<p dir="ltr">Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), and human immunodeficiency virus-1 (HIV) are major public health concerns, individually and in combination. The status of the host immune system, previous <i>Mtb</i> infection and HIV-mediated T cell exhaustion, can have significant impacts on immune dynamics during reinfection. Individuals with asymptomatic latent TB infection (LTBI) may be protected against <i>Mtb </i>reinfection, as demonstrated by animal and <i>in vitro </i>studies. However, the underlying dynamics and protective mechanisms of LTBI are poorly understood. In HIV, long-term infection in children and associated T cell exhaustion leads to weakened immune responses to HIV reinfection. The complexity of these infections, particularly in the context of the heightened vulnerability of HIV+ individuals to TB, underscores the need for novel investigative approaches to study host-pathogen and pathogen-pathogen interactions. To this, we have developed an agent-based model (ABM) as a mechanistic computational tool to simulate the immune response to <i>Mtb </i>and HIV, separately and during coinfection. Our ABM integrates clinical and experimental data; simulates immune cell dynamics between macrophages, CD4+ and CD8+ T cells; and produces emergent granuloma-like structures – a critical response to <i>Mtb</i>. This <i>in silico</i> approach allows us to efficiently explore host-pathogen interactions and their clinical implications. By unraveling the complex interplay of immune cell activation, T cell exhaustion, and pathogen dynamics, our model offers insights that could guide the development of targeted therapies. By quantifying the multifaceted nature of these diseases and their interactions, we highlight the potential of computational approaches in understanding and treating complex diseases, individually and in combination.</p>

[EN] The first generation of Terrestrial Digital Television(DTV) has been in service for over a decade. In 2013, several countries have already completed the transition from Analog to Digital TV Broadcasting, most of which in Europe. In South America, after several studies and trials, Brazil adopted the Japanese standard with some innovations. Japan and Brazil started Digital Terrestrial Television Broadcasting (DTTB) services in December 2003 and December 2007 respectively, using Integrated Services Digital Broadcasting - Terrestrial (ISDB-T), also known as ARIB STD-B31. In June 2005 the Committee for the Information Technology Area (CATI) of Brazilian Ministry of Science and Technology and Innovation MCTI approved the incorporation of the IC-Brazil Program, in the National Program for Microelectronics (PNM) . The main goals of IC-Brazil are the formal qualification of IC designers, support to the creation of semiconductors companies focused on projects of ICs within Brazil, and the attraction of semiconductors companies focused on the design and development of ICs in Brazil. The work presented in this thesis originated from the unique momentum created by the combination of the birth of Digital Television in Brazil and the creation of the IC-Brazil Program by the Brazilian government. Without this combination it would not have been possible to make these kind of projects in Brazil. These projects have been a long and costly journey, albeit scientifically and technologically worthy, towards a Brazilian DTV state-of-the-art low complexity Integrated Circuit, with good economy scale perspectives, due to the fact that at the beginning of this project ISDB-T standard was not adopted by several countries like DVB-T. During the development of the ISDB-T receiver proposed in this thesis, it was realized that due to the continental dimensions of Brazil, the DTTB would not be enough to cover the entire country with open DTV signal, specially for the case of remote localizations far from the high urban density regions. Then, Eldorado Research Institute and Idea! Electronic Systems, foresaw that, in a near future, there would be an open distribution system for high definition DTV over satellite, in Brazil. Based on that, it was decided by Eldorado Research Institute, that would be necessary to create a new ASIC for broadcast satellite reception. At that time DVB-S2 standard was the strongest candidate for that, and this assumption still stands nowadays. Therefore, it was decided to apply to a new round of resources funding from the MCTI - that was granted - in order to start the new project. This thesis discusses in details the Architecture and Algorithms proposed for the implementation of a low complexity Intermediate Frequency(IF) ISDB-T Receiver on Application Specific Integrated Circuit (ASIC) CMOS. The Architecture proposed here is highly based on the COordinate Rotation Digital Computer (CORDIC) Algorithm, that is a simple and efficient algorithm suitable for VLSI implementations. The receiver copes with the impairments inherent to wireless channels transmission and the receiver crystals. The thesis also discusses the Methodology adopted and presents the implementation results. The receiver performance is presented and compared to those obtained by means of simulations. Furthermore, the thesis also presents the Architecture and Algorithms for a DVB-S2 receiver targeting its ASIC implementation. However, unlike the ISDB-T receiver, only preliminary ASIC implementation results are introduced. This was mainly done in order to have an early estimation of die area to prove that the project in ASIC is economically viable, as well as to verify possible bugs in early stage. As in the case of ISDB-T receiver, this receiver is highly based on CORDIC algorithm and it was prototyped in FPGA. The Methodology used for the second receiver is derived from that used for the ISDB-T receiver, with minor additions given the project characteristics. / [ES] La primera generación de Televisión Digital Terrestre(DTV) ha estado en servicio por más de una década. En 2013, varios países completaron la transición de transmisión analógica a televisión digital, la mayoría de ellas en Europa. En América del Sur, después de varios estudios y ensayos, Brasil adoptó el estándar japonés con algunas innovaciones. Japón y Brasil comenzaron a prestar el servicio de Difusión de Televisión Digital Terrestre (DTTB) en diciembre de 2003 y diciembre de 2007 respectivamente, utilizando Radiodifusión Digital de Servicios Integrados Terrestres (ISDB-T), también conocida como ARIB STD-B31. En junio de 2005, el Comité del Área de Tecnología de la Información (CATI) del Ministerio de Ciencia, Tecnología e Innovación de Brasil - MCTI aprobó la incorporación del Programa CI-Brasil, en el Programa Nacional de Microelectrónica (PNM). Los principales objetivos de la CI-Brasil son la formación de diseñadores de CIs, apoyar la creación de empresas de semiconductores enfocadas en proyectos de circuitos integrados dentro de Brasil, y la atracción de empresas de semiconductores interesadas en el diseño y desarrollo de circuitos integrados. El trabajo presentado en esta tesis se originó en el impulso único creado por la combinación del nacimiento de la televisión digital en Brasil y la creación del Programa de CI-Brasil por el gobierno brasileño. Sin esta combinación no hubiera sido posible realizar este tipo de proyectos en Brasil. Estos proyectos han sido un trayecto largo y costoso, aunque meritorio desde el punto de vista científico y tecnológico, hacia un Circuito Integrado brasileño de punta y de baja complejidad para DTV, con buenas perspectivas de economía de escala debido al hecho que al inicio de este proyecto, el estándar ISDB-T no fue adoptado por varios países como DVB-T. Durante el desarrollo del receptor ISDB-T propuesto en esta tesis, se observó que debido a las dimensiones continentales de Brasil, la DTTB no sería suficiente para cubrir todo el país con la señal de televisión digital abierta, especialmente para el caso de localizaciones remotas, apartadas de las regiones de alta densidad urbana. En ese momento, el Instituto de Investigación Eldorado e Idea! Sistemas Electrónicos, previeron que en un futuro cercano habría un sistema de distribución abierto para DTV de alta definición por satélite en Brasil. Con base en eso, el Instituto de Investigación Eldorado decidió que sería necesario crear un nuevo ASIC para la recepción de radiodifusión por satélite, basada el estándar DVB-S2. En esta tesis se analiza en detalle la Arquitectura y algoritmos propuestos para la implementación de un receptor ISDB-T de baja complejidad y frecuencia intermedia (IF) en un Circuito Integrado de Aplicación Específica (ASIC) CMOS. La arquitectura aquí propuesta se basa fuertemente en el algoritmo Computadora Digital para Rotación de Coordenadas (CORDIC), el cual es un algoritmo simple, eficiente y adecuado para implementaciones VLSI. El receptor hace frente a las deficiencias inherentes a las transmisiones por canales inalámbricos y los cristales del receptor. La tesis también analiza la metodología adoptada y presenta los resultados de la implementación. Por otro lado, la tesis también presenta la arquitectura y los algoritmos para un receptor DVB-S2 dirigido a la implementación en ASIC. Sin embargo, a diferencia del receptor ISDB-T, se introducen sólo los resultados preliminares de implementación en ASIC. Esto se hizo principalmente con el fin de tener una estimación temprana del área del die para demostrar que el proyecto en ASIC es económicamente viable, así como para verificar posibles errores en etapa temprana. Como en el caso de receptor ISDB-T, este receptor se basa fuertemente en el algoritmo CORDIC y fue un prototipado en FPGA. La metodología utilizada para el segundo receptor se deriva de la utilizada para el re / [CA] La primera generació de Televisió Digital Terrestre (TDT) ha estat en servici durant més d'una dècada. En 2013, diversos països ja van completar la transició de la radiodifusió de televisió analògica a la digital, i la majoria van ser a Europa. A Amèrica del Sud, després de diversos estudis i assajos, Brasil va adoptar l'estàndard japonés amb algunes innovacions. Japó i Brasil van començar els servicis de Radiodifusió de Televisió Terrestre Digital (DTTB) al desembre de 2003 i al desembre de 2007, respectivament, utilitzant la Radiodifusió Digital amb Servicis Integrats de (ISDB-T), coneguda com a ARIB STD-B31. Al juny de 2005, el Comité de l'Àrea de Tecnologia de la Informació (CATI) del Ministeri de Ciència i Tecnologia i Innovació del Brasil (MCTI) va aprovar la incorporació del programa CI Brasil al Programa Nacional de Microelectrònica (PNM). Els principals objectius de CI Brasil són la qualificació formal dels dissenyadors de circuits integrats, el suport a la creació d'empreses de semiconductors centrades en projectes de circuits integrats dins del Brasil i l'atracció d'empreses de semiconductors centrades en el disseny i desenvolupament de circuits integrats. El treball presentat en esta tesi es va originar en l'impuls únic creat per la combinació del naixement de la televisió digital al Brasil i la creació del programa Brasil CI pel govern brasiler. Sense esta combinació no hauria estat possible realitzar este tipus de projectes a Brasil. Estos projectes han suposat un viatge llarg i costós, tot i que digne científicament i tecnològica, cap a un circuit integrat punter de baixa complexitat per a la TDT brasilera, amb bones perspectives d'economia d'escala perquè a l'inici d'este projecte l'estàndard ISDB-T no va ser adoptat per diversos països, com el DVB-T. Durant el desenvolupament del receptor de ISDB-T proposat en esta tesi, va resultar que, a causa de les dimensions continentals de Brasil, la DTTB no seria suficient per cobrir tot el país amb el senyal de TDT oberta, especialment pel que fa a les localitzacions remotes allunyades de les regions d'alta densitat urbana.. En este moment, l'Institut de Recerca Eldorado i Idea! Sistemes Electrònics van preveure que, en un futur pròxim, no hi hauria a Brasil un sistema de distribució oberta de TDT d'alta definició a través de satèl¿lit. D'acord amb això, l'Institut de Recerca Eldorado va decidir que seria necessari crear un nou ASIC per a la recepció de radiodifusió per satèl¿lit. basat en l'estàndard DVB-S2. En esta tesi s'analitza en detall l'arquitectura i els algorismes proposats per l'execució d'un receptor ISDB-T de Freqüència Intermèdia (FI) de baixa complexitat sobre CMOS de Circuit Integrat d'Aplicacions Específiques (ASIC). L'arquitectura ací proposada es basa molt en l'algorisme de l'Ordinador Digital de Rotació de Coordenades (CORDIC), que és un algorisme simple i eficient adequat per implementacions VLSI. El receptor fa front a les deficiències inherents a la transmissió de canals sense fil i els cristalls del receptor. Esta tesi també analitza la metodologia adoptada i presenta els resultats de l'execució. Es presenta el rendiment del receptor i es compara amb els obtinguts per mitjà de simulacions. D'altra banda, esta tesi també presenta l'arquitectura i els algorismes d'un receptor de DVB-S2 de cara a la seua implementació en ASIC. No obstant això, a diferència del receptor ISDB-T, només s'introdueixen resultats preliminars d'implementació en ASIC. Això es va fer principalment amb la finalitat de tenir una estimació primerenca de la zona de dau per demostrar que el projecte en ASIC és econòmicament viable, així com per verificar possibles errors en l'etapa primerenca. Com en el cas del receptor ISDB-T, este receptor es basa molt en l'algorisme CORDIC i va ser un prototip de FPGA. La metodologia utilitzada per al segon receptor es deriva de la utilitzada per al receptor I / Rodrigues De Lima, E. (2016). Architecture and algorithms for the implementation of digital wireless receivers in FPGA and ASIC: ISDB-T and DVB-S2 cases [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/61967

The continuous migration to smaller feature sizes puts high demands on materials and technologies for future ultra-large-scale integrated circuits. Particularly, the copper-based interconnect system will reach fundamental limits soon. Their outstanding properties make metallic carbon nanotubes (CNTs) an ideal material to partially replace copper in future interconnect architectures. Here, a low contact resistance to existing metal lines is crucial. The present thesis contributes to the theory and numerical description of electronic transport in metallic CNTs with metal contacts. Different theoretical approaches are applied to various contact models and electrode materials (Al, Cu, Pd, Ag, Pt, Au) are compared. Ballistic transport calculations are based on the non-equilibrium Greens function formalism combined with tight-binding (TB), extended Hückel theory (EHT) and density functional theory (DFT). Simplified contact models allow a qualitative investigation of both the influence of geometry and CNT length, and the strength and extent of the contact on the transport properties. In addition, such simple contact models are used to compare the influence of different electronic structure methods on transport. It is found that the semiempirical TB and EHT are inadequate to quantitatively reproduce the DFT-based results. Based on this observation, an improved set of Hückel parameters is developed, which remedies this insufficiency. A systematic investigation of different contact materials is carried out using well defined atomistic metal-CNT-metal structures, optimized in a systematic way. Analytical models for the CNT-metal interaction are proposed. Based on that, electronic transport calculations are carried out, which can be extended to large systems by applying the computationally cheap improved EHT. The metal-CNT-metal systems can then be ranked by average conductance: Ag ≤ Au < Cu < Pt ≤ Pd < Al. This corresponds qualitatively with calculated contact distances, binding energies and work functions of CNTs and metals. To gain a deeper understanding of the transport properties, the electronic structure of the metal-CNT-metal systems and their respective parts is analyzed in detail. Here, the energy resolved local density of states is a valuable tool to investigate the CNT-metal interaction and its influences on the transport. / Die kontinuierliche Verkleinerung der Strukturgrößen stellt hohe Anforderungen an Materialen und Technologien zukünftiger hochintegrierter Schaltkreise. Insbesondere die Leistungsfähigkeit kupferbasierte Leitbahnsystem wird bald an fundamentale Grenzen stoßen. Aufgrund ihrer hervorragenden Eigenschaften könnten metallische Kohlenstoffnanoröhren (engl. Carbon Nanotubes, CNTs) Kupfer in zukünftigen Leitbahnsystemen teilweise ersetzen. Dabei ist ein geringer Kontaktwiderstand mit vorhandenen Leitbahnen von entscheidender Bedeutung. Die vorliegende Arbeit liefert grundlegende Beiträge zur Theorie und zur numerischen Beschreibung elektronischer Transporteigenschaften metallischer CNTs mit Metallkontakten. Dazu werden verschiedene theoretische Ansätze auf diverse Kontaktmodelle angewandt und eine Auswahl von Elektrodenmaterialen (Al, Cu, Pd, Ag, Pt, Au) verglichen. Die Beschreibung ballistischen Elektronentransports erfolgt mittels des Formalismus der Nichtgleichgewichts-Green-Funktionen in Kombination mit Tight-Binding (TB), erweiterter Hückel-Theorie (EHT) und Dichtefunktionaltheorie (DFT). Vereinfachte Kontaktmodelle dienen der qualitativen Untersuchung des Einflusses von Geometrie und Länge der Nanoröhren, sowie von Stärke und Ausdehnung des Kontaktes. Darüber hinaus erlauben solch einfache Modelle mit geringem numerischen Aufwand den Einfluss verschiedener Elektronenstrukturmethoden zu untersuchen. Es zeigt sich, dass die semiempirischen Methoden TB und EHT nicht in der Lage sind die Ergebnisse der DFT quantitativ zu reproduzieren. Ausgehend von diesen Ergebnissen wird ein verbesserter Satz von Hückel-Parametern generiert, der diesen Mangel behebt. Die Untersuchung verschiedener Kontaktmaterialien erfolgt an wohldefinierten atomistischen Metall-CNT-Metall-Strukturen, welche systematisch optimiert werden. Analytische Modelle zur Beschreibung der CNT-Metall-Wechselwirkung werden vorgeschlagen. Darauf aufbauende Berechnungen der elektronischen Transporteigenschaften, können mit Hilfe der verbesserten EHT auf große Systeme ausgedehnt werden. Die Ergebnisse ermöglichen eine Reihung der Metall-CNT-Metall-Systeme hinsichtlich ihrer Leitfähigkeit: Ag ≤ Au < Cu < Pt ≤ Pd < Al. Dies korrespondiert qualitativ mit berechneten Kontaktabständen, Bindungsenergien und Austrittarbeiten der CNTs und Metalle. Zum tieferen Verständnis der Transporteigenschaften erfolgt eine detaillierte Analyse der elektronischen Struktur der Metall-CNT-Metall-Systeme und ihrer Teilsysteme. Dabei erweist sich die energieaufgelöste lokale Zustandsdichte als nützliches Werkzeug zur Visulisierung und zur Charakterisierung der Wechselwirkung zwischen CNT und Metall sowie deren Einfluss auf den Transport.

The continuous migration to smaller feature sizes puts high demands on materials and technologies for future ultra-large-scale integrated circuits. Particularly, the copper-based interconnect system will reach fundamental limits soon. Their outstanding properties make metallic carbon nanotubes (CNTs) an ideal material to partially replace copper in future interconnect architectures. Here, a low contact resistance to existing metal lines is crucial. The present thesis contributes to the theory and numerical description of electronic transport in metallic CNTs with metal contacts. Different theoretical approaches are applied to various contact models and electrode materials (Al, Cu, Pd, Ag, Pt, Au) are compared. Ballistic transport calculations are based on the non-equilibrium Greens function formalism combined with tight-binding (TB), extended Hückel theory (EHT) and density functional theory (DFT). Simplified contact models allow a qualitative investigation of both the influence of geometry and CNT length, and the strength and extent of the contact on the transport properties. In addition, such simple contact models are used to compare the influence of different electronic structure methods on transport. It is found that the semiempirical TB and EHT are inadequate to quantitatively reproduce the DFT-based results. Based on this observation, an improved set of Hückel parameters is developed, which remedies this insufficiency. A systematic investigation of different contact materials is carried out using well defined atomistic metal-CNT-metal structures, optimized in a systematic way. Analytical models for the CNT-metal interaction are proposed. Based on that, electronic transport calculations are carried out, which can be extended to large systems by applying the computationally cheap improved EHT. The metal-CNT-metal systems can then be ranked by average conductance: Ag ≤ Au < Cu < Pt ≤ Pd < Al. This corresponds qualitatively with calculated contact distances, binding energies and work functions of CNTs and metals. To gain a deeper understanding of the transport properties, the electronic structure of the metal-CNT-metal systems and their respective parts is analyzed in detail. Here, the energy resolved local density of states is a valuable tool to investigate the CNT-metal interaction and its influences on the transport. / Die kontinuierliche Verkleinerung der Strukturgrößen stellt hohe Anforderungen an Materialen und Technologien zukünftiger hochintegrierter Schaltkreise. Insbesondere die Leistungsfähigkeit kupferbasierte Leitbahnsystem wird bald an fundamentale Grenzen stoßen. Aufgrund ihrer hervorragenden Eigenschaften könnten metallische Kohlenstoffnanoröhren (engl. Carbon Nanotubes, CNTs) Kupfer in zukünftigen Leitbahnsystemen teilweise ersetzen. Dabei ist ein geringer Kontaktwiderstand mit vorhandenen Leitbahnen von entscheidender Bedeutung. Die vorliegende Arbeit liefert grundlegende Beiträge zur Theorie und zur numerischen Beschreibung elektronischer Transporteigenschaften metallischer CNTs mit Metallkontakten. Dazu werden verschiedene theoretische Ansätze auf diverse Kontaktmodelle angewandt und eine Auswahl von Elektrodenmaterialen (Al, Cu, Pd, Ag, Pt, Au) verglichen. Die Beschreibung ballistischen Elektronentransports erfolgt mittels des Formalismus der Nichtgleichgewichts-Green-Funktionen in Kombination mit Tight-Binding (TB), erweiterter Hückel-Theorie (EHT) und Dichtefunktionaltheorie (DFT). Vereinfachte Kontaktmodelle dienen der qualitativen Untersuchung des Einflusses von Geometrie und Länge der Nanoröhren, sowie von Stärke und Ausdehnung des Kontaktes. Darüber hinaus erlauben solch einfache Modelle mit geringem numerischen Aufwand den Einfluss verschiedener Elektronenstrukturmethoden zu untersuchen. Es zeigt sich, dass die semiempirischen Methoden TB und EHT nicht in der Lage sind die Ergebnisse der DFT quantitativ zu reproduzieren. Ausgehend von diesen Ergebnissen wird ein verbesserter Satz von Hückel-Parametern generiert, der diesen Mangel behebt. Die Untersuchung verschiedener Kontaktmaterialien erfolgt an wohldefinierten atomistischen Metall-CNT-Metall-Strukturen, welche systematisch optimiert werden. Analytische Modelle zur Beschreibung der CNT-Metall-Wechselwirkung werden vorgeschlagen. Darauf aufbauende Berechnungen der elektronischen Transporteigenschaften, können mit Hilfe der verbesserten EHT auf große Systeme ausgedehnt werden. Die Ergebnisse ermöglichen eine Reihung der Metall-CNT-Metall-Systeme hinsichtlich ihrer Leitfähigkeit: Ag ≤ Au < Cu < Pt ≤ Pd < Al. Dies korrespondiert qualitativ mit berechneten Kontaktabständen, Bindungsenergien und Austrittarbeiten der CNTs und Metalle. Zum tieferen Verständnis der Transporteigenschaften erfolgt eine detaillierte Analyse der elektronischen Struktur der Metall-CNT-Metall-Systeme und ihrer Teilsysteme. Dabei erweist sich die energieaufgelöste lokale Zustandsdichte als nützliches Werkzeug zur Visulisierung und zur Charakterisierung der Wechselwirkung zwischen CNT und Metall sowie deren Einfluss auf den Transport.

This quantitative, descriptive study investigated risk factors for MDR-TB in Addis Ababa, Ethiopia. A total of 439 medical records belonging to MDR-TB and non MDR-TB patients managed in public health centres from January 2008 to December 2011 were analysed. Data were transcribed from each TB patient‟s medical records using a specifically designed checklist. The findings revealed that male gender, previous history of TB treatment, poor treatment adherence, an outcome of failure after TB re-treatment, previous category of failure, pulmonary involvement of TB infection and HIV infection were associated with MDR-TB. The findings illustrate that efforts should be made to prioritise the development and implementation of effective MDR TB screening and treatment protocols for these high risk groups to improve treatment outcome and minimize the emergence of XDR TB. / Health Studies / M. Public Health

A tuberculose (TB) é uma doença causada pelo Mycobacterium tuberculosis. De acordo com estimativas da Organização Mundial da Saúde, a tuberculose é responsável pela morte de ~2 a 3 milhões de pessoas/ano no mundo e nos próximos 15 anos cerca de 1 bilhão de pessoas deverão ser infectadas, e destas, aproximadamente 35 milhões deverão morrer. Apesar de existirem vários medicamentos sendo utilizados no tratamento da doença, constatasse o crescimento no número de casos devido, principalmente, às variedades resistentes do M. tuberculosis. Considerando-se o aparecimento de cepas resistentes em TB, recomenda-se que novos medicamentos e/ou alvos biológicos alternativos devam ser intensivamente pesquisados. A ribonucleotídeo redutase (RNR), por exemplo, é uma proteína de interesse, pois catalisa uma etapa importante e única na síntese de novo dos dNTPs, reduzindo o ribonucleosídeo 5\' -difosfato ao seu correspondente desoxirribonucleosídeo 5\' -difosfato. A RNR é importante na síntese do DNA, e portanto, na divisão das células. Esta enzima importante, que possuí 16% de homologia com a RNR de mamíferos, é um alvo potencial para o desenvolvimento de novos fármacos, com provável aplicação no tratamento do câncer, da malária e do tripanossoma. Sabe-se que diferentes classes de compostos, através de diferentes mecanismos de ação, inibem a RNR, incluindo as &#945;-(N)-heterocíclicas carboxaldeído tiossemicarbazonas, um dos inibidores mais potentes da RNR. Sabe-se que alguns derivados da tiossemicarbazona, inibidoras da RNR de células tumorais, apresentam atividade frente o M. tuberculosis atuando provavelmente através do mesmo mecanismo, envolvendo a inibição da correspondente RNR. Neste contexto, nesta tese de doutorado, foram aplicadas diferentes abordagens de QSAR/QSAR-3D no estudo de 40 derivados da 2-piridino-carboxaldeído tiossemicarbazona, inibidores da RNR de células H.Ep.-2, retirados de literatura selecionada (French & Blanz-Jr. 1974). Estes compostos foram divididos em cinco séries, a saber: séries A, B, C, D, e E contendo, respectivamente, 40, 39, 30, 23 e 22 compostos, na tentativa de tornar estas séries estruturalmente mais homogêneas. Para cada série, foram criados três grupos de treinamento e os respectivos grupos de teste (I, II e III), visando-se avaliar o poder de predição dos modelos gerados através das análises de QSAR/QSAR-3D. Para as análises de QSAR clássico, foram utilizados como variáveis independentes, os descritores mais relevantes gerados através do programa DRAGON e, pré-selecionados por PLS. Considerando-se a ausência de informações sobre a estrutura cristalográfica da enzima RNR do M. tuberculosis, os estudos de QSAR-3D foram iniciados empregando-se metodologias propostas em CoMFA e, em CoMSIA, implementadas no programa SYBYL. Além destas, foi realizada a modelagem por homologia da RNR do M. tuberculosis, utilizando-se o programa WHATIF. Para as abordagens CoMFA e CoMSIA as geometrias otimizadas através do método semi-empírico AM1 foram alinhadas átomo-a-átomo e, através da similaridade dos respectivos campos estéricos e eletrostáticos, utilizando-se o programa SEAL. Nos dois procedimentos a geometria do composto não substituído, um dos mais ativos na série, foi utilizada como molde considerando-se a ausência de informações sobre a conformação bioativa. A modelagem da RNR por homologia foi realizada utilizando-se como molde as estruturas cristalográficas, respectivamente, do C. ammoniagenes (código PDB 1KGN) e da S. typhimurium (código PDB 1R2F), sambas apresentando valores de identidade superior a 65%. Mais recentemente foram publicados os dados cristalográficos para a cadeia beta (subunidade menor) da RNR do M. tuberculosis (código PDB 1UZR). Os modelos CoMFA e CoMSIA gerados apresentaram valores aceitáveis para os coeficientes de correlação de predição, com altos valores para os coeficientes de correlação ajustados e baixos valores para os erros padrões. Os melhores modelos CoMFA e CoMSIA foram obtidos considerando o grupo com substituintes apenas na posição 5 do anel piridínico. Razoáveis coeficientes de correlação de predição para os modelos CoMSIA com altos coeficientes de correlação de ajuste e baixos valores para os erros padrões forma obtidos. Os mapas de contorno gerados em CoMFA e CoMSIA sugerem que grupos aceptores de ligações de hidrogênio próximos ao nitrogênio do anel piridínico deverá aumentar o valor da atividade inibitória. Esta observação está em boa concordância com os dados da literatura, na qual a formação de um complexo entre a TSC e o íon Ferro foi sugerido para a inibição da RNR. Estes estudos deverão permitir um melhor entendimento sobre as características estruturais desta classe de TSC inibidoras da RNR, como agentes antitumorais, em termos dos campos estéricos, eletrostáticos, hidrofóbico, doador e aceptor de ligações de hidrogênio, bem como a contribuição para o desenvolvimento racional de novos inibidores para esta importante enzima. Adicionalmente, dois compostos preparados em nosso laboratório, demonstraram atividade frente o M. tuberculosis, em testes realizados in vivo. / Tuberculosis is an illness caused by Mycobacterium tuberculosis. Data from World Health Organization (WHO) estimates, that about 2-3 millions of human population died by Mycobacterium tuberculosis infection and that during the next 15 years about 1 billion will be infected and 35 million will certainly die. Although, in the clinic it was found several antiTBdrugs, these numbers will increase due several reasons including M. tuberculosis resistant strains. It has been stressed the importance of novel medicines and/or alternative biological targets research projects. It is known that Ribonucleotide reductase (RNR), is an enzyme that catalyses the rate limiting step in the de novo synthesis of dNTPs, reducing the ribonucleoside 5\'-diphosphates to the corresponding deoxyribonuc1eoside 5\' -diphosphates. RNR has a critical role in the DNA synthesis and, hence, cell division. This key enzyme, that shows 16% homology when compared with mammals RNR, is a potential target for drug design of cell growth inhibitors, with potential application in cancer therapy, antimalaria and trypanosome chemotherapy. It is known that different types of compounds or species by means of different mechanism pathways can show RNR inhibition, including &#945;-(N)-heterocyclic carboxaldehydes thiosemicarbazones that are one of the most potent classes of RNR inhibitors. More than that, some of them, that shows activity against M. tuberculosis seems to follow the same mechanism pathways proposed to the thiosemicarbazones tumor cells activity that means, that they probably are RNR inhibitors. In this study, a series of 40 &#945;-(N)-2-formyl-pyridine thiosemicarbazone derivatives tested against RNR of H.ep.-2-cells (human epidermoid carcinoma), taken from selected literature (French & Blanz-Jr. 1974), has quantitatively analyzed by means of several QSAR/3D-QSAR approaches. These compounds were divided into 5 individual subsets, namely A, B, C, D, and E, having 40, 39, 30, 23 e 22 compounds, respectively. This procedure has been done in order to achieve more structurally homogeneous subsets. For each set, three individual training and test sets (I,II and III) have been created in order to evaluate the predictivity power of the generated QSAR/3D-QSAR models. QSAR analysis have been done using descriptors generated by DRAGON program that have been further pre-selected by PLS procedures. Considering that crystallographic data of RNR M. tuberculosis are not available in the literature, 3D-QSAR studies have been done these applying, initially, CoMFA and CoMSIA approaches, implemented in SYBYL. Homology model studies have been performed with WHATIF program CoMFA e CoMSIA approaches used optimized geometry obtained by semi-empirical AM1 methods that have been aligned by two different methods. Rigid alignment, in which the compounds were fitted atom-by-atom onto a template, based on the root mean square fit. The N(l) and C(2) atoms of the pyridine moiety and the heavy atoms of thiosemicarbazone backbone of TSC were used as template structure. (2) Field based, in which the steric and electrostatic fields, generated by the SEAL program were considered in the alignment. In both procedures the unsubstituted 2-formylpyridine thiosemicarbazone in its syn conformation, has been taken as template. Homology RNR models were done using as template crystallographic data of ammoniagenes (1KGN) and S. typhimurium (1R2F) as template, respectively, with identity larger than 65%. More recent1y new crystallographic data have been published for the beta chain (smaller subunity) of RNR do M. tuberculosis (1UZR). CoMFA and CoMSIA generated models showed acceptable predictive correlation coefficients with high fitted correlation coefficients and low standard errors. Betler CoMFA and CoMSIA models have been derived considering a homogeneous subset of TSC substituted only at 5-position in pyridine ring. Reasonable predictive correlation coefficients for CoMSIA models with high fitted correlation coefficients and very low standard errors were obtained. The derived CoMFA and CoMSIA countour maps suggested that a hydrogen bond acceptor near the nitrogen pyridine ring could enhance inhibitory activity value. This observation is in good agreement with literature, in which a complex formation between TSC and iron ion has been suggested, to RNR inhibition. These studies are expected to enhance the understanding of the structural features of this class of TSC-RNR inhibitors as antitumor agents in terms of steric, electrostatic, hydrophobic and hydrogen donor and acceptor fields as well as to contribute to rational design of inhibitors of this key enzyme. Additionally, two compounds that have been prepared by us showed activity against M. tuberculosis using in vivo test system.

A tuberculose (TB) é uma doença causada pelo Mycobacterium tuberculosis. De acordo com estimativas da Organização Mundial da Saúde, a tuberculose é responsável pela morte de ~2 a 3 milhões de pessoas/ano no mundo e nos próximos 15 anos cerca de 1 bilhão de pessoas deverão ser infectadas, e destas, aproximadamente 35 milhões deverão morrer. Apesar de existirem vários medicamentos sendo utilizados no tratamento da doença, constatasse o crescimento no número de casos devido, principalmente, às variedades resistentes do M. tuberculosis. Considerando-se o aparecimento de cepas resistentes em TB, recomenda-se que novos medicamentos e/ou alvos biológicos alternativos devam ser intensivamente pesquisados. A ribonucleotídeo redutase (RNR), por exemplo, é uma proteína de interesse, pois catalisa uma etapa importante e única na síntese de novo dos dNTPs, reduzindo o ribonucleosídeo 5\' -difosfato ao seu correspondente desoxirribonucleosídeo 5\' -difosfato. A RNR é importante na síntese do DNA, e portanto, na divisão das células. Esta enzima importante, que possuí 16% de homologia com a RNR de mamíferos, é um alvo potencial para o desenvolvimento de novos fármacos, com provável aplicação no tratamento do câncer, da malária e do tripanossoma. Sabe-se que diferentes classes de compostos, através de diferentes mecanismos de ação, inibem a RNR, incluindo as &#945;-(N)-heterocíclicas carboxaldeído tiossemicarbazonas, um dos inibidores mais potentes da RNR. Sabe-se que alguns derivados da tiossemicarbazona, inibidoras da RNR de células tumorais, apresentam atividade frente o M. tuberculosis atuando provavelmente através do mesmo mecanismo, envolvendo a inibição da correspondente RNR. Neste contexto, nesta tese de doutorado, foram aplicadas diferentes abordagens de QSAR/QSAR-3D no estudo de 40 derivados da 2-piridino-carboxaldeído tiossemicarbazona, inibidores da RNR de células H.Ep.-2, retirados de literatura selecionada (French & Blanz-Jr. 1974). Estes compostos foram divididos em cinco séries, a saber: séries A, B, C, D, e E contendo, respectivamente, 40, 39, 30, 23 e 22 compostos, na tentativa de tornar estas séries estruturalmente mais homogêneas. Para cada série, foram criados três grupos de treinamento e os respectivos grupos de teste (I, II e III), visando-se avaliar o poder de predição dos modelos gerados através das análises de QSAR/QSAR-3D. Para as análises de QSAR clássico, foram utilizados como variáveis independentes, os descritores mais relevantes gerados através do programa DRAGON e, pré-selecionados por PLS. Considerando-se a ausência de informações sobre a estrutura cristalográfica da enzima RNR do M. tuberculosis, os estudos de QSAR-3D foram iniciados empregando-se metodologias propostas em CoMFA e, em CoMSIA, implementadas no programa SYBYL. Além destas, foi realizada a modelagem por homologia da RNR do M. tuberculosis, utilizando-se o programa WHATIF. Para as abordagens CoMFA e CoMSIA as geometrias otimizadas através do método semi-empírico AM1 foram alinhadas átomo-a-átomo e, através da similaridade dos respectivos campos estéricos e eletrostáticos, utilizando-se o programa SEAL. Nos dois procedimentos a geometria do composto não substituído, um dos mais ativos na série, foi utilizada como molde considerando-se a ausência de informações sobre a conformação bioativa. A modelagem da RNR por homologia foi realizada utilizando-se como molde as estruturas cristalográficas, respectivamente, do C. ammoniagenes (código PDB 1KGN) e da S. typhimurium (código PDB 1R2F), sambas apresentando valores de identidade superior a 65%. Mais recentemente foram publicados os dados cristalográficos para a cadeia beta (subunidade menor) da RNR do M. tuberculosis (código PDB 1UZR). Os modelos CoMFA e CoMSIA gerados apresentaram valores aceitáveis para os coeficientes de correlação de predição, com altos valores para os coeficientes de correlação ajustados e baixos valores para os erros padrões. Os melhores modelos CoMFA e CoMSIA foram obtidos considerando o grupo com substituintes apenas na posição 5 do anel piridínico. Razoáveis coeficientes de correlação de predição para os modelos CoMSIA com altos coeficientes de correlação de ajuste e baixos valores para os erros padrões forma obtidos. Os mapas de contorno gerados em CoMFA e CoMSIA sugerem que grupos aceptores de ligações de hidrogênio próximos ao nitrogênio do anel piridínico deverá aumentar o valor da atividade inibitória. Esta observação está em boa concordância com os dados da literatura, na qual a formação de um complexo entre a TSC e o íon Ferro foi sugerido para a inibição da RNR. Estes estudos deverão permitir um melhor entendimento sobre as características estruturais desta classe de TSC inibidoras da RNR, como agentes antitumorais, em termos dos campos estéricos, eletrostáticos, hidrofóbico, doador e aceptor de ligações de hidrogênio, bem como a contribuição para o desenvolvimento racional de novos inibidores para esta importante enzima. Adicionalmente, dois compostos preparados em nosso laboratório, demonstraram atividade frente o M. tuberculosis, em testes realizados in vivo. / Tuberculosis is an illness caused by Mycobacterium tuberculosis. Data from World Health Organization (WHO) estimates, that about 2-3 millions of human population died by Mycobacterium tuberculosis infection and that during the next 15 years about 1 billion will be infected and 35 million will certainly die. Although, in the clinic it was found several antiTBdrugs, these numbers will increase due several reasons including M. tuberculosis resistant strains. It has been stressed the importance of novel medicines and/or alternative biological targets research projects. It is known that Ribonucleotide reductase (RNR), is an enzyme that catalyses the rate limiting step in the de novo synthesis of dNTPs, reducing the ribonucleoside 5\'-diphosphates to the corresponding deoxyribonuc1eoside 5\' -diphosphates. RNR has a critical role in the DNA synthesis and, hence, cell division. This key enzyme, that shows 16% homology when compared with mammals RNR, is a potential target for drug design of cell growth inhibitors, with potential application in cancer therapy, antimalaria and trypanosome chemotherapy. It is known that different types of compounds or species by means of different mechanism pathways can show RNR inhibition, including &#945;-(N)-heterocyclic carboxaldehydes thiosemicarbazones that are one of the most potent classes of RNR inhibitors. More than that, some of them, that shows activity against M. tuberculosis seems to follow the same mechanism pathways proposed to the thiosemicarbazones tumor cells activity that means, that they probably are RNR inhibitors. In this study, a series of 40 &#945;-(N)-2-formyl-pyridine thiosemicarbazone derivatives tested against RNR of H.ep.-2-cells (human epidermoid carcinoma), taken from selected literature (French & Blanz-Jr. 1974), has quantitatively analyzed by means of several QSAR/3D-QSAR approaches. These compounds were divided into 5 individual subsets, namely A, B, C, D, and E, having 40, 39, 30, 23 e 22 compounds, respectively. This procedure has been done in order to achieve more structurally homogeneous subsets. For each set, three individual training and test sets (I,II and III) have been created in order to evaluate the predictivity power of the generated QSAR/3D-QSAR models. QSAR analysis have been done using descriptors generated by DRAGON program that have been further pre-selected by PLS procedures. Considering that crystallographic data of RNR M. tuberculosis are not available in the literature, 3D-QSAR studies have been done these applying, initially, CoMFA and CoMSIA approaches, implemented in SYBYL. Homology model studies have been performed with WHATIF program CoMFA e CoMSIA approaches used optimized geometry obtained by semi-empirical AM1 methods that have been aligned by two different methods. Rigid alignment, in which the compounds were fitted atom-by-atom onto a template, based on the root mean square fit. The N(l) and C(2) atoms of the pyridine moiety and the heavy atoms of thiosemicarbazone backbone of TSC were used as template structure. (2) Field based, in which the steric and electrostatic fields, generated by the SEAL program were considered in the alignment. In both procedures the unsubstituted 2-formylpyridine thiosemicarbazone in its syn conformation, has been taken as template. Homology RNR models were done using as template crystallographic data of ammoniagenes (1KGN) and S. typhimurium (1R2F) as template, respectively, with identity larger than 65%. More recent1y new crystallographic data have been published for the beta chain (smaller subunity) of RNR do M. tuberculosis (1UZR). CoMFA and CoMSIA generated models showed acceptable predictive correlation coefficients with high fitted correlation coefficients and low standard errors. Betler CoMFA and CoMSIA models have been derived considering a homogeneous subset of TSC substituted only at 5-position in pyridine ring. Reasonable predictive correlation coefficients for CoMSIA models with high fitted correlation coefficients and very low standard errors were obtained. The derived CoMFA and CoMSIA countour maps suggested that a hydrogen bond acceptor near the nitrogen pyridine ring could enhance inhibitory activity value. This observation is in good agreement with literature, in which a complex formation between TSC and iron ion has been suggested, to RNR inhibition. These studies are expected to enhance the understanding of the structural features of this class of TSC-RNR inhibitors as antitumor agents in terms of steric, electrostatic, hydrophobic and hydrogen donor and acceptor fields as well as to contribute to rational design of inhibitors of this key enzyme. Additionally, two compounds that have been prepared by us showed activity against M. tuberculosis using in vivo test system.

The eco-epidemiology of bovine tuberculosis (Tb) in wild deer (mainly red deer Cervus elaphus) in New Zealand was investigated. Bovine Tb is caused by Mycobacterium bovis. Specific aims were to clarify the likely routes of infection in deer, and to determine the status of deer as hosts of Tb, the likely rates and routes of inter- and intra-species transmission between deer and other wildlife hosts, the role of deer in spreading Tb, and the likely utility of deer as sentinels of Tb presence in wildlife. As the possum (Trichosurus vulpecula) is the main wildlife host of Tb, the research also included some investigation of transmission routes in possums. Patterns of infection were measured in 994 deer killed between 1993 and 2003. Tb prevalence varied between areas (range 8–36%). Few deer had generalised infection, with 21–68% of infected deer having no visible lesions, depending on the area. The retropharyngeal lymph nodes and oropharyngeal tonsils were commonly infected. No dependent fawns less than 0.75 years old were infected, indicating intra-species transmission is rare in wild deer. Where possums were not controlled, the net (cumulative) force of infection in young (1–4 y) deer was 0.10–0.24 per year in males and 0.09–0.12 per year in females, but much lower in older deer (less than 0.05 per year). Possum control reduced the net force of infection quickly, and eventually to zero. However, Tb persisted in possum-controlled areas through immigration of infected deer and, for almost a decade, through the survival of resident deer infected before possum control. Tb was lost from infected deer at an exponential rate of 0.13 per year, mostly as a result of deer recovering from infection rather than dying from it. Wild deer do die of Tb, but there was no discernible effect on age structure. The occurrence of infection in deer was not linked to the local deer or possum density at their kill sites (i.e. in their home range), but the area-wide prevalence of Tb in deer was closely correlated with Tb levels in possums, which were in turn correlated with area-wide measures of possum density. For wild deer in New Zealand, Tb is a persistent but usually inconsequential disease of the lymphatic system. It is acquired mainly by young independent deer, usually orally via the tonsils, and probably as a result of licking infected possums. Many species fed on deer carrion, including possums. Most possums encountering carrion did not feed on it, but a few fed for long periods. Other scavengers such ferrets (Mustela furo), hawks (Circus approximans), and weka (a hen-sized flightless native bird; Gallirallus australis) fed in a way that probably increased the infectivity of carrion to possums. Commercial deer hunting may have facilitated the historical establishment of Tb in possums. Scavenging (including cannibalism) and interactions with dead and dying possums are identified for the first time as potentially important routes for transmission of Tb to possums, and I develop new hypotheses involving peri- and post-mortem transmission in possums that explain many of the epidemiological patterns that are characteristic of the disease in possum. In continuous native forest, deer home range size averaged 250 hectares for six young females, and over twice that for two males. Over 90% of infected deer are likely to die within 2 km (females) or 6 km (males) of where they acquired Tb, but deer could occasionally carry Tb up to 30 km. Deer will be useful as sentinels, but only where other sentinels are rare, because the force of infection for a deer with a single infected possum in its home range is only 0.004 per year, compared to greater than 0.2 per year for deliberately released pigs. Deer are occasionally capable of initiating new cycles of infection in wildlife, but deer control is not essential to eradicate Tb from wildlife.

Text in English with questionnaire in Amharic / Purpose: The purpose of the study was to evaluate the effectiveness of the tuberculosis directly observed treatment, short-course (DOTS) strategy with respect to patient centeredness and satisfaction, and propose a model in support of the DOTS strategy in Addis Ababa, Ethiopia. Method: The study was conducted in Addis Ababa, Ethiopia using a mixed-method approach. An interviewer-administered questionnaire was used to collect quantitative data from 601 randomly selected TB patients who were on TB treatment followup in 30 health facilities.Three focus group discussions were conducted with 23 TB experts purposefully selected from 10 sub-city health offices and health bureau. Moreover, telephonic interviews were conducted with 25 defaulted TB patients who had been attending TB treatment in the health facilities. The quantitative data were described using mean, median, percentage and frequencies. Logistic regression and exploratory factor analysis were used to extract associated factors using SPSS version 21 software. Thematic analysis was used for qualitative data analysis. Deductive and inductive reasoning was used to propose a descriptive model with substantiating literatures. Findings: Of the 601 TB patients included, 40% of them perceived they had not received a patient-centred TB care (PC-TB care) with DOTS strategy. Gender (AOR=0.45, 95%CI 0.3, 0.7), good communication (AOR=3.2, 95%CI 1.6, 6.1), treatment supporter (AOR=3.4, 95%CI 2.1, 5.5) were associated with the perceived PC-TB care. Thirty-seven percent of TB patients were following their TB treatment with feeling of dissatisfaction with DOTS strategy. Gender (AOR=2.2; 95%CI 1.3, 3.57), place of residence (AOR=3.4; 95%CI 1.6, 7.6), presence of symptoms (AOR=0.6, 95%CI 0.40, 0.94) and treatment-supporter (AOR=4.3, 95%CI 2.7, 6.8) were associated with satisfaction of TB patients. TB experts and defaulted TB patients pointed out that DOTS strategy is not providing comprehensive PC-TB care except the provision of facility choice where to follow during initiation of the treatment. DOTS delivery system inflexibility, loose integration, HCPs’ characteristic, communication skill and motivation and the community awareness were explored factor with patient centeredness of DOTS. DOTS delivery system, incompatible of diagnosis and patient beliefs were the identified categories to default. The proposed PC-TB care model core constructs are patient, community, health care providers, health care organisation and TB care delivery system. The core constructs are directed by policy and monitoring and evaluation components. Conclusion: DOTS strategy is limited to provide fully integrated PC-TB care and did not provide full satisfaction to TB patients. Therefore, a support that makes the TB care patient-centred are important and the proposed PC-TB care model needs to be tested, practiced and evaluated for its performance toward increments of patient centeredness of TB care. / Health Studies / D.Litt. et Phil. (Health Studies)

The lack of a contextualised, relevant communication strategy focusing specifically on HAST diseases in the Limpopo Province was the impetus for this research. The purpose of this study was, therefore, to explore the knowledge, perceptions and utilisation of health facilities for HAST in order to develop an acceptable and effective communication strategy for the Province to address the high rate of HAST diseases. The study followed a qualitative approach guided by the major tenets of the Health Belief Model, namely, to determine modifying factors, individual beliefs and cues for action. An in-depth literature review was followed by focus group interviews with the community members and personal interviews with District and Provincial Deputy Directors. Based on these findings, a communication strategy was drafted and piloted for three months in one of the districts in Limpopo. Further refinement of the communication strategy followed after member-checking and further interviews with directors HAST. The final strategy specifically focused on risk groups with each of the diseases in terms of their beliefs and perceptions. It further resulted in guidelines for health providers in terms of the content and implementation of effective communication strategies within the context of educational, cultural, social and economic factors relevant to Limpopo / Health Studies / D. Litt. et Phil. (Health Studies)