Indiana University-Purdue University Indianapolis (IUPUI) / Breast cancer remains the most prevalent malignancy diagnosed in women. More than two thirds of all diagnosed breast cancers are estrogen receptor (ER)-positive and are dependent on estrogen signaling. Drugs for the treatment of ER-positive breast cancer can be divided into three classes: selective estrogen receptor modulators (SERMs), selective estrogen receptor down-regulators (SERDs) and aromatase inhibitors (AIs). However, the efficacy and safety of SERMs, SERDs and AIs are compromised by side effects or tumor resistance. One possible way of improving treatment efficacy and safety profiles is to develop agents with dual aromatase inhibitory and ER modulatory activity. Over the past 30 years, tamoxifen, a SERM, has become the most widely used drug for the adjuvant treatment of breast cancer. The metabolism of tamoxifen has a complex profile involving both active and inactive metabolites, among which endoxifen, 4-hydroxytamoxifen (4-HT) and norendoxifen (Nor) have been shown to have ER modulatory activity. Previous studies have also shown that norendoxifen is a potent AI in vitro. These preliminary studies support the utilization of tamoxifen metabolites as lead compounds for the development of dual AI/SERM(D) agents. Hydroxynorendoxifen (Hdn) was identified as a novel tamoxifen metabolite, with an average plasma concentration of 0.82 nM. Nor and Hdn were potent and relatively selective AIs, with Kis of 70 nM and 20 nM, respectively. Nor and Hdn have high binding affinity for ER-α and ER-β, with EC50 values less than 35 nM. Nor and Hdn can inhibit breast cancer cell proliferation with high potency, with IG50s of 25 nM and 9 nM, respectively. Nor and Hdn can suppress progesterone receptor (PGR) mRNA expression level by reducing it by 68% and 86%. Moreover, a series of Nor analogues were shown to have both potent aromatase inhibitory activity and high ERs binding affinity. Results from this dissertation will contribute to three aspects: 1) the identification of Hdn as a tamoxifen metabolite illustrated a more comprehensive metabolism profile of tamoxifen; 2) the data suggest Nor and Hdn possess dual aromatase inhibitory and ER antagonistic activity; 3) a series of Nor analogues were characterized as lead compounds for the development of dual AI/SERM(D) agents.

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La fotónica de silicio es actualmente la tecnología mejor posicionada para reemplazar las conexiones electrónicas tanto dentro de los mismos chips, como entre ellos mismos, con el fin de mejorar su rendimiento. Las principales ventajas de la tecnología fotónica de silicio residen en su bajo coste y en su compatibilidad con las actuales técnicas de fabricación desarrolladas por la industria microelectrónica. Dicha compatibilidad permitiría fabricar tanto chips ópticos como chips híbridos que incluyan componentes ópticos y electrónicos. Los moduladores y los conmutadores optoelectrónicos resultan dispositivos fundamentales en aplicaciones de telecomunicaciones. Las principales funciones de los conmutadores y moduladores optoelectrónicos son el enrutamiento y la transmisión de datos de alta velocidad. Esta tesis aborda el diseño y la optimización de la parte eléctrica y óptica (en menor medida) con el fin de optimizar el rendimiento de tales dispositivos desde el punto de vista optoelectrónico. Además, también se tratará la introducción de nuevos materiales compatibles con el silicio y sus procesos de fabricación, como el dióxido de vanadio o el titanato de bario con el fin de demostrar sus propiedades y aplicarlas a los dispositivos optoelectrónicos con el fin de mejorar su rendimiento. / Silicon photonics is nowadays the most promising technology to replace electrical inter- and intra-connections of the chips, increasing the performance in this way. The main advantages of silicon photonics technology lie on its low cost and its compatibility with the fabrications processes of microelectronics industry developed during years which allows the mass production of silicon photonics chips as well hybrid electronic and photonic devices in the same chip. Optoelectronics switches and modulators are key building blocks in photonic devices for tele/datacom applications. Such switches and modulators are devices which provides routing functionalities and the transmission of high speed data respectively. The work of this thesis delves with the design and optimization of silicon based switches and modulators spotlighting the electrical elements. Additionally, the work of this theses deals with the introduction of new silicon-compatible materials as vanadium dioxide and barium titanate, with the aim of demonstrating its functionalities and develop high-performance optoelectronic devices. / La fotònica de silici és actualment la tecnologia millor posicionada per a reemplaçar les connexions electròniques tant dins del propis xips, com entre ells mateixos, amb la finalitat de millorar el seu rendiment. Els principals avantatges de la tecnologia fotònica de silici resideixen en el seu baix cost i en la seua compatibilitat amb les actuals tècniques de fabricació desenvolupades per la indústria microelectrònica. Aquesta compatibilitat permetria fabricar tant xips òptics com a xips híbrids que incloguen components òptics i electrònics. Els moduladors i els commutadors optoelectrònics resulten dispositius fonamentals en aplicacions de telecomunicacions. Les principals funcions dels commutadors i moduladors optoelectrònics són l'encaminament i la transmissió de dades d'alta velocitat. Aquesta tesi aborda el disseny i l'optimització de la part elèctrica i òptica (en menor mesura) amb la finalitat d'optimitzar el rendiment de tals dispositius des del punt de vista optoelectrònic. A més, també es tractarà la introducció de nous materials compatibles amb el silici i els seus processos de fabricació, com el diòxid de vanadi o el titanato de bari amb la finalitat de demostrar les seues propietats i aplicar-les als dispositius optoelectrònics amb la finalitat de millorar el seu rendiment. / Rosa Escutia, Á. (2018). High-efficient electrodes for novel optoelectronic devices in silicon photonics [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/110364

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This thesis deals with optical synthesis of unmodulated and modulated microwave signals. Generation of microwave signals based on optical heterodyning is discussed in detail. The effect of phase noise of laser on heterodyned output has been studied for different phase noise profiles. Towards this, we propose a generic algorithm to numerically model the linewidth broadening of a laser due to phase noise. Generation of microwave signals is demonstrated practically by conducting an optical heterodyning experiment. Signals ranging in frequency from 12.5 MHz to 27 GHz have been generated. Limitations of optical heterodyning based approach in terms of phase noise performance and frequency stability are discussed and practically demonstrated. A hardware-efficient Optical Phase Locked Loop (OPLL) is proposed to overcome these issues. Phase noise tracking performance of the proposed OPLL has been experimentally demonstrated. Phase noise values as low as -105 dBc/Hz at 10 KHz offset have been achieved. Optical modulators, owing to their extremely low electro-optic response time, can support high frequency modulating signals. This makes them highly attractive in comparison to their microwave counterparts. In this thesis, we propose techniques to generate microwave signals modulated at very high bit rates by down-converting the corresponding modulated optical signals to microwave domain. Down-conversion required for this process is achieved by optical heterodyning. The proposed concept has been theoretically analyzed, simulated and experimentally validated. Amplitude Modulated and ASK modulated microwave signals have been generated as Proof-of-Concept. Limitations posed by OPLL in generation of angle modulated microwave signals by optical heterodyning have been brought out. Schemes overcoming these limitations have been proposed towards generation of BPSK and QPSK modulated microwave signals. Integrated Optics (IO) technology has been studied as a means of implementation of the proposed concepts. IO components like Sinusoidal bends, Y-branch splitters and Electro-Optic-Modulators (EOMs) have been designed towards optical synthesis of modulated microwave signals. Propagation of modulated optical signal through these IO components has also been studied. An all-optic scheme based on Optical Beam Forming is proposed for transmission of QPSK modulated signal. Limitation of phase-shifting based approach, in terms of beam-squint, has been brought out. True-Time-Delay based approach has been proposed for applications demanding wide instantaneous bandwidth to avoid beam-squint. Algorithms / numerical methods required for analyses and simulations associated with the above-mentioned tasks have been evolved. This study is envisaged to provide useful insight into the realization of high-speed, compact, light-weight data transmitting systems based on Integrated Optics for future onboard spacecraft applications. This work, we believe, is a step towards realization of an Integrated Optic System-on-Chip solution for specific microwave data transmission applications.

α7 Neuronal nicotinic acetylcholine receptors are one of two major classes of receptors responsible for cholinergic neurotransmission in the central nervous system. The existence of α7 neuronal nAChRs in different regions of the nervous system suggests their involvement in certain essential physiological functions as well as in disorders such as Alzheimer’s disease (AD), drug dependence, and depression. This project was aimed toward the discovery and development of small–molecule arylguanidines that modulate α7 nAChR function with improved subtype-selectivity through an allosteric approach. Identifying the required structural features of these small molecules allowed optimization of their negative allosteric modulator (NAM) actions at α7 neuronal nAChRs. MD-354 (3-chlorophenylguanidine) was the first small–molecule NAM at α7 nAChRs; however, it also binds at 5-HT3 receptors. The N-methyl analog of MD-354 appeared to be more selective toward α7 nAChRs than 5-HT3 receptors. Comparative studies using two series of novel compounds based on MD-354 and its N-methyl analog explored the aryl 3-position and investigated whether or not the MD-354 series and the N-methyl series bind in the same manner. Biological potencies of the MD-354 series and the N-methyl series of compounds, obtained from electrophysiological assays with Xenopus laevis oocytes expressing human α7 nAChRs in two-electrode voltage-clamp assays, showed that N-(3-iodophenyl)-N- methylguanidine (28) is the most potent analog at α7 nAChRs. Our comparative study and Hansch analyses indicated different binding modes of the two series. In addition, we investigated: i) the length/size of the aliphatic side chain at the anilinic nitrogen, ii) the effect of alkylating the guanidine nitrogen atoms, and iii) the necessity of the presence of these nitrogen atoms for the inhibitory effects of arylguanidines at α7 nAChRs. In efforts to explain the varied functional activity of these arylguanidines, homology models of the extracellular domain and the transmembrane domain of human α7 nAChRs were developed, allosteric sites identified, and docking studies and hydropathic analysis conducted. The 3D quantitative structure-activity relationships for our compounds were also analyzed using CoMFA. A pharmacophore for arylguanidines as α7 nAChR NAMs was identified. Together, these data should be useful for the subsequent design of novel arylguanidine analogs for their potential treatment of neurological disorders.

La technique d’usinage par impulsions laser femtosecondes possède de nombreux avantages du fait des spécificités physique de l’interaction laser/matière en mode ultra-bref et est donc susceptible d’intéresser le monde industriel. Néanmoins elle présente aussi certaines limitations, principalement en terme de flexibilité et de productivité, limitant l’accès à ce marché. Pour repousser ces limites, nous proposons d’adjoindre des techniques de contrôle du faisceau, à la fois en taille, et plus généralement en forme, exploités par ailleurs dans d’autres domaines scientifiques (pincettes optiques notamment). Ces techniques reposent sur l’utilisation de modulateurs spatiaux de lumière (SLM). Deux solutions sont proposées : la modulation d’amplitude en configuration d’imagerie, et la modulation de phase pure en configuration de Fourier. Le formalisme, les différentes problématiques et la mise en oeuvre de ces deux techniques au sein d’une station de travail prototype que nous avons développée sont présentés. Enfin, nous mettons en évidence le gain apporté par ces techniques sur des problématiques concrètes, tels que l’usinage de réseaux résonant à l’échelle nanométrique, la réduction du temps d’usinage de ces réseaux (ou d’autres motifs), et l’amélioration de la qualité d’usinage de rainures / Femtosecond laser machining processes present many interesting properties owing to the specificities of the light/matter interaction in ultrafast regime. Thus the process may be of prime interest in industrial applications. However some aspects are not compatible with industrialization: namely a lack of flexibility and productivity. To overcome this limitations we propose to add beam shaping techniques in the process that allow control of the beam both in size and shape. These techniques are based on Spatial Light Modulators (SLM). Two different solutions are proposed: amplitude modulation in a geometrical conjugation scheme, and pure phase modulation in a Fourier scheme. Both are integrated in a prototype workstation. We justify the different choices made during the development by the analysis of the formalisms and specific problematics. Finally, enhancements of the femtosecond laser machining process are practically demonstrated in three different fields: reducing the resolution to nanometric scale, reducing the processing time of different texturations and enhancing the quality of simple grooves by modifying only the beam shape

Tendo em vista o notável crescimento da aquicultura mundial e principalmente a brasileira, torna-se cada vez mais importante o desenvolvimento de tecnologias que favoreçam esta prática. No entanto, a intensificação da piscicultura faz aumentar as chances de ocorrência de epizootias nos sistemas de produção como resultado do maior estresse imposto aos animais (lotação, manejo, transporte etc). Este estudo determinou a eficácia na utilização de imunoestimulantes dietéticos (levamisol e vitamina E) e a farmacocinética do imunoestimulante levamisol em juvenis de surubim Pseudoplatystoma sp. O levamisol dietético não afetou as variáveis de desempenho, mas influenciou positivamente o sistema imunológico inespecífico do cachara, afetando a atividade da lisozima sérica, sendo o melhor resultado observado para a concentração de levamisol de 247 mg kg-1 de ração. No estudo com vitamina E, não foram registrados efeitos sobre as variáveis de desempenho; ainda, na dose dietética 166 mg kg-1 o acetato de DL-?-tocoferol promoveu aumento das globulinas séricas. O estudo farmacocinético revelou-se que o levamisol é eliminado do sangue do cachara em 12 horas, sendo a meia-vida de distribuição (t1/2?) de 0,10 horas, e para o intervalo de eliminação meia-vida (t1/2?) de 1,86 horas. / Continuous stress negatively influences the immune system of farmed fish, increasing diseases susceptibility. In such a context, preventive measures, such as the administration of immunostimulants, are better suited for diseases control than using drugs and chemicals as remedies. This study aimed to evaluate the effects of dietary immunostimulants (levamisole and vitamin E) as well as the pharmacokinetic study of levamisole in juvenile of Pseudoplatystoma sp. Dietary levamisole did not affect growth parameters. However, increased lysozyme activity and lysozyme concentration, the best effects were recorded for fish fed 247 mg levamisole per kg of feed. In the vitamin E assay, no differences in growth parameters were recorded. However, vitamin E levels positively influenced the innate immune system increasing serum globulins at dose of 166 mg kg-1 of DL-?-tocoferol acetate. Also, at pharmacokinetic study levamisole is shown to be completely eliminated from fish blood on a 12-h period, being the distribution half-life (t1/2?) of 0.10 hours, whilst for the elimination interval the half-life (t1/2?) was 1.86 hours.

O trabalho de doutorado teve como objetivo desenvolver um modulador óptico baseado em filme magnetostrictivo para aplicação como magnetômetro. A modelagem e simulação do dispositivo foi realizada utilizando software com cálculo por método dos elementos finitos (MEF) e teve como finalidade auxiliar iterativamente os processos de projeto e fabricação do modulador. A originalidade da proposta baseia-se na construção de um guia de onda em óptica integrada recoberto por um filme magnetostrictivo para permitir a modulação , via efeito elasto-óptico, da onda guiada pela aplicação de campos magnéticos externos. O campo magnético aplicado provoca a deformação o material magnetostrictivo que induz uma modificação no perfil de esforço aplicado ao substrato. O substrato tem suas propriedades ópticas alteradas devido ao efeito elasto-óptico, o que provoca mudanças nas propriedades da luz transmitida. O trabalho tem seu início com o estudo e a caracterização de filmes magnetostrictivos de Tb25F275 e Tb23Co77 depositados por sputtering sobre substratos de silício. Uma técnica para preparação das amostras e medição da magnetostricção foi estabelecida e os coeficientes de magnetostrição dos filmes foram determinados a partir das medições diretas dos deslocamentos das amostras, em função dos campos magnéticos aplicados, utilizando a técnica de Atomic Force Microscopy (AFM). Os resultados experimentais obtidos permitiram a realização de simulações por MEF para verificação dos modos de guiamento da luz gerados pelo perfil de esforços induzidos termicamente no processo de deposição do filme magnetostrictivo sobre substrato de B12GeO4 (BGO). Foi modelado e simulado também o efeito da aplicação do campo magnético sobre o guia óptico obtido inicialmente pelo efeito de esforço térmico. No resultado das simulações foi possível verificar as alterações do índice de refração efetivo e da intensidade óptica do modo guiado em função de campos magnéticos aplicados ao modulador. Ao final do trabalho realizaram-se a fabricação de alguns protótipos. Os resultados das caracterizações dos moduladores construídos permitirão, no futuro, ajustar os modelos de simulação elaborados. / The doctoral work aims are the development and simulation of an optical modulator based on the effect of magnetostriction for application as magnetometer. The multiphysics simulations were performed using the Finite Elements Method (FEM). In the manufacturing process of optical modulator integrated optics techniques were applied. The originality of the proposal is based on the construction of an integrated optical waveguide covered by a magnetostrictive film to allow the modulation of the guided wave, through the elasto-optical effect, by the application of external magnetic fields. The applied magnetic field causes deformation of the magnetostrictive material that induces a modification of the stress profile produced in substrate. The substrate has its optical properties altered due to the elasto-optical effect, which causes changes in the properties of transmitted light. The work begins with the study and characterization of TbFe and TbCo2 magnetostrictive films deposited by sputtering on silicon substrates. A method for sample preparation and measurement of magnetostriction was established. The magnetostrictive coefficient of the films was determined from the direct measurement of displacements of samples by AFM technique for magnetic fields applied. The experimental results obtained allowed to perform MEF simulations to verify the light guided modes generated by the profile of thermally induced stress created by deposition process of magnetostrictive film on B12GeO4 (BGO) substrate. It was also modeled and simulated the effect of the application of magnetic field on the optical guide obtained initially by the effect of thermal stress. In simulation results, it was possible to verify the changes of effective refractive index and optical intensity of guided modes as functions of magnetic fields applied to the modulator. At the end of the work, some prototypes were fabricated. The results of characterizations of the built modulators will allow, in the future, adjustments in simulation models.