Digital Commons Network^™

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 …

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 …

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 …

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 …

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 …

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 …

From Geology To Art History: Ceramist Alexandre Brongniart’S Overlooked Contribution To The Developing Science Of Art History In The Early Nineteenth Century, Julia A. Carr-Trebelhorn

Theses and Dissertations--Art and Visual Studies

Alexandre Brongniart was known for his work as an important geologist and as an administrator at the Sèvres Porcelain Manufactory, but his roles as art historian and museologist are overlooked. Brongniart created a holistic methodology taken directly from science and applied it to ceramic art of all cultures and eras. He had a uniquely modern perspective on time, world culture, and archeology. Brongniart wrote about the art of Asia and the Americas on an equal status with that of the Classical West at least fifty years before it became a mainstream idea. Brongniart integrated scientific principle and practice into the …

The Relationship Of Somatosensory Perception And Fine-Force Control In The Adult Human Orofacial System, Nicole M. Etter

Theses and Dissertations--Rehabilitation Sciences

The orofacial area stands apart from other body systems in that it possesses a unique performance anatomy whereby oral musculature inserts directly into the underlying cutaneous skin, allowing for the generation of complex three-dimensional deformations of the orofacial system. This anatomical substrate provides for the tight temporal synchrony between self-generated cutaneous somatosensation and oromotor control during functional behaviors in this region and provides the necessary feedback needed to learn and maintain skilled orofacial behaviors.

The Directions into Velocity of Articulators (DIVA) model highlights the importance of the bidirectional relationship between sensation and production in the orofacial region in children learning …

Expression And Splicing Of Alzheimer’S Disease Risk Gene Phosphatidylinositol-Binding Clathrin Assembly Protein, Ishita Parikh

Theses and Dissertations--Physiology

Recent Genome Wide Association Studies (GWAS) have identified a series of single nucleotide polymorphism (SNP)s that are associated with Alzheimer’s disease (AD). One of the SNPs, rs3851179 (G/A), is near the gene phosphatidylinositol-binding clathrin assembly protein (PICALM). To evaluate whether this SNP is associated with PICALM expression, we quantified PICALM mRNA in 56 brain cDNA samples. Using linear regression analysis, we analyzed PICALM expression relative to rs3851179, AD status, and cell type specific markers. An association was detected between rs3851179 and PICALM, microvessel mRNA, glial fibrillary acidic protein (GFAP) mRNA, and synaptophysin (SYN) mRNA. To gain clarity …

Nucleoside Reverse Transcriptase Inhibitors Are Anti-Inflammatory And Target Dry Age-Related Macular Degeneration, Benjamin J. Fowler

Theses and Dissertations--Physiology

Age-related macular degeneration (AMD) is a principal cause of blindness in the United States and other industrialized nations. An estimated 10 million Americans are afflicted with AMD, which is comparable in scope to the 12 million living with cancer, or the 5 million with Alzheimer’s disease. The prevalence of AMD steadily increases with age, affecting 2% of the population at age 40, and one in four people by age 80. For reasons that are not fully understood, AMD is more common in lightly-pigmented and female populations. Treatment of AMD is largely an unmet need: There are no FDA approved therapies …

Attenuating Trigeminal Neuropathic Pain By Repurposing Pioglitazone And D-Cycloserine In The Novel Trigeminal Inflammatory Compression Mouse Model, Danielle N. Lyons

Theses and Dissertations--Physiology

Approximately 22% of the United States population suffers from a chronic orofacial pain condition. One such condition is known as trigeminal neuropathic pain frequently reported as continuous aching and burning pain, often accompanied by intermittent electrical shock-like sensations. Dental procedures or trauma are known causes of peripheral trigeminal nerve injury and inflammation. Patients who have this type of facial pain also suffer from emotional distress. For these reasons, trigeminal neuropathic pain needs to be studied in more detail to improve the understanding of the etiology and maintenance of this condition, as well as to develop effective treatment strategies. The first …

Trpa1 Channels In Cochlear Supporting Cells Regulate Hearing Sensitivity After Noise Exposure, Alejandra C. Velez-Ortega

Theses and Dissertations--Physiology

TRPA1 channels are sensors for noxious stimuli in a subset of nociceptive neurons. TRPA1 channels are also expressed in cells of the mammalian inner ear, but their function in this tissue remains unknown given that Trpa1^–/– mice exhibit normal hearing, balance and sensory mechanotransduction. Here we show that non-sensory (supporting) cells of the hearing organ in the cochlea detect tissue damage via the activation of TRPA1 channels and subsequently modulate cochlear amplification through active cellshape changes.

We found that cochlear supporting cells of wild type but not Trpa1^–/– mice generate inward currents and robust long-lasting Ca²⁺ responses …

Identification Of Soils On Firefighter Turnout Gear From The Philadelphia Fire Department, Tabitha N. Huston

Theses and Dissertations--Retailing and Tourism Management

The purpose of this research was to identify the composition of soils on firefighter turnout gear from the Philadelphia Fire Department and to determine which soils contain hazardous materials. The objective of the research was to identify the composition of soils remaining on the firefighter turnout gear to enable the industry to design an effective cleaning procedure for removal of soils. A pilot study was conducted on hoods from the Philadelphia fire department to evaluate the test methods that would be used to identify the composition of soils. Soils that had been identified from previous studies were targeted in the …

Evaluation Of Pcr-Based Methods For Rapid, Accurate Detection And Monitoring Of Verticillium Dahliae In Woody Hosts By Real-Time Polymerase Chain Reaction, Baker Diwan Getheeth Aljawasim

Theses and Dissertations--Plant Pathology

Verticillium wilt, caused by Verticillium dahliae Kleb, is one of the most economically important diseases of woody hosts such as ash (Fraxinus spp.), sugar maple (Acer saccharum), and redbud (Cercis canadensis). The causal agent has a broad host range, including not only woody hosts but also important vegetable and field crops, and it is distributed worldwide. Diagnosis of V. dahliae in infected woody hosts is often based on the occurrence of vascular discoloration and time-consuming isolation. However, not all woody hosts exhibit vascular discoloration symptoms, and not all vascular discoloration symptoms are due to infection …

The Effects Of Mountaintop Removal Mining And Valley Fills On Stream Salamander Communities, Brenee' Lynn Muncy

Theses and Dissertations--Forestry and Natural Resources

Mountaintop removal mining and valley filling (MTR/VF) is a common form of land conversion in Central Appalachia and threatens the integrity of stream ecosystems. We investigated the effects of MTR/VF on stream salamander occupancy probabilities and community structure by conducting area constrained active searches for stream salamanders within intermittent streams located in mature forest (i.e., control) and those impacted by MTR/VF. During March to June of 2013, we detected five stream salamander species (Desmognathus fuscus, D. monticol, Eurycea cirrigera, Pseudotriton ruber, and Gyrinophilus porphyriticus) and found that the probability of occupancy was greatly reduced in MTR/VF streams compared …

Influence Of Spoil Type On Afforestation Success And Hydrochemical Function On A Surface Coal Mine In Eastern Kentucky, Kenton L. Sena

Theses and Dissertations--Forestry and Natural Resources

Surface coal mining in Appalachia has contributed to a suite of ecological impacts, both terrestrial and aquatic. Conventional reclamation in Appalachia leads to the development of hay/pasture systems dominated by nonnative grasses and legumes, with soils that are chemically and physically unfavorable to native tree growth. Several studies have shown that more weathered minespoils provide a better growth medium than unweathered spoils in Appalachia. Spoil segregation plots were constructed on Bent Mountain in Pike County, KY, to compare the suitability of three mine spoil types (BROWN weathered sandstone, GRAY unweathered sandstone, and MIXED sandstones and shales). In 2013 (after nine …

Use Of Genomic Tools To Discover The Cause Of Champagne Dilution Coat Color In Horses And To Map The Genetic Cause Of Extreme Lordosis In American Saddlebred Horses, Deborah G. Cook

Theses and Dissertations--Veterinary Science

Champagne dilution of coat color in horses is caused by dominant gene action. Three sire families were identified as segregating for this trait. Genome wide linkage analysis using 104 microsatellite DNA markers was used to map the gene to ECA14 (LOD > 11.0). Four genes, namely SPARC, SLC36A1, SLC36A2 and SLC36A3, were selected from the region implicated by linkage and their exons sequenced. DNA sequences were compared for two homozygotes for Champagne dilution, two heterozygotes and two horses without dilution. A single base change in exon 2 of SLC36A1 was found unique to horses exhibiting Champagne dilution. This change in base …

Modulation Of Type-I Interferon Mediated Immune Response: A Novel Innate Immune Evasion Strategy Of Equine Herpesvirus 1, Sanjay Sarkar

Theses and Dissertations--Veterinary Science

Equine herpesvirus-1 (EHV-1) is one of the major viral pathogens causing respiratory disease, abortion, perinatal mortality and neurologic disease among horses resulting in significant economic losses to the equine industry. The virus can also remain latent in the horses and recrudesce at any time. Type-I interferons (IFNs) act as a first line of defense against many viral infections.

In this study we investigated the type-I IFN response against the neuropathogenic T953 strain of EHV-1 in equine endothelial cells (EECs). The results showed that after a transient induction of IFN-β mRNA as well as protein at an early time (3h) post …

Monitoring The Influence Of Acid Deposition On Soil And Implications To Forest Health In The Daniel Boone National Forest, Tyler M. Sanderson

Theses and Dissertations--Forestry and Natural Resources

Combustion of fossil fuels has contributed to many environmental problems including acid deposition. The Clean Air Act (CAA) was created to reduce ecological problems by cutting emissions of sulfur and nitrogen. Reduced emissions and rainfall concentrations of acidic ions have been observed since the enactment of the CAA, but soils continue to receive some acid inputs. Soils sensitive to acid deposition have been found to have low pH, a loss of base cations and a shift in the mineral phase controlling the activity of Al³⁺ and/or SO₄^2-. If inputs continue, soil may be depleted of base …

Anti-Müllerian Hormone In Stallions And Mares: Physiological Variations, Clinical Applications, And Molecular Aspects, Anthony N.J. Claes

Theses and Dissertations--Veterinary Science

Anti-Müllerian hormone (AMH) is a homodimeric glycoprotein that is best known for its role in regression of the Müllerian duct in the male fetus. Accumulating evidence indicates that AMH also has an important role during different physiological processes after birth. In contrast to other species, relatively little is known about AMH in the horse. In chapter one, developmental and seasonal changes in serum AMH concentrations in male horses were determined, and the use of AMH for determination of retained cryptorchid testes was established. In chapter two, the interrelationship between plasma AMH concentrations, antral follicle counts (AFC), and age in mares …

Role Of Viral And Host Factors In Influenza Virus Mediated Inhibition Of Interleukin-23, Ashish Tiwari

Theses and Dissertations--Veterinary Science

Influenza virus is one of the major respiratory pathogens of humans as well as animals, including equines. There is an increasing evidence that bacterial infections are the most common cause of the death during influenza. In horses also, secondary bacterial pneumonia can lead to death, and surviving horses may take up to six months for the complete recovery resulting in heavy economic loss to the equine industry. Interleukin (IL)-23 mediated innate immune response has been shown to protect the host from various respiratory bacterial infections. However, studies to investigate the role of host and viral factors in the regulation of …

Studies On Equine Placentitis, Igor Frederico Canisso

Theses and Dissertations--Veterinary Science

Two types of placentitis were studied: ascending and nocardioform placentitis. Although the first diagnosis of nocardioform placentitis was made three decades ago, little is known about the disease, due to the lack of an experimental model. In attempt to develop a research model, Crossiela equi was inoculated through intrauterine, intravenous, intrapharyngeal, and oral routes, but none of the routes resulted in nocardioform placentitis. This may indicate that unidentified factors may play a role in disease pathogenesis and that simple presence of bacteria is not sufficient to induce nocardioform placentitis. The second and major component of this dissertation involved the identification …