Digital Commons Network^™

A Brief Elevation Of Serum Amyloid A Is Sufficient To Increase Atherosclerosis, Joel C. Thompson

Theses and Dissertations--Pharmacology and Nutritional Sciences

Cardiovascular disease is now the leading cause of death worldwide. Serum amyloid A (SAA), a positive acute phase reactant, along with C-reactive protein is used clinically as a marker of cardiovascular disease risk. However, recent data has shed light on a possible causal role of SAA in the development of atherosclerosis, the most pervasive form of cardiovascular disease. Several inflammatory diseases such as diabetes and obesity are known to confer increased risk of developing cardiovascular disease. Individuals with these diseases all have modest but persistent elevation of SAA. To determine if SAA caused the development of atherosclerosis, apoe^-/-chow …

Macroeconomic Effects And Microeconomic Determinants Of Fertility, Maria R. Apostolova-Mihaylova

Theses and Dissertations--Economics

This dissertation focuses on the relationship between the education-based fertility gap and economic growth and on policy as a determinant of fertility.

In the first essay I evaluate the impact of differential fertility (the difference between fertility rates of women with high educational attainment and women with low educational attainment) on economic growth by accounting for critical marginal effects and the general level of educational attainment in a given country. I also examine the possibility that this effect varies based on level of inequality and income levels. I find that for a less developed country with high income inequality, higher …

Immobilizing Mutation In An Unconventional Myosin15a Affects Not Only The Structure Of Mechanosensory Stereocilia In The Inner Ear Hair Cells But Also Their Ionic Conductances, Diana Syam

Theses and Dissertations--Medical Sciences

In the inner and outer hair cells (OHCs) of the inner ear, an unconventional myosin 15a localizes at the tips of mechanosensory stereocilia and plays an important role in forming and maintaining their normal structure. A missense mutation makes the motor domain of myosin 15a dysfunctional and is responsible for the congenital deafness DFNB3 in humans and deafness and vestibular defects in Shaker-2 (Sh2) mouse model. All hair cells of homozygous Shaker-2 mice (Myo15^sh2/sh2) have abnormally short stereocilia, but, only stereocilia of Myo15^sh2/sh2OHCs start to degenerate after the first few days of postnatal development …

Contaminated Chi-Square Modeling And Its Application In Microarray Data Analysis, Feng Zhou

Theses and Dissertations--Statistics

Mixture modeling has numerous applications. One particular interest is microarray data analysis. My dissertation research is focused on the Contaminated Chi-Square (CCS) Modeling and its application in microarray. A moment-based method and two likelihood-based methods including Modified Likelihood Ratio Test (MLRT) and Expectation-Maximization (EM) Test are developed for testing the omnibus null hypothesis of no contamination of a central chi-square distribution by a non-central Chi-Square distribution. When the omnibus null hypothesis is rejected, we further developed the moment-based test and the EM test for testing an extra component to the Contaminated Chi-Square (CCS+EC) Model. The moment-based approach is easy and …

Genetic Association Testing Of Copy Number Variation, Yinglei Li

Theses and Dissertations--Statistics

Copy-number variation (CNV) has been implicated in many complex diseases. It is of great interest to detect and locate such regions through genetic association testings. However, the association testings are complicated by the fact that CNVs usually span multiple markers and thus such markers are correlated to each other. To overcome the difficulty, it is desirable to pool information across the markers. In this thesis, we propose a kernel-based method for aggregation of marker-level tests, in which first we obtain a bunch of p-values through association tests for every marker and then the association test involving CNV is based on …

Natural Phenomena As Potential Influence On Social And Political Behavior: The Earth’S Magnetic Field, Jackie R. East

Theses and Dissertations--Political Science

Researchers use natural phenomena in a number of disciplines to help explain human behavioral outcomes. Research regarding the potential effects of magnetic fields on animal and human behavior indicates that fields could influence outcomes of interest to social scientists. Tests so far have been limited in scope. This work is a preliminary evaluation of whether the earth’s magnetic field influences human behavior it examines the baseline relationship exhibited between geomagnetic readings and a host of social and political outcomes. The emphasis on breadth of topical coverage in these statistical trials, rather than on depth of development for any one model, …

Beyond Peroxisome: Abcd2 Modifies Pparα Signaling And Identifies A Subclass Of Peroxisomes In Mouse Adipose Tissue, Xiaoxi Liu

Theses and Dissertations--Pharmacy

ABCD2 (D2) has been proposed as a peroxisomal long-chain acyl-CoA transporter that is essential for very long chain fatty acid metabolism. In the livers of mice, D2 is highly induced by fenofibrate, a PPARα ligand that has been widely used as a lipid lowering agent in the treatment of hypertriglyceridemia. To determine if D2 is a modifier of fibrate responses, wild-type and D2 deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that …

Quantification Of Factors Governing Drug Release Kinetics From Nanoparticles: A Combined Experimental And Mechanistic Modeling Approach, Kyle Daniel Fugit

Theses and Dissertations--Pharmacy

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies.

A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release …

Synthesis And Biological Evaluation Of Novel Resveratrol And Combretastatin A4 Derivatives As Potent Anti-Cancer Agents, Nikhil Reddy Madadi

Theses and Dissertations--Pharmacy

Resveratrol has been reported as a potential anticancer agent but cannot be used as an antitumor drug due to its chemical and metabolic instability. We have designed and synthesized 184 novel compounds related to resveratrol in an attempt to produce more potent and drug-like molecules. We have identified a tetrazole analog of resveratrol, ST-145(a) as a lead anticancer agent from the resveratrol analog series of compounds with a GI₅₀ value of less than 10nM against almost all the human cancer cell lines in the National Cancer Institute’s screening panel.

In a separate study, we tested the hypothesis that the …

Multi-Component Microparticulate/Nanoparticulate Dry Powder Inhalation Aerosols For Targeted Pulmonary Delivery, Xiaojian Li

Theses and Dissertations--Pharmacy

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution.

The physicochemical properties of multi-component dry …

Human Butyrylcholinesterase Mutants For Cocaine Detoxification, Shurong Hou

Theses and Dissertations--Pharmacy

Cocaine is one of the most reinforcing drugs of abuse and has caused serious medical and social problems. There is no FDA-approved medication specific for cocaine. It is of a high priority to develop an effective therapeutic treatment for cocaine abuse. Human butyrylcholinesterase (BChE) has been recognized as a promising candidate of enzyme therapy to metabolize cocaine into biologically inactive metabolites and prevent it from reaching central nervous system (CNS). However, the catalytic activity of wide-type human BChE against cocaine is not sufficiently high for treatment of cocaine abuse. Dr. Zhan’s lab has successfully designed and discovered a series of …

Lobelane Analogs With Various Methylene Linker Lengths And Acyclic Lobelane Analogs As Potential Pharmacotherapies To Treat Methamphetamine Abuse, Zheng Cao

Theses and Dissertations--Pharmacy

Methamphetamine interacts with vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine (DA) uptake and promotes DA release from presynaptic vesicles, increasing cytosolic DA available for methamphetamine-induced reverse transport by DA transporters. By inhibiting VMAT2, lobelane, a defunctionalized, saturated lobeline analog, decreases methamphetamine-evoked DA release and methamphetamine self-administration in rats. In this dissertation structure-activity relationships around the lobelane structure were investigated on racemic lobelane analogs with varying methylene linker lengths at central piperidine ring. Affinity for dihydrotetrabenazine (DTBZ) sites on VMAT2 and for inhibition of VMAT2 function was determined to be 0.88-63 and 0.024-4.6 µM, respectively, and positively correlated. The most potent …

Mechanisms Of Cyclooxygenase-2-Dependent Human Aortic Smooth Muscle Cell Phenotypic Modulation, Oreoluwa O. Adedoyin

Theses and Dissertations--Pharmacy

Abdominal aortic aneurysm (AAA) is a disease of the aorta characterized by pathological remodeling and progressive weakening of the vessel resulting in the increased risk of rupture and sudden death. In a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, progression of AAAs is associated with reduced differentiation of smooth muscle cells (SMCs) at the site of lesion development. In the mouse model, the effectiveness of cyclooxygenase-2 (COX-2) inhibition for attenuating AAA progression is associated with maintenance of a differentiated SMC phenotype. However, the safety of COX-2 inhibitors is currently in question due to the increased …

Investigating Structure And Protein-Protein Interactions Of Key Post-Type Ii Pks Tailoring Enzymes, Theresa E. Downey

Theses and Dissertations--Pharmacy

Type II polyketide synthase (PKS) produced natural products have proven to be an excellent source of pharmacologically relevant molecules due to their rich biological activities and chemical scaffolds. Type II-PKS manufactured polyketides share similar polycyclic aromatic backbones leaving their diversity to stem from various chemical additions and alterations facilitated by post-PKS tailoring enzymes. Evidence suggests that post-PKS tailoring enzymes form complexes in order to facilitate the highly orchestrated process of biosynthesis. Thus, protein-protein interactions between these enzymes must play crucial roles in their structures and functions. Despite the importance of these interactions little has been done to study them. In …

The Off-Label Use Of Atypical Antipsychotics And Its Impact On Attention Deficit/Hyperactivity Disorder (Adhd), Minji Sohn

Theses and Dissertations--Pharmacy

Atypical antipsychotics (AAPs) (also known as second-generation antipsychotics) are the US Food and Drug Administration (FDA) approved medications for schizophrenia, bipolar I disorder, depression and autism. Compared to the typical antipsychotics, AAPs were marketed as reducing adverse side effects such as extrapyramidal symptoms. This resulted in extensive use of AAPs for not only the FDA approved indications but also other conditions that are not approved. However, several post-marketing clinical trials evaluated the use of AAPs and reported serious adverse side effects, including metabolic syndrome, cardiovascular events, or death.

The extensive use of AAPs by pediatrics is an important policy problem …

Flavonoids With Novel Nicotinic Activity As Potential Pharmacotherapies To Treat Ethanol-Induced Neurotoxicity, Joseph A. Lutz

Theses and Dissertations--Pharmacy

Ethanol causes neurotoxicity via several mechanisms at different points in the cycle of dependence, including neuroinflammation and oxidative stress during ethanol exposure as well as excitotoxicity during ethanol withdrawal. The primary therapeutic implication is that ethanol-induced neurotoxicity requires multifunctional pharmacotherapies which reduce all mechanisms. Using an innovative pharmacological high throughput screening method on a large plant extract library we discovered flavonoids with alpha7 nicotinic acetylcholine receptor (nAChR) activity. In addition to their well-known anti-inflammatory and antioxidant properties, this novel activity means they can potentially reduce excitotoxicity and therefore makes them ideal for inhibition of ethanol-induced neurotoxicity. Rhamnetin, the candidate compound, …

Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin

Theses and Dissertations--Pharmacy

Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using …

How Do Consumers Use Social Shopping Websites? The Impact Of Social Endorsements, Pei Xu

Theses and Dissertations--Business Administration

Social endorsements are user-generated endorsements of products or services, such as “likes” and personal collections, in an online social platform. We examine the effect of prior social endorsements on subsequent users’ tendency to endorse or examine a product in a social shopping context, where a social platform connect consumers and enable a collaborative shopping experience. This research consists of two parts. In part I, we identify two ways prior social endorsements can affect subsequent user behavior: as a crowd endorsement, which is an aggregate number of endorsements a product receives for anyone who comes across the product, and as …

Obtaining Genuine Family Involvement: Unpacking The System Of Care Values And Principles, Deborah A. Cohen

Theses and Dissertations--Social Work

Despite the federal government’s $1.5 billion investment between 1993 and 2010 to fund 164 separate community-based systems of care, there has been an extremely limited attempt to measure the impact of system of care. The impetus for this research is the struggle for how the value based concept of system of care is communicated within a community. While child mental health services researchers have published a number of randomized control trials to explore individual level supports for youth served in a system of care community, researchers have struggled to devise a way to measure system of care philosophy diffusion.

While …

Multiscale Modeling Of The Mine Ventilation System And Flow Through The Gob, William Chad Wedding

Theses and Dissertations--Mining Engineering

The following dissertation introduces the hazard of methane buildup in the gob zone, a caved region behind a retreating longwall face. This region serves as a reservoir for methane that can bleed into the mine workings. As this methane mixes with air delivered to the longwall panel, explosive concentrations of methane will be reached.

Computational fluid dynamics (CFD) is one of the many approaches to study the gob environment. Several studies in the past have researched this topic and a general approach has been developed that addresses much of the complexity of the problem. The topic of research herein presents …

Development Of Industry Oriented Cfd Code For Analysis / Design Of Face Ventilation Systems, Todor P. Petrov

Theses and Dissertations--Mining Engineering

Two of the main safety and health issues recognized during deep cut coal mining are methane and dust hazards. Advances in continuous miner technology have improved safety and productivity. However, these advances have created some environmental problems, notably more dust and methane being generated at the face during coal extraction.

Results of studies performed in the last three decades concerning the face ventilation for deep cut mining showed very complicated airflow behavior. The specifics of flow patterns developed by the face ventilation systems presents significant challenge for analytical description even for equipment-free entry. Fortunately, there are methods, such as numerical …

Computational Investigation Of Injectable Treatment Strategies For Myocardial Infarction, Hua Wang

Theses and Dissertations--Mechanical and Aerospace Engineering

Heart failure is an important medical disease and impacts millions of people throughout the world. In order to treat this problem, biomaterial injectable treatment injected into the myocardium of the failing LV are currently being developed. Through this treatment, the biomaterial material injections can reduce wall stresses during the cardiac remodeling process. By using computational techniques to analyze the effects of a treatment involving the injection of biomaterial material into the LV after MI, the material parameters of the hydrogel injections can be optimized. The results shows that the hydrogel injections could reduce the global average fiber stress and the …

Estimating Passive Material Properties And Fiber Orientation In A Myocardial Infarction Through An Optimization Scheme Using Mri And Fe Simulation, Dimitri Mojsejenko

Theses and Dissertations--Mechanical and Aerospace Engineering

Myocardial infarctions induce a maladaptive ventricular remodeling process that independently contributes to heart failure. In order to develop effective treatments, it is necessary to understand the way and extent to which the heart undergoes remodeling over the course of healing. There have been few studies to produce any data on the in-vivo material properties of infarcts, and much less on the properties over the time course of healing. In this paper, the in-vivo passive material properties of an infarcted porcine model were estimated through a combined use of magnetic resonance imaging, catheterization, finite element modeling, and a genetic algorithm optimization …

Combining Sustainable Value Stream Mapping And Simulation To Assess Manufacturing Supply Chain Network Performance, Daniel T. Sparks

Theses and Dissertations--Mechanical and Aerospace Engineering

Sustainable Value Stream Mapping (Sus-VSM) builds upon traditional VSM to capture additional sustainability aspects of the product flow, such as environmental and societal aspects. This work presents research to expand the utility of Sus-VSM to supply chain networks, develop a general approach towards improving supply chain sustainability, and examine the benefits of implementing simulation and a design of experiments (DOE) style analysis. Metrics are identified to assess economic, environmental, and societal sustainability for supply chain networks and visual symbols are developed for the Supply Chain Sus-VSM (SC Sus-VSM) to allow users to easily identify locations where sustainability can be improved. …

Sustainable Lifetime Value Creation Through Innovative Product Design: A Product Assurance Model, K. Daniel Seevers

Theses and Dissertations--Mechanical and Aerospace Engineering

In the field of product development, many organizations struggle to create a value proposition that can overcome the headwinds of technology change, regulatory requirements, and intense competition, in an effort to satisfy the long-term goals of sustainability. Today, organizations are realizing that they have lost portfolio value due to poor reliability, early product retirement, and abandoned design platforms. Beyond Lean and Green Manufacturing, shareholder value can be enhanced by taking a broader perspective, and integrating sustainability innovation elements into product designs in order to improve the delivery process and extend the life of product platforms.

This research is divided into …

A Metrics-Based Sustainability Assessment Of Cryogenic Machining Using Modeling And Optimization Of Process Performance, Tao Lu

Theses and Dissertations--Mechanical and Aerospace Engineering

The development of a sustainable manufacturing process requires a comprehensive evaluation method and fundamental understanding of the processes. Coolant application is a critical sustainability concern in the widely used machining process. Cryogenic machining is considered a candidate for sustainable coolant application. However, the lack of comprehensive evaluation methods leaves significant uncertainties about the overall sustainability performance of cryogenic machining. Also, the lack of practical application guidelines based on scientific understanding of the heat transfer mechanism in cryogenic machining limits the process optimization from achieving the most sustainable performance.

In this dissertation, based on a proposed Process Sustainability Index (ProcSI …

Lean Fire Management: A Focused Analysis Of The Incident Command System Based On Toyota Production System Principles, Jeremiah S. Fugate

Theses and Dissertations--Mechanical and Aerospace Engineering

A primary role of the Incident Command System is to learn from past incidents, as illustrated by its origins in the wildland firefighting community. Successful emergency response operations under the Incident Command System has prompted its nationwide spread, this promulgation critically relies on the system’s capability to stabilize and continuously improve various aspects of emergency response through effective organizational learning. The objective of this study is to evaluate the potential to apply fundamental principles of the Toyota Production System (Lean manufacturing) to improve learning effectiveness within the Incident Command System. An in-depth review of literature and training documents regarding both …

Fabrication Of Magnetic Two-Dimensional And Three-Dimensional Microstructures For Microfluidics And Microrobotics Applications, Hui Li

Theses and Dissertations--Mechanical and Aerospace Engineering

Micro-electro-mechanical systems (MEMS) technology has had an increasing impact on industry and our society. A wide range of MEMS devices are used in every aspects of our life, from microaccelerators and microgyroscopes to microscale drug-delivery systems. The increasing complexity of microsystems demands diverse microfabrication methods and actuation strategies to realize. Currently, it is challenging for existing microfabrication methods—particularly 3D microfabrication methods—to integrate multiple materials into the same component. This is a particular challenge for some applications, such as microrobotics and microfluidics, where integration of magnetically-responsive materials would be beneficial, because it enables contact-free actuation. In addition, most existing microfabrication methods …

Heat Transfer Characteristics In Wildland Fuelbeds, Justin English

Theses and Dissertations--Mechanical and Aerospace Engineering

The fundamental physics governing wildland fire spread are still largely misunderstood. This thesis was motivated by the need to better understand the role of radiative and convective heat transfer in the ignition and spread of wildland fires. The focus of this work incorporated the use of infrared thermographic imaging techniques to investigate fuel particle response from three different heating sources: convective dominated heating from an air torch, radiative dominated heating from a crib fire, and an advancing flame front in a laboratory wind tunnel test. The series of experiments demonstrated the uniqueness and valuable characteristics of infrared thermography to reveal …

Primary And Secondary Prevention Of Hepatitis C Virus Among Rural Appalachian People Who Use Drugs, Dustin B. Stephens

Theses and Dissertations--Clinical and Translational Science

Hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide, with 3% of the global population chronically infected. Clinical impacts in the United States are projected to increase for two decades, and mortality attributed to HCV now exceeds HIV. Injection drug use (IDU) is the most common route of transmission in the developed world. Advances in treatment offer hope of mitigating HCV impacts, but substantial barriers obstruct people who inject drugs (PWID) from receiving care, particularly in medically underserved regions including Central Appalachia. This study assessed IDU paraphernalia sharing longitudinally over 24 months in a sample of …