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El polietileno es un polímero versátil de bajo costo usado en numerosas aplicaciones, desde partes de automóviles hasta envases de comida, juguetes, films, pañales y bolsas de residuos, cuya demanda mundial es de aproximadamente 76 millones de toneladas métricas al año. Junto con el polipropileno, representa casi dos tercios de los termoplásticos “commodities” usados en el mundo, estimados en 130 millones de toneladas métricas en 2011. Una de las tecnologías más utilizadas en el mundo para la fabricación comercial de polietileno es la de fase gas. La inversión de capital y los requerimientos energéticos para operar los reactores de fase gas son relativamente bajos comparados con otros procesos existentes para la producción de polietileno. Esta ventaja, sumada a la gran flexibilidad en cuanto a las variaciones de índices de fluidez y densidades de los productos que se pueden producir en estos reactores, hace de este proceso un tema de estudio sumamente interesante. En esta tesis se desarrolló un modelo integrado del reactor de lecho fluidizado y sus equipos auxiliares, para modelar la operación de una planta que produce polietileno de baja densidad lineal, utilizando etileno como monómero y 1‐buteno como comonómero, en presencia de un catalizador tipo Ziegler‐Natta. Para ello se realizó inicialmente una búsqueda bibliográfica donde se analizaron los diferentes modelos para polimerización de etileno en fase gas ya desarrollados por otros autores. Para la representación de la operación del reactor de lecho fluidizado, se implementaron dos modelos: un modelo simplificado de mezclado perfecto, y un modelo más complejo de dos fases, donde la fase gas tiene burbujas de tamaño constante. Luego se ampliaron ambos modelos incorporando los equipos que conforman el reciclo de la planta, es decir, el compresor, el intercambiador, y el mezclador de la corriente fresca con la corriente de reciclo. Finalmente, se realizó un ajuste inicial de los parámetros cinéticos de cada uno de los modelos y también de algunas condiciones operativas (caudal de catalizador y velocidad superficial del gas) con el objetivo de minimizar la diferencia entre los valores calculados y experimentales de temperatura del reactor y peso molecular promedio en peso y en número del polímero. Los valores de pesos moleculares promedio en peso y en número se obtuvieron experimentalmente a partir de muestras de polietileno de dos productos comerciales que se producen en una planta de tecnología fase gas ubicada en Bahía Blanca, utilizando cromatografía por exclusión de tamaños. Ambos modelos del reactor autónomo, con sus respectivos set de parámetros estimados, fueron capaces de predecir apropiadamente los valores típicos de temperatura del reactor, conversión y los pesos moleculares promedio en número y en peso, para las condiciones de proceso industriales estudiadas en esta tesis. Asimismo, ambos modelos integrados fueron capaces de reproducir adecuadamente los valores de las variables de los estados estacionarios para los cuales se ajustaron los parámetros. En lo que respecta a las perturbaciones en ciertas variables, la respuesta de los modelos integrados fue disímil. El comportamiento del modelo de mezclado perfecto resultó inestable ante perturbaciones en ciertas variables del proceso, por causas que fue imposible precisar en detalle. Por el contrario, el modelo de dos fases de burbuja constante fue capaz de reproducir apropiadamente el comportamiento del proceso industrial ante perturbaciones acotadas de variables clave como la temperatura y caudal de agua de enfriamiento, velocidad superficial del gas, flujo másico del catalizador, y concentraciones de monómero, comonómero e hidrógeno. En consecuencia, el modelo integrado de dos fases con tamaño de burbuja constante, se utilizó para realizar diversos análisis de sensibilidad para determinar el impacto que tienen diferentes variables operativas y de diseño sobre la estabilidad térmica del reactor, su capacidad productiva y las características del producto obtenido. Esto permitió profundizar la comprensión del comportamiento de los reactores de lecho fluidizado, lo que sin duda redunda en una mejor preparación para la toma de decisiones en planta. Finalmente, se puede mencionar que entre los usos potenciales de este modelo matemático se incluyen la simulación y testeo de esquemas de control de calidad en línea, la predicción de los efectos de políticas de transición de grado en las distribuciones de peso molecular y composición; y el ser útil como herramienta de optimización del proceso, por ejemplo definidas las características moleculares que debe tener el polietileno para cierto tipo de aplicaciones finales, encontrar las condiciones operativas que permitan obtenerlo y además, maximicen la productividad.

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No / Synthetic Biology aspires to design, compose and engineer biological systems that implement specified behaviour. When designing such systems, hypothesis testing via computational modelling and simulation is vital in order to reduce the need of costly wet lab experiments. As a case study, we discuss the use of computational modelling and stochastic simulation for engineered genetic circuits that implement Boolean AND and OR gates that have been reported in the literature. We present performance analysis results for nine different state-of-the-art stochastic simulation algorithms and analyse the dynamic behaviour of the proposed gates. Stochastic simulations verify the desired functioning of the proposed gate designs.

This research presents a mathematical model for the transportation and distribution of COVID-19 vaccine, a simulation model for fleet optimization, and a measurement model for "Healthcare 4.0." Essay 1 examines the development of a distribution model using mixed integer programming (MIP) with the objective of maximizing the number of vaccinated individuals, minimizing transportation costs across the entire network, and ensuring widespread access. This research primarily focuses on the distribution aspect of the vaccine and accordingly devises a model for transportation and distribution that ensures swift and efficient delivery of the COVID-19 vaccine. Essay 2 provides a simulation-based model to enhance logistics performance by including drones along with vaccine trucks and air cargo in the vaccine distribution fleet. The simulation model focuses on minimization of the overall cost of distribution of medical supplies. This second study shows that the types of vehicles utilized have an impact on overall system performance. The selection of the appropriate mix for the mode of transportation impacts transportation costs and lead time. To increase the responsiveness and cost-effectiveness of the logistics system for delivery of the vaccine a proper fleet configuration is required. The model developed in this study is validated via application in Telangana, India as well as through confirmation about the applicability of the model with healthcare executives. Essay 3 introduces a measurement model and constructs for Healthcare 4.0, specifically tailored for implementation by healthcare service providers. While the concept of Healthcare 4.0 and its various components have been explored in the literature, the existing body of research primarily consists of conceptual and theoretical studies, indicating that Healthcare 4.0 is still a relatively nascent research domain. In order to facilitate practical and theoretical advancements in this field, it is imperative to refine the constructs and establish a consensus on perspectives and definitions. To address this need, the items pertaining to Healthcare 4.0 for healthcare service organizations were developed through an extensive literature review and interviews conducted with practitioners in the field. The resulting theoretical model was further validated by surveying experienced professionals from the healthcare industry, utilizing Mturk as a platform.

Supported Ni and Rh catalysts were developed for the reforming of two greenhouse gases, methane and carbon dioxide to syngas (a mixture of hydrogen and carbon monoxide). This is an endothermic, equilibrium limited reaction. To overcome the thermodynamic limitations, a commercially available porous membrane (Vycor glass) was used in a combined reactor-separator configuration. This was to selectively remove one or more of the products from the reaction chamber, and consequently shift the equilibrium to the right. However, the separation mechanism in this membrane involved Knudsen diffusion, which provided only partial separations. Consequently, there was some transport of reactants across the membrane and this led to only marginal improvements in performance. To overcome this limitation, a new membrane was developed by modifying the Vycor substrate by the chemical vapor deposition of a silica precursor. This new membrane, termed Nanosil, provided high selectivity to hydrogen at permeabilities comparable to the support material. Application of this membrane in the combined reactor-separator unit provided higher conversions than that obtained using the Vycor membrane. / Ph. D.

Calcium (Ca) homeostasis is the maintenance of a stable plasma Ca concentration in the human body in the presence of Ca variability in the physiological environment (e.g. by ingestion and/or excretion). For normal physiological function, the total plasma Ca concentration must be maintained within a very narrow range (2.2-2.4mM). Meeting such stringent requirements is the task of a regulatory system that employs parathyroid hormone (PTH) and calcitriol (CTL) to regulate Ca flux between the plasma and the kidneys, intestines and bones. On the other hand, plasma phosphate control is less tightly, but simultaneously, regulated via the same hormonal actions. Chronic imbalances in plasma Ca levels are associated with disorders of the regulatory organs, which cause abnormal hormonal secretion and activity. These changes in hormonal activity may lead to long-term problems, such as, osteoporosis (increased loss of bone mineral density), which arises from primary hyperparathyroidism (PHPT) – hyper secretion of PTH. Existing in silico models of Ca homeostasis in humans are often cast in the form of a single monolithic system of differential equations and are not easily amenable to the sort of tractable quantitative analysis from which one can acquire useful fundamental insight. In this research, the regulatory systems of plasma Ca and plasma phosphate are represented as an engineering control system where the physiological sub-processes are mapped onto corresponding block components (sensor, controller, actuator and process) and underlying mechanisms are represented by differential equations. Following validation of the overall model, Ca-related pathologies are successfully simulated through induced defects in the control system components. A systematic approach is used to differentiate PHPT from other diseases with similar pathophysiologies based on the unique hormone/ion responses to short-term Ca disturbance in each pathology model. Additionally, based on the changes in intrinsic parameters associated with PTG behavior, the extent of PHPT progression can be predicted and the enlarged gland size estimated a priori. Finally, process systems engineering methods are used to explore therapeutic intervention in two Ca-related pathologies: Primary (PHPT) and Secondary (SHPT) Hyperparathyroidism. Through parametric sensitivity analysis and parameter space exploration, the calcium-sensing receptor (sensor) is identified as a target site in both diseases and the extent of potential improvement is determined across the spectrum of severity of PHPT. The findings are validated against existing drug therapy, leading to a method of predicting drug dosage for a given stage of PHPT. Model Predictive Control is used in drug therapy in SHPT to customize the drug dosage for individual patients given the desired PTH outcome, and drug administration constraints. / Ph. D.

Aspergillus fumigatus is a ubiquitous fungus associated with several airway complications and diseases including asthma, allergies, cystic fibrosis, and most commonly invasive aspergillosis. The airway epithelium, a protective barrier, is the first anatomical site to interact with A. fumigatus. Although this host-fungal interaction is often asymptomatic for immunocompetent individuals, for immunocompromised persons, due to a weakened competence of the immune system, they have an increased likelihood of fungal infection. This dissertation aims to investigate the effect of A. fumigatus on the transcriptional response of human airway epithelial cells, focusing on the relationship between innate immunity and iron regulation from the host perspective. The trace element iron is needed by both the fungus and the host for cellular maintenance and survival, but tightly controlled iron regulation in the host is required to prevent oxidative stress and cell death. The research methods in this dissertation employ a systems biology approach, by incorporating mathematical modeling, RNA-seq analysis, and experimental biology techniques to assess the role of airway epithelial cells in the host-fungal interaction. Both the quantitative and qualitative research design allows for characterization of airway epithelial cells and the downstream changes in iron importer genes. This study addresses literature gaps through analysis of the host transcriptome using multiple time points, by performing an extensive evaluation of the effect of cytokines on iron importer genes, and conceptualization of a comprehensive mathematical model of the airway epithelial cell. The major findings suggest the following: 1) airway epithelial cells avidly respond to A. fumigatus through modification of the expression of immune response related genes at different infection stages, 2) during A. fumigatus co-incubation with airway epithelial cells, the iron importers genes respond in strikingly different ways, and 3) cytokines have a significant effect on the increase in expression of an iron importer gene. We illuminated the role of airway epithelial cells in fungal recognition and activation of the immune response in signaling cascades that consequently modify iron importer genes and hope to use this information as a platform to discover potential therapeutic targets. / Ph. D.