Cardiac and Mitochondrial Impacts of Acute Pulmonary Xenobiotic Exposure

With every breath, we breathe in foreign materials, xenobiotic particles. These particles can interact with our tissues and influence the systems within. Airborne xenobiotic particles classically refer to ambient particulate matter (PM), but with technological advancement and the flourishing of nanotechnology, engineered nanomaterials (ENMs) have become entwined in the definition. Because the term xenobiotic particles encompasses particles with a broad range of size, shapes and chemical composition, definition of the properties that induce toxicity can be difficult, yet crucial to understand and predicting which of these characteristics is capable of inducing toxicity. This concept is crucial as nanotechnology moves forward and continues to introduce particles with new, unique properties. Beginning to identify the health impacts of xenobiotic particles it is important to consider ambient air pollution and the solid fraction of this mixture, particulate matter (PM). PM itself is a non-uniform, composite particle containing particles ranging in size and chemical composition. Further, PM composition can vary geographically and has been shown to differentially affect cardiovascular susceptibilities and outcomes. Within the Appalachian region, coal is a multi-billion dollar industry and comes in two forms: underground and surface mining. Surface mining is growing throughout the region due to its less labor-intensive methods, which employs large machinery to remove the soil and rock from on top of mineral deposits. One form of surface mining utilizes explosives to remove this overburden, mountaintop removal mining (MTM). Even though the mining companies attempt to abate fugitive dust, the populations surrounding these mining operations have a higher incidence of chronic cardiovascular disease mortality rates. This suggests that the PM created by MTM (PMMTM) may induce cardiac stress leading to cardiovascular disease. Nanotechnology is rapidly growing into a multi-billion dollar industry and is already incorporated into consumer products including everything from sporting equipment and food storage to personal care products and biomedical applications. With the rapid growth of nanotechnology, the toxicological impact of the ENMs driving expansion cannot keep pace with the advancement. Nano-sized particles differ in their physicochemical properties as compared to their micron-sized counterparts and while these properties imbue them with the novel applications driving nanotechnology, they may also be driving toxicological impacts. ENMs are carefully and methodically produced in particles of varying size, shape and chemical composition to accomplish different consumer-based end-products. Multi-walled carbon nanotubes (MWCNT) are a rapidly growing ENM with uniquely strong and electrical properties making it useful in everything from sporting equipment to electronics. Titanium dioxide (nano-TiO2) is a relatively inert ENM widely used as a photocatalyst and pigment in paints and personal care products. Exposure to these materials has shown adverse pulmonary and cardiovascular effects but the cardiac functional impacts following exposure have not been well characterized. Further, the subcellular cardiac mechanisms impacted by xenobiotic exposure have not been well defined. The mitochondrion may be a target of xenobiotic exposure propagating toxicity. Within the cardiomyocyte, mitochondrial analyses are further complicated by the presence of spatially and biochemically distinct subpopulations of mitochondria: the subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. The SSM sit below the sarcolemma while the IFM reside within the contractile apparatus. The goal of the current studies was to investigate the cardiac and mitochondrial impacts following an acute pulmonary xenobiotic exposure. To complete this goal, we utilized pulmonary exposure techniques, state of the art echocardiographic assessment, and mitochondrial functional analyses following xenobiotic exposure. Following a pulmonary exposure to PMMTM, we identified a significant decrease in cardiac ejection fraction and fractional shortening concomitant with an increase in cardiac apoptosis. Investigation into the source of apoptotic signaling suggested the mitochondria as central into apoptotic initiation and leads to both SSM and IFM respiratory dysfunction. Similarly, when we exposed animals to MWCNT we identified cardiac dysfunction developing after SSM and IFM respiratory dysfunction. Yet, further investigation into the mitochondrial affects identified that the IFM produced more reactive oxygen species (ROS) following exposure. Finally, following exposure to nano-vTiO2 cardiac diastolic dysfunction was observed indicative of restrictive filling during diastole. Following exposure, there was a significant decrease in mitochondrial respiratory function and an increase in ROS production and damage in the IFM. To attenuate the mitochondrial ROS production and damage leading to cardiac dysfunction, we utilized a novel transgenic animal overexpressing the antioxidant mitochondrial phospholipid hydroperoxide glutathione peroxidase (mPHGPx). MPHGPx has been previously shown to be efficient in protecting the inner mitochondrial membrane (IMM) from ROS damage and preserve the mitochondrion\u27s function and proteome. The IMM is essential to protect as the complexes within the mitochondrial electron transport chain (ETC) reside within the locale. Overexpressing mPHGPx attenuated mitochondrial ROS production and damage as well as the cardiac diastolic dysfunction observed following exposure to nano-TiO2. (Abstract shortened by UMI.)

Numerical Methods for Parameter Estimation in Stochastic Systems

The objective of this work is to provide numerical simulations in support of a collection of existing results on estimation in two distinct types of stochastic systems. In the first chapter, we consider a linear time-invariant higher-order system of order that is subject to white noise perturbation. We numerically illustrate the result that the quadratic variation estimator of the white noise local variance is asymptotically biased when a forward-difference approach is used for numerically approximating the derivatives of the stochastic process, and that the bias can be eliminated by instead applying a specific alternative numerical differentiation scheme. Moreover, we consider the result that the straightforward discretization of a least squares estimation procedure for unknown parameters in the system leads to an asymptotically biased estimate. In the second chapter, we consider a controlled Markov chain, taking values on a finite state space, whose transition probabilities are assumed to depend on an unknown parameter belonging to a compact set. We first provide numerical illustration of the result that under a particular identifiability condition, the maximum likelihood estimator of this parameter is strongly consistent. Next, we illustrate that under alternative assumptions the sequence of maximum likelihood estimates converges and retains a desirable property relating to the Markov chain's transition probabilities. Additionally, we present a survey of several other related results

Comparing Distance-Based Vs. Time-Based Exercise Prescriptions Of Walking And Running For Improvement Of Cardiovascular Disease Risk Factors

The many benefits of participation in a regular physical activity program are well-documented (Haskell et al., 2007; Pate et al., 1995). Brisk walking and jogging are commodes of exercise that is easily measured and evaluated by a self-report method that is comin both clinical and research settings. Some research has suggested that walking for distance as opposed to walking for time may be a stronger predictor of overall amount of accumulated exercise or physical activity (Williams, 2012a). To our knowledge, research has not been conducted directly comparing a distance-based versus time-based brisk walking prescription for the improvement of cardiovascular risk factors. The primary purpose of this study was to compare walking/running for distance to walking/running for time as part of a weight loss intervention to assess similarities or differences. Another purpose was to evaluate included the feasibility of a previously published regression equation in predicting energy expenditure for walking or running for a one-mile distance before and after exercise weight loss intervention. This study folloa between-subjects, repeated measures design with each participant reporting for pre-intervention as well as post-intervention testing. Twenty-one overweight, but otherwise healthy participants [10 for distance-based (dist) group, 11 for time-based (time) group] were recruited but only 15 participants completed the study (9 time, 6 dist). Informed consent was obtained from the participants who fit the inclusion criteria based on the physical activity readiness questionnaire and body composition measurements using dxa. Participants were required to complete four testing sessions at the beginning of intervention and three testing sessions at the completion of intervention. Each testing session was separated by 24 hours. The time intervention group walked and ran for self-reported exercise time completed per day, and accumulated per week. The dist intervention group walked and ran for self-reported exercise distance completed per day, and accumulated per week. Each participant was measured for the following postabsorptive variables: lipid panel which included (total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides), glucose, resting metabolic rate (rmr). Body composition, vo2 max, measured kcal/mile and predicted kcal/mile were also measured before and following intervention. A mixed-factor repeated- measures anova (rm-anova) was used to compare all cardiovascular disease risk-related dependent variables before and after intervention (body weight, body composition, blood lipids & glucose, rmr, vo2 max) for within-subjects and between-subjects comparisons. A mixed-factor repeated-measures anova was also used to compare weekly adherence rates to the exercise program. If interactions occurred, they were folloup with a sidak adjustment for multiple pairwise comparisons. Overall, the groups adhered to the exercise programs at similar rates. Significant interactions were shown for mean body weight loss between groups as well as mean blood glucose level (p \u3c 0.05). The dist group lost an average of 4.0 kg while the time group gained an average of 1.1 kg. The dist group exhibited a decline in their blood glucose level by an average of 10.5 mg/dl while the time group shoan increase in their blood glucose level by an average of 4.7 mg/dl. Additionally, running one-mile was significantly more expensive metabolically than walking the mile at both pre- and post-intervention. Also, excess post-exercise oxygen consumption was significantly greater in the five minutes following running compared to walking. To the best of the author\u27s knowledge, the present study is the first to directly compare a distance-based vs. A time-based exercise program for walking and running for improvement of risk factors of cvd. The results of the particular study would suggest that a distance-based exercise prescription of walking or running should provide a clinician or researcher with a closer estimation of overall ee and resultantly weight loss and reduction of particular risk factors for cvd

Cross-Validation Of A Recently Published Equation Predicting Energy Expenditure To Run Or Walk A Mile In Normal Weight And Overweight Adults

An equation recently published by Loftin, et al. (2010) was cross-validated using 30 subjects consisting of 10 normal weight walkers, 10 overweight walkers, and 10 distance runners. Gender was balanced across sub-groups. Participants walked or ran for 5 minutes at their preferred pace. Preferred walking pace was determined by six timed 50-ft trials and preferred running pace by the runner\u27s typical training pace. Energy expenditure (EE) was determined via indirect calorimetry and reported in absolute units (kcal), and corrected to a mile distance. Body composition was assessed via DXA. EE per mile was predicted using the Loftin, et al. (2010) equation. The equation [Kcal = mass (kg) x 0.789 ? gender (men=1, women=2) x 7.634 + 51.109; R2 = 0.632, SEE = 10.9 kcal/mile] yielded a mean of 99.7 ± 10.9 kcal/mile which was significantly different (p \u3c 0.05) than the measured mean of the cross-validation group (107.8 ± 15.5 kcal/mile). However, the mean was within the standard error of the estimate of the original equation. Further analysis included a Chow test which yielded no significant differences between regression coefficients of the original equation and the cross-validation (CV) group [Kcal = mass (kg) x 0.825 ? gender (men=1, women=2) x 1.687 + 47.6; R2 = 0.625, SEE = 9.82 kcal/mile] equation. Also, absolute EE per mile for the CV group was similar across sub-groups. It appears the Loftin, et al. regression equation is useful for exercise prescription in that it allows for the prediction of EE for either walking or running a mile in normal weight and overweight adults

A Stochastic System Model for PageRank: Parameter Estimation and Adaptive Control

A key feature of modern web search engines is the ability to display relevant and reputable pages near the top of the list of query results. The PageRank algorithm provides one way of achieving such a useful hierarchical indexing by assigning a measure of relative importance, called the PageRank value, to each webpage. PageRank is motivated by the inherently hypertextual structure of the World Wide Web; specifically, the idea that pages with more incoming hyperlinks should be considered more popular and that popular pages should rank highly in search results, all other factors being equal. We begin by overviewing the original PageRank algorithm and discussing subsequent developments in the mathematical theory of PageRank. We focus on important contributions to improving the quality of rankings via topic-dependent or "personalized" PageRank, as well as techniques for improving the efficiency of PageRank computation based on Monte Carlo methods, extrapolation and adaptive methods, and aggregation methods We next present a model for PageRank whose dynamics are described by a controlled stochastic system that depends on an unknown parameter. The fact that the value of the parameter is unknown implies that the system is unknown. We establish strong consistency of a least squares estimator for the parameter. Furthermore, motivated by recent work on distributed randomized methods for PageRank computation, we show that the least squares estimator remains strongly consistent within a distributed framework. Finally, we consider the problem of controlling the stochastic system model for PageRank. Under various cost criteria, we use the least squares estimates of the unknown parameter to iteratively construct an adaptive control policy whose performance, according to the long-run average cost, is equivalent to the optimal stationary control that would be used if we had knowledge of the true value of the parameter. This research lays a foundation for future work in a number of areas, including testing the estimation and control procedures on real data or larger scale simulation models, considering more general parameter estimation methods such as weighted least squares, and introducing other types of control policies

Roger Williams: seventh century puritan

Roger Williams, founder of Rhode Island and rebel against the Puritan theocracy, has traditionally been viewed by historians as a progenitor of modern democratic institutions and practices. He is seen as a twentieth century thinker. His writings are received as political tracts couched in the rhetoric of theology, and his activity in Rhode Island is studied as an experiment in democracy. This thesis presents a different interpretation ofthe life and writings of Roger Williams

GASCan 2 payload integration

This project, conducted in cooperation with the NASA Advanced Space Design Program, is part of an ongoing effort to place an experiment package into space. The goal of this project is to build and test flight-ready hardware that can be launched from the Space Shuttle. Get Away Special Canister 2 (GASCan 2) consists of three separate experiments. The Ionospheric Properties and Propagation Experiment (IPPE) determines effects of the ionosphere on radio wave propagation. The Microgravity Ignition experiment (MGI) tests the effects of combustion in a microgravity environment. The Rotational Fluid Flow experiment (RFF) examines fluid behavior under varying levels of gravity. This year the following tasks were completed: design of the IPPE antenna, X- and J-cell battery boxes, J-cell battery box enclosure, and structural bumpers; construction of the MGI canisters, MGI mounting brackets, IPPE antenna, and battery boxes; and the selection of the RFF's operating fluid and the analysis of the fluid behavior under microgravity test conditions