functional aspects of HDL may represent a more appropriate therapeutic target. To study one of the functional aspects of HDL, the present work describes the development of a practical method that provides an integrated view of a fundamental step of lipid metabolism, namely, the lipid transfer among different lipoprotein classes. This phenomenon in the HDL subfractions is yet unexplored, and could provide new insights on the pathophysiology of CAD. The method described here allows the measurement of the ability of HDL3 to receive the major lipid classes from a radioactively labeled nanoparticle that resemble LDL. The possible interfering factors at the lipid transfer to HDL3 were studied. The increase in the assay temperature from 0 to 40 °C results in a progressive increase in the net transfer of all lipids to HDL3. The increase in incubation time above 60 minutes resulted in a reduced transfer of cholesterol esters to HDL3 with a concomitant increase in the transfer of phospholipids to the latter. The method presented adequate intra and inter-assay precision, with a coefficient of variation smaller than 5% for all lipids. The average percentage of free cholesterol, phospholipids, triacilglycerol an cholesterol transfer to HDL3 was respectively of 1,1±0,06; 13,5±0,15; 2±0,05 e 0,84±0,04% in 45 healthy individuals and 1,0±0,04; 15,8±0,44; 1,77±0,04 e 1,0±0,06% in 45 CAD patients. There was no difference in the age, BMI, total cholesterol, HDL-C, LDL-C, triacilglycerol, apo A-1, apo B, CETP, PLTP and LCAT but the CAD patients had higher levels of total cholesterol and free cholesterol. The method described here is practical, precise and potentially relevant as a tool to study HDL function.

Les benzoxaboroles sont des dérivés cycliques d'acides boroniques, récemment développés en médecine comme agents thérapeutiques. Dans cette thèse, une étude fondamentale de la formulation des benzoxaboroles dans des matériaux a été effectuée, utilisant le benzoxaborole le plus simple ainsi qu'un dérivé fluoré, l'AN2690 (antifongique approuvé par la FDA). L'étude a commencé par la détermination des données spectroscopiques de ces molécules à l'état solide, sous leur forme acide (à partir des molécules cristallisées), et basique (utilisant des matériaux modèles à base de benzoxaborolates) ; une variété de paramètres RMN a ainsi été établie pour chaque forme de la molécule. Par la suite, une première formulation a été développée par association de benzoxaborolates à un matériau inorganique de type « hydroxyde double lamellaire » (HDL Mg/Al-NO3). Un taux de charge à ~30 % massique en benzoxaboroles a pu être atteint, et des cinétiques de libérations rapides ont été observées. Cependant, une sensibilité des molécules au caractère basique de la matrice a été mise en évidence, et la structure de ces matériaux s'est avérée complexe, évoluant d'un mode d'intercalation normale à une structure de type « staging », en fonction du taux d'hydratation de l'espace interlamellaire. Dans une deuxième formulation, nous avons incorporé les benzoxaboroles, à divers taux de charge (jusqu'à 25% en masse), dans un polymère biorésorbable, l'acide poly-L-lactique (PLLA), avec une mise en forme en films et fibres, ces dernières étant formées par électrospinning. Dans ce cas, plusieurs vitesses de libération ont été obtenues, en modulant la composition et les conditions de préparation des matériaux, et les tests cellulaires réalisés (migration de cellules cancéreuses et tests antifongiques) sont en bonne corrélation avec ces cinétiques. Cette étude, dans son ensemble, permet d'élargir la gamme de formulations envisageables pour les benzoxaboroles, mais souligne aussi les enjeux associés à leur formulation dans des matériaux, du fait de la réactivité intrinsèque de la fonction benzoxaborole / Benzoxaboroles are cyclic derivatives of boronic acids, which have recently been developed as therapeutic agents. In this thesis, a fundamental study was carried out on the formulation of benzoxaboroles in materials, using the simplest benzoxaborole molecule and its fluorinated derivative, AN2690 (an antifungal agent approved by the FDA). The spectroscopic signatures of these molecules were first determined in the solid state, by looking at their acid form (using the crystallized molecules) and their basic form (using model materials based on benzoxaborolates), and this led to the establishment of the NMR parameters of each form of the molecules. A first formulation was then performed by association of benzoxaborolates with an inorganic material, a “layered double hydroxide” (Mg/Al-NO3 LDH). A loading capacity of ~ 30 wt% could be reached for this system and fast release kinetics were observed. However, the molecules were found to be sensitive to the basic character of the matrix. The resulting structure of these materials was also complex, due to the evolution from a normal mode of intercalation to a “staging” structure by dehydration of the interlamellar space. In a second formulation, the benzoxaboroles were incorporated at different loadings (up to 25 wt %), in a bioresorbable polymer, poly L lactic acid (PLLA), and shaped under the form of films and also fibers (which were obtained by electrospinning). Different release rates were achieved by varying the composition or the preparation conditions of the materials. Cellular assays investigating the migration of cancer cells and the inhibition of fungi showed a good correlation between these release rates and the cellular responses. Overall, this study allowed not only to increase the span of possible formulations of the benzoxaboroles, but also to highlight the issues related to their formulation in materials, due to the inherent reactivity of the benzaxoborole function.