The explosive growth in the ability to sequence DNA due to next-generation sequencing (NGS) technologies has brought an unprecedented ability to characterize an individual's exome inexpensively. This ability provides clinicians with additional tools to evaluate the likely genetic factors underlying heritable diseases. With this added capacity comes a need to identify relationships between the genetic variations observed in a patient and the disease with which the patient presents. This dissertation focuses on computational techniques to inform molecular diagnostics from NGS data. The techniques focus on three distinct domains in the characterization of disease-associated variants from exome sequencing. First, strategies for producing complete and non-artifactual candidate variant lists are discussed. The process of converting patient DNA to a list of variants from the reference genome is very complex, and numerous modes of error may be introduced during the process. For this, a Random Forest classifier was built to capture biases in a laboratory variant calling pipeline, and a C4.5 decision tree was built to enable discovery of thresholds for false positive reduction. Additionally, a strategy for augmenting exome capture experiments through evaluation of RNA-sequencing is discussed. Second, a novel positive and unlabeled learning for prioritization (PULP) strategy is proposed to identify candidate variants most likely to be associated with a patient's disease. Using a number of publicly available data sources, PULP ranks genes according to how alike they are to previously discovered disease genes. This strategy is evaluated on a number of candidate lists from the literature, and demonstrated to significantly enrich ordered candidate variants lists for likely disease-associated variants. Finally, the Training for Recognition and Integration of Phenotypes in Ocular Disease (TRIPOD) web utility is introduced as a means of simultaneously training and learning from clinicians about heritable ocular diseases. This tool currently contains a number of case studies documenting a wide range of diseases, and challenges trainees to virtually diagnose patients based on presented image data. Annotations by trainee and expert alike are used to construct rich phenotypic profiles for patients with known disease genotypes. The strategies presented in this dissertation are specifically applicable to heritable retinal dystrophies, and have resulted in a number of improvements to the accurate molecular diagnosis of patient diseases. However, these works also provide a generalizable framework for disease-associated variant identification in any heritable, genetically heterogeneous disease, and represent the ongoing challenge of accurate diagnosis in the information age.

The goal of this investigation was to marry two theories of supportive communication outcomes in order to test a comprehensive model of social support for people with obsessive-compulsive disorder (OCD). The theoretical frameworks utilized in this investigation were the theory of conversationally-induced reappraisals and the dual-process theory of supportive communication outcomes. These theoretical frameworks provide a foundation for the conversation of how social network members can help their loved ones with OCD manage their distressing symptoms as they explore the types of social support message features (verbal person-centeredness) that are most productive in achieving emotional improvement for those experiencing emotional distress. The union of these two theories in the context of social support and OCD management led to the testing of seven hypotheses. Participants (n = 168) who self-identified as living with OCD at some point in their life were recruited to fill out an online questionnaire. Results indicated support for the theory of conversationally-induced reappraisals, but not for the dual-process theory of supportive communication outcomes. Overall, the findings of this investigation highlighted the utility of emotional support messages high in verbal person-centeredness as they led those with OCD to reassess the intrusive nature of their symptoms, a process which promoted overall affective improvement. These associations suggest that social network members can help their loved ones with OCD manage their symptoms through supportive communication.

This dissertation contributes to the current understanding of human capital and its importance for earnings inequality and taxation. Human capital is typically defined as the stock of knowledge or skills acquired through education and working experience. The first chapter analyzes student borrowing behaviors in postsecondary education in the United States, the second chapter studies cross-country differences in earnings inequality within an endogenous growth model of human capital accumulation, and the third chapter examines the impact of endogenous human capital formations over a life-cycle on optimal fiscal policy. In Chapter 1, I document that new federal student loans for higher education in the United States have risen more than 5 times over the past 20 years. What caused this dramatic increase? I develop a heterogeneous life-cycle model of human capital accumulation to analyze individual college and borrowing decisions. Using this framework, I assess the quantitative contributions of changes in the college wage premium, college costs, maximum borrowing limits, and loan interest rates to explain the significant rise of federal student loans. I find that the calibrated model accounts for 57 percent of the actual increase in loans from 1990 to 2011. Increases in the college wage premium and college costs are important factors in generating the sharp rise in loans and, particularly, the increase in the fraction of borrowers and borrowing amounts. The expansion of credit availability and decreased loan interest rates have a relatively minimal impact on individual college and borrowing decisions. Chapter 2 explores why earnings inequality has been substantially higher in the US than in European countries over the last 30 years. I focus on the role of differences in tax progressivity, intergenerational earnings persistence, returns to education investments, and public education spending. I develop a growth model of human capital accumulation, and show analytically how those factors affect the dynamics of earnings inequality. The calibrated model accounts for 31 percent of the observed differences in earnings inequality between European countries and the US for 2003-07. Differences in returns to education investments and intergenerational earnings persistence are quantitatively important, suggesting the potential role of educational policy in ameliorating rising earnings inequality. Chapter 3, written jointly with Martin Gervais, analyzes the role of endogenous human capital accumulation in shaping optimal fiscal policy within a life-cycle growth model. We show that when investment in human capital is not verifiable---making the tax code incomplete---a non-zero capital income tax becomes optimal in order to alleviate the distortionary effects of the labor income tax on investment in human capital. This is true even if the government has access to a full set of age-dependent labor and capital income taxes. The main result is in sharp contrast to the finding in Jones et al. (1997) that all interest taxes are zero in infinitely-lived agent models with endogenous human capital formation.

Bacterial biofilm infection is a common (~ 2 to 4%) complication for recipients of surgically implanted medical devices. Due to the tremendous increase in antibiotic resistance when these bacteria enter the biofilm phenotype, present treatment requires explantation and replacement of the device, often with multiple surgeries and always with much longer patient recovery time. The specific objective of this study was to quantify the degree of biofilm deactivation from exposure to thermal shock for varying temperature and time durations. While extreme temperature (>150˚C) is routinely used to sterilize (e.g. autoclaves), such temperatures have a severe cost within the body. Despite extensive studies on thermal deactivation of bacteria in the planktonic phenotype over a wide range of temperatures (e.g., pasteurization protocols), surprisingly little is known about the thermal deactivation of biofilms except under extreme conditions. Here, the deactivation of Pseudomonas aeruginosa biofilms is reported. These biofilms were cultured at 37°C for 24 hours in a drip-flow reactor and subjected to heat shocks on the range of 50°C to 80°C for durations of 1 to 30 minutes. Heat shocks were delivered by immersion in thermostatted media for the prescribed time and the resulting concentration of colony forming units (CFU/mL) were quantified using direct enumeration. Up to 6.6 orders of magnitude reduction in CFU concentration was observed, indicating that thermal deactivation is a reasonable approach to biofilm mitigation. Integrating this approach with a magnetic nanoparticle implant coating will result in an innovative treatment for implant infections in situ without explantation or device replacement.

A long held hypothesis in mitochondrial biology holds that increases in mitochondrial Ca2+ levels stimulate the activity of matrix dehydrogenases that catalyze production of NADH and eventually donate electrons to electron transport in order to increase ATP formation. At the same time, mitochondrial Ca2+ overload is a deleterious event leading to opening of the mitochondrial permeability transition pore, increasing reactive oxygen species and initiating pathways that contribute to cell death. These fundamental hypotheses are best studied in the heart because of the critical energy supply-demand relationship in myocardium, but were untestable in vivo until the discovery of the mitochondrial Ca2+ uniporter (MCU). The molecular identity of the MCU pore forming subunit was recently discovered, which allowed me to study a transgenic mouse with myocardial delimited expression of a dominant negative MCU. My lab developed mice with myocardial-delimited transgenic expression of a dominant negative MCU to test these fundamental hypotheses and to determine how MCU controls physiological and pathological stress responses in vivo, ex vivo, and in situ. My studies provide new, unanticipated information that contributes to our understanding the relationship between mitochondrial Ca2+, oxygen utilization, cardiac pacemaking and pathologic stress responses in heart. Here, I show that mice with myocardial-targeted MCU inhibition have hearts with surprisingly high oxygen consumption rates due to elevated cytoplasmic Ca2+ in response to physiological stress. Loss of MCU effectively preserved inner mitochondrial membrane potential and prevented an oxidative burst thought to drive myocardial injury and death, but nevertheless failed to protect myocardium from ischemia-reperfusion injury. Increases in oxygen consumption, elevation in cytoplasmic Ca2+ and transcriptional reprogramming mitigate the protective actions of MCU inhibition in vivo. Mice with myocardial selective MCU inhibition have a reduced response to isoproterenol-induced heart rate increase but have normal baseline heart rates. My studies provide novel insight into how MCU contributes to myocardial Ca2+ homeostasis, metabolism, and transcription leading to surprising actions on physiological and pathophysiological responses in heart.

The application of spatial methods to epidemic estimation and prediction problems is a vibrant and active area of research. In many cases, however, well thought out and laboratory supported models for epidemic patterns may be easy to specify but extremely difficult to fit efficiently. While this problem exists in many scientific disciplines, epidemic modeling is particularly prone to this challenge due to the rate at which the problem scope grows as a function of the size of the spatial and temporal domains involved. An additional barrier to widespread use of spatiotemporal epidemic models is the lack of user friendly software packages capable of fitting them. In particular, compartmental epidemic models are easy to understand, but in most cases difficult to fit. This class of epidemic models describes a set of states, or compartments, which captures the disease progression in a population. This dissertation attempts to expand the problem scope to which spatio-temporal compartmental epidemic models are applicable both computationally and practically. In particular, a general family of spatially heterogeneous SEIRS models is developed alongside a software library with the dual goals of high computational performance and ease of use in fitting models in this class. We emphasize the task of model specification, and develop a framework describing the components of epidemic behavior. In addition, we establish methods to estimate and interpret reproductive numbers, which are of fundamental importance to the study of infectious disease. Finally, we demonstrate the application of these techniques both under simulation, and in the context of a diverse set of real diseases, including Ebola Virus Disease, Smallpox, Methicillin-resistant Staphylococcus aureus, and Influenza.

"Spark and Ruin: a Story of Re-beginning" is a multi-media concert dance work that addresses empathy as a physical and cognitive reactionary state, and utilizes dancing bodies as agents to facilitate this empathic experience. This work developed out of "The Flint Project," which investigates Flint, Michigan, "the most violent city in America," and a community characterized by racial tension and severe distinctions in class and social standing. This post-industrial, urban community serves as a microcosm through which we can examine how racial, social, and cultural politics intersect to establish systematic practices that challenge the possibility of the "American Dream." "The Flint Project" is a vehicle for creative research that investigates these systems and develops the material into a live performed event, "Spark and Ruin: a Story of Re-beginning". This performance includes installations featuring live performers and also various forms of media (including photography, film, and interactive "stations"). All of this material is constructed to contextualize the material for the viewer in a proscenium-style full-length dance performance. The objective of this piece is to establish a space for viewers to empathize with the material--to create an experience that will evolve into inquiry of systematic inequality as well as self-reflection of perception and bias. In facilitating this level of questioning, I aim to move viewers with compassion and heightened awareness of social inequity, as well as opportunities to chge the systems that enforce it.

As consumer demand for higher quality video at lower bit-rate increases, so does the need for more sophisticated methods of compressing videos into manageable file sizes. This research attempts to address these concerns while still maintaining reasonable encoding times. Modern segmentation and grouping analysis are used with code vectorization techniques and other optimization paradigms to improve quality and performance within the next generation coding standard, High Efficiency Video Coding. This research saw on average a 50% decrease in run-time by the encoder with marginal decreases in perceived quality.

Since the beginning of humankind, architecture has been a sacred source for all civilizations, and that has provided a gateway for man to reach the heavens above. In terms of concept and value, Persian art and architecture is considered as a rich source to be acknowledged. Within Persian architecture, the emphasis was placed strongly on beauty and sacred geometry; Persians calculated the proportions of heaven reflected upon them in the dimensions of buildings on the earth. Iranian culture has utilized the written word as an art form; this goes beyond normal means of communication. Iranian calligraphers produced eloquent styles and patterns through their divine talent, and this was displayed in the architecture. Parviz Tanavoli, as the greatest contemporary artist of Iran, has a strong tendency to be attracted to words and letters which has a long history in Iranian culture. Experimenting through aspects of cultural interaction in fine and applied arts has led to the understanding that when aesthetic elements of cultures are used to create a new design, it leads to both a new aesthetic creation and a fresh understanding of the cultures involved. This collection was designed and manufactured by concentrating on organic and curved forms and utilizing them in the design practice, while having a touch on cultural elements such as patterns and alphabets. The curved abstract shapes create a conceptual harmony, depicted in Persian patterns via functional three dimensional pieces.

Electroanalytical techniques are used to investigate mass transport through density gradient films; lanthanide triflate reduction and oxidation in a Nafion/acetonitrile matrix; and magnetic field effects on hydrogen evolution reaction (HER), oxygen reduction reaction (ORR), and lanthanide electrochemistry. Graded density films are more dense at the electrode surface and become less dense out into solution due to a brush polymer structure. Fick's second law expands to account for a diffusion coefficient that varies with distance x normal to the electrode surface. Confocal microscopy, cyclic voltammetry, and computer simulations are used to investigate density graded Ficoll® films. Mass transport approaches steady state (scan rate independence) at slow scan rates where the diffusion length samples the entire film. The use of Ficoll to template an ion exchange polymer is explored by casting Nafion® Ficoll composites. Lanthanide electrochemistry is enabled in acetonitrile at a Nafion modified platinum electrode in the presence of triflate ligands. Formal potentials are shifted into the voltage window of acetonitrile accessible due to triflate complexation. The Nafion further solubilizes the compounds. The mechanism (ECEC) is studied with cyclic voltammetry and x-ray photoelectron spectroscopy. Magnetic field effects on electrochemical systems have been of interest to researchers for the past 65 years. Mass transport effects, such as magnetohydrodynamics and magnetic field gradient effects have been reported, but the Leddy group focuses on electron transfer effects. Electrode surfaces are modified with composite films of magnetic microparticles suspended in ion exchange polymer Nafion. Effects are verified to be electron transfer related and due to the magnetization of chemically inert microparticles. The magnets catalyze the rates of important electron transfer reactions such as hydrogen evolution and oxygen reduction. Magnetic field effects on HER at various noncatalytic metal electrodes are explored with linear scan voltammetry. There is a correlation between the magnetic susceptibility of the electrode metals and the HER exchange currents (reaction rates). Exchange currents are 103× larger for a paramagnetic metal electrode than a diamagnetic one with the same work function. The overpotential at diamagnetic electrodes is decreased by modification with a Nafion + magnetic microparticle composite film. A decrease in overpotential of ∼70 % for all electrodes except platinum is observed. The overpotential decrease correlates with the magnetic susceptibility of the particles. Magnets can enhance differences between lanthanide cyclic voltammograms by shifting current densities at a given potential and enhancing current based on the number of 4f electrons and magnetic moment of each lanthanide ion. Magnetic field effects on ORR in acetonitrile are investigated with cyclic voltammetry. In aprotic solvents, ORR proceeds by a one electron transfer reaction to paramagnetic O2.–. Enhanced reversibility and electron transfer kinetics are observed as well as a decrease in overpotential of ∼100 mV. Magnetic field effects on ORR in a lanthanide triflate solution are also examined. Electron transfer kinetics and reversibility are further enhanced in the presence of lanthanide triflate.