Digital Commons Network^™

Wnt/Β-Catenin Mediated Cancer Stem Cell Activation In Hepatocellular Carcinoma., Harshulkumar M. Pandit

Electronic Theses and Dissertations

Hepatocellular carcinoma (HCC) is one of the deadliest cancers, with variable presentation, high chemotherapy resistance and early tumor recurrence. In this dissertation, we have systematically enriched, identified and characterized HCC cancer stem cells (CSCs) from 3 different HCC cell lines (Hepa1-6, HepG2, and Hep3B) using in vitro serum-free culture method. Enriched spheroids acquired CSC properties, primarily self-renewal capability, spheroid formation ability, and drug resistance. Heterogeneous CSCs enriched from Hepa1-6 cells demonstrated higher tumor initiation and proliferation capability in vivo, compared to control HCC cells in orthotopic immunocompetent mouse model. EpCAM+ CSCs were significantly enriched within heterogeneous Hepa1-6 CSC spheroids. Consequently, …

Social Determinants Of Health And A Grounded Mixed-Methods Approach To Explain Declining Life Expectancy In Eastern Kentucky : 1980 – 2014., William Renda

Electronic Theses and Dissertations

Trends in life expectancy for the United States from 1980-2014 suggest general improvement overall. However, eastern Kentucky stands out with a cluster of counties experiencing declining life expectancy. Given that life expectancy is an excepted indicator of overall population health, this anomaly in eastern Kentucky warrants investigation. This thesis uses a grounded mixed methods approach to explore this trend across the greater Appalachian region. Content and discourse analysis of interviews with public health and medical professionals in the study area revealed key themes perceived as being related to declining life expectancy, which informed variable selection for regression analysis. Regression models …

The N-Terminal Methyltransferase Homologs Nrmt1 And Nrmt2 Exhibit Novel Regulation Of Activity Through Heterotrimer Formation., Jon David Faughn

Electronic Theses and Dissertations

Protein, DNA, and RNA methyltransferases have an ever-expanding list of novel substrates and catalytic activities. Even within families and between homologs, it is becoming clear the intricacies of methyltransferase specificity and regulation are far more diverse than originally thought. In addition to specific substrates and distinct methylation levels, methyltransferase activity can be altered through formation of complexes with close homologs. This work involves the N-terminal methyltransferase homologs NRMT1 and NRMT2. NRMT1 is a ubiquitously expressed distributive trimethylase. NRMT2 is a monomethylase expressed at low levels and in a tissue-specific manner. They are both nuclear methyltransferases with overlapping target consensus sequences …

A Novel Fibroblast Growth Factor 1 Variant Reverses Nonalcoholic Fatty Liver Disease In Type 2 Diabetes., Qian Lin

Electronic Theses and Dissertations

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with type 2 diabetes (T2D). Our recently engineered FGF1 partial agonist, carrying triple mutations (FGF1^△HBS) exhibits greatly reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1. This study tests the preventive and therapeutic effects of FGF1^△HBS on NAFLD in db/db T2D and explores potential mechanisms. The results showed that administration of FGF1^△HBS to 2-month-old db/db mice for 2 months constantly lowered blood glucose levels, improved insulin sensitivity, and lowered liver weight, lipid deposition, and …

Bayesian Analytical Approaches For Metabolomics : A Novel Method For Molecular Structure-Informed Metabolite Interaction Modeling, A Novel Diagnostic Model For Differentiating Myocardial Infarction Type, And Approaches For Compound Identification Given Mass Spectrometry Data., Patrick J. Trainor

Electronic Theses and Dissertations

Metabolomics, the study of small molecules in biological systems, has enjoyed great success in enabling researchers to examine disease-associated metabolic dysregulation and has been utilized for the discovery biomarkers of disease and phenotypic states. In spite of recent technological advances in the analytical platforms utilized in metabolomics and the proliferation of tools for the analysis of metabolomics data, significant challenges in metabolomics data analyses remain. In this dissertation, we present three of these challenges and Bayesian methodological solutions for each. In the first part we develop a new methodology to serve a basis for making higher order inferences in metabolomics, …

Deciphering The Role Of Human Arylamine N-Acetyltransferase 1 (Nat1) In Breast Cancer Cell Metabolism Using A Systems Biology Approach., Samantha Marie Carlisle

Electronic Theses and Dissertations

Background: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. NAT1 can additionally hydrolyze acetyl-coenzyme A (acetyl-CoA) in the absence of an arylamine substrate. NAT1 expression varies inter-individually and is elevated in several cancers including estrogen receptor positive (ER+) breast cancers. Additionally, multiple studies have shown the knockdown of NAT1, by both small molecule inhibition and siRNA methods, in breast cancer cells leads to decreased invasive ability and proliferation and decreased anchorage-independent colony formation. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Additionally, consequences …

Unfolded Protein Response Pathways In Skeletal Muscle Homeostasis., Kyle R. Bohnert

Electronic Theses and Dissertations

Skeletal muscle mass, contractile properties, and metabolic function are regulated through the coordinated activation of multiple intracellular signaling pathways and genetic reprogramming. The endoplasmic reticulum (ER) plays a pivotal role in protein folding and calcium homeostasis in many cell types, including skeletal muscle. Disruption of calcium levels or accumulation of misfolded proteins in the ER lumen leads to stress, which results in the activation of a signaling network called the unfolded protein response (UPR). Further, recent studies have suggested that in certain conditions, UPR pathways can be activated independent of ER stress. However, the role of ER stress and the …

Investigating The Impact Of Nrmt1 Cancer Mutants On Catalytic Specificity And The Dna Damage Response., Kaitlyn Marie Shields

Electronic Theses and Dissertations

Protein methylation is an established and critical posttranslational modification controlling multiple cellular events. Alterations in protein methylation have been implicated in many diseases, including cancer. My work focused on the N-terminal trimethylase NRMT1 and the N-terminal monomethylase NRMT2. Previous work proposed that NRMT2 assists NRMT1 by priming its substrates for trimethylation. Importantly, NRMT1 mutations have been found in cancers, and loss of NRMT1 has been shown to promote oncogenic phenotypes in cancer cells. Together, this suggests that altered activities of NRMT1/2 may play a role in cancer progression. Although NRMT1/2 are 50% identical, they differ in key aromatic residues in …

Weight Stigma And Motivation To Exercise : Exploring Associations And Constructs From The Basic Needs Theory., Stephanie R. Mcdonough

Electronic Theses and Dissertations

Social influences, such as weight stigma, perpetuate rates of overweight and obesity, as well as contribute to poor physical and psychological health. It has been postulated that weight stigma negatively affects motivation to exercise, though the literature is mixed and underlying mechanisms of action are not well conceived. The present study aimed to: (1) explore the relationship between frequency of experienced weight stigma and exercise motivation and behavior (2) assess how frequency of experienced weight stigma might differ based on participant characteristics such as body weight and (3) consider unique associations between frequency of personal experiences with weight-based stigma, exercise …

Alpha-Amino Methylation And Acetylation Are Novel Regulators Of Myl9 Function., Christopher David Nevitt

Electronic Theses and Dissertations

Dysregulation of alpha-amino post-translational modifications (Nα-PTMs) is found in multiple cancers and developmental disorders. However, the exact roles Nα-PTMs play in regulating protein function remain poorly understood. I sought to clarify the role of Nα-methylation and Nα-acetylation in the regulation of Myosin Regulatory Light Chain 9 (MYL9). MYL9 is a key cytoskeletal regulator and transcription factor and is the first protein confirmed to undergo both Nα-methylation and Nα-acetylation. Through this work I revealed novel regulatory features of MYL9, while also presenting a framework by which to understand the coordinated regulation of proteins by Nα-methylation and Nα-acetylation. Nα-PTM selective mutants of …

Understanding The Relationship Between Positive Affect And Cortisol In Lung Cancer Patients., Lauren Ann Zimmaro

Electronic Theses and Dissertations

Positive psychobiological processes within lung cancer patients are drastically understudied. This dissertation explores the nature of positive affect (PA) and potential associations with diurnal cortisol among lung cancer patients, given the prognostic significance of diurnal cortisol rhythms. Theoretical underpinnings and current literature involving PA, cancer, and diurnal cortisol are first reviewed. An original integrated model of PA and cortisol among cancer patients is then presented, from which the proposed dissertation study and analyses are derived. Sixty-one non-small cell lung cancer patients provided self-report assessment of mood (PANAS PA and NA subscales, CES-D PA subscale), medical and demographic characteristics, and 10-day …

Coal Ash Exposure And Behavioral Impairments Among Children In Louisville, Kentucky., Chisom Nmesoma Odoh

Electronic Theses and Dissertations

Introduction: Coal ash, generated from the combustion of coal is principally made up of fly ash, which consists of small particles and metals that can affect the development of children. Coal ash is predominately stored in landfills and surface impoundments, of which many are in proximity to residential areas. According to the Environmental Protection Agency, 25% of residents in proximity to electric power plants are children. Few studies have reported a positive association between coal ash and its by-products and neurobehavioral disorders. The purpose of this study was to explore the relationship between coal ash and its components and …

Canonical Nuclear Factor-Κb Signaling In Satellite Stem Cell Homeostasis And Function., Alex R. Straughn

Electronic Theses and Dissertations

Satellite cells are adult stem cells that are required for the regeneration of skeletal muscle following injury. However, the signaling mechanisms that regulate satellite stem cell homeostasis and function in adult animals remain less understood. Nuclear factor-kappa B (NF-kB) is a major nuclear transcription factor that regulates the gene expression of a plethora of molecules involved in cellular proliferation, differentiation, survival, and the inflammatory immune response. NF-kB can be activated through a canonical or non-canonical pathway. However, the role of canonical NF-kB signaling in the regulation of satellite stem cell function during skeletal muscle regeneration has not been yet investigated …

Evaluation Of Drug-Loaded Gold Nanoparticle Cytotoxicity As A Function Of Tumor Tissue Heterogeneity., Hunter Allan Miller

Electronic Theses and Dissertations

The inherent heterogeneity of tumor tissue presents a major challenge to nanoparticle-medicated drug delivery. This heterogeneity spans from the molecular to the cellular (cell types) and to the tissue (vasculature, extra-cellular matrix) scales. Here we employ computational modeling to evaluate therapeutic response as a function of vascular-induced tumor tissue heterogeneity. Using data with three-layered gold nanoparticles loaded with cisplatin, nanotherapy is simulated with different levels of tissue heterogeneity, and the treatment response is measured in terms of tumor regression. The results show that tumor vascular density non-trivially influences the nanoparticle uptake and washout, and the associated tissue response. The drug …

The Role Of Hardiness In The Relation Between Perceived Daily Discrimination And Depressive Symptoms In Community College Students., Rosamond J. Smith

Electronic Theses and Dissertations

In the current study, perceived daily discrimination (PDD) is conceptualized as a chronic stressor which repeatedly activates a stress response and results in depressive symptoms, per the theory of allostatic load. Psychological hardiness is explored as a potential moderator of the relation between PDD and depressive symptoms, because individuals who repeatedly demonstrate hardiness may be primed for making cognitive reappraisals of potential stressors and/or for mobilizing appropriate coping strategies, thus limiting the body’s repeated stress responses and subsequent depressive symptoms. This cross-sectional survey of a diverse sample of 305 community college students included measures of hardiness (Dispositional Resilience Scale, …

Perinatal Nicotine With Or Without Early Life Influenza Infection Leads To Lung Dysfunction With Age., Ryan Carroll Mcallister

Electronic Theses and Dissertations

Obstructive Airway Diseases (OADs) affect millions of people worldwide, and are characterized by chronic inflammation and tissue remodeling in the lung. It has been proposed that the development of OAD is greatly influenced (and perhaps pre-determined) by early life events, such as maternal smoking or a viral infection. However, direct evidence of this is limited and the mechanisms involved remain unclear. Our laboratory previously developed a murine model of perinatal nicotine exposure, and reported that nicotine leads to airway remodeling and decreased pulmonary function in the offspring. We discovered these effects were mediated through the α7 nicotinic acetylcholine receptor (nAChR). …

Dead Wood And Decomposition In A Tropical Forest : Vertical Patterns, Long-Term Processes, And The Role Of Lightning., Evan Matthew Gora

Electronic Theses and Dissertations

This dissertation investigates the distribution, production, and decomposition of dead wood (or woody debris) in a lowland tropical forest within the Barro Colorado Nature Monument in Panama. Although the importance of woody debris is widely accepted, information describing components of WD pools and fluxes is generally separated in both time and space, particularly in understudied tropical forests. Here I provide a comprehensive inventory of woody debris in a lowland tropical forest (Chapter 1). Woody debris is highly aggregated and difficult to quantify, and this study demonstrates that historic estimates of woody debris pools and fluxes underestimate their uncertainty. In a …

Does Rumination Mediate The Relationship Between Everyday Discrimination And Blood Pressure?, Sarah J. Roane

Electronic Theses and Dissertations

Social stressors, such as perceived discrimination, account for some health disparities by triggering a series of physiological responses (Selye, 1955) which may be prolonged by perseverative cognition such as rumination (Brosschot et al., 2005). In the current study, I investigated whether everyday discrimination is positively associated with both brooding or reflection rumination in Black/African American (AA) individuals, as well as whether brooding or reflection rumination mediate the potential associations between everyday discrimination and blood pressure. Data were collected from a community college sample and analyses were conducted using the whole sample (N = 286; 57.3% female; 51.6% White and 29.8% …

Cross-Validation Of The Body Compassion Scale In A Sample Of Women In Perimenopause., Jennifer K. Altman

Electronic Theses and Dissertations

This study is a cross-validation of the Body Compassion Scale (BCS) to confirm its factor structure and to assess concurrent validity in women in perimenopause. Body compassion is a construct developed by the author referring to the level of compassion with which an individual relates to her body. It is based in contemporary mindfulnessand acceptance-based conceptual models. The body is central to the experience of women in perimenopause. Moreover, this important transition has been largely medicalized— with little attention given to experiential aspects of this natural phase of life. A total of 281 women in perimenopause completed online questionnaires assessing …

Room Temperature Operation Of Quantum Cascade Lasers Monolithically Integrated Onto A Lattice-Mismatched Substrate, Rowel Go

Electronic Theses and Dissertations

Quantum Cascade Lasers (QCLs) are semiconductor devices that, currently, have been observed to emit radiation from ~ 2.6 μm to 250 μm (1 to 100 terahertz range of frequencies.) They have established themselves as the laser of choice for spectroscopic gas sensing in the mid-wavelength infrared (3-8 μm) and long-wavelength infrared (8-15 μm) region. In the 4-12 μm wavelength region, the highest performing QCL devices, in terms of wall-plug efficiency and continuous wave operation, are indium phosphide (InP) based. The ultimate goal is to incorporate this InP-based QCL technology to silicon (Si) substrate since most opto-electronics are Si-based. The main …

Comparison Of A Modified And Traditional Rapid Infiltration Basin For Treatment And Control Of Nutrients In Wastewater Effluent, Jessica Cormier

Electronic Theses and Dissertations

Rapid infiltration basins (RIB) have been historically used in Florida for groundwater recharge, effluent disposal, or a combination of both. However, this technique has proven ineffective in providing nitrogen control unless the RIB is modified in some manner. In this study, a traditional RIB was compared to a modified RIB constructed with manufactured biosorption activated media (BAM) to evaluate nitrate removal from reclaimed water. The RIBs are used for reclaimed and excess storm water disposal. Few, if any, studies have been published where BAM-modified RIBs have been used for this purpose. In this work, a mixture of clay, tire crumb, …

The Population Ecology And Behavior Of The Cave Salamander, Eurycea Lucifuga (Rafinesque, 1822)., Joseph Gavin Bradley

Electronic Theses and Dissertations

The Cave Salamander, Eurycea lucifuga (Rafinesque, 1822), is a little-known species, yet a common inhabitant of caves in the eastern United States. Salamanders are often important components of ecological communities and ecosystems, influencing critical processes such as nutrient cycling and community composition through their predation on invertebrates. Cave-dwelling salamanders such as E. lucifuga may thus appreciably influence the relatively simple ecosystems and communities of caves. Any such influence may be particularly important because these habitats and the organisms that reside in them are often of conservation concern. I used non-invasive methods to study the demographics, movements, and habitat selection of …

Transgender And Racial Identities Negotiation Processes Of Transgender Asians, Asian Americans, And Pacific Islanders : A Transcendental Phenomenological Examination., Jayden Thai

Electronic Theses and Dissertations

While the field of transgender (trans) research is vastly growing and expanding, little is known about the process in which trans Asian and Pacific Islanders (API) individuals experience, navigate, and negotiate their trans and API cultural identities. The aims of this study were to: 1) examine the navigation and negotiation process for trans API individuals related to their cultural identities and values; 2) enhance, enrich, and diversify existing trans and API literature by generating foundational and complex understanding of trans API identity processes; and 3) challenge hegemonic narratives regarding trans API individuals’ lived experiences. Moustakas’ (1994) transcendental phenomenological qualitative methodology …

Impact Of Reproductive Mode On Skeletal Development In A Reproductively Bimodal Squamate Species, Amanda Tedder

Electronic Theses and Dissertations

Viviparity has evolved multiple times within squamates. Eggshells are reduced in viviparous forms, which reduces calcium available to embryos during development. This study tested the hypothesis that reduced calcium impacts neonates of viviparous forms. Developmental series from oviparous and viviparous populations of Zootoca vivipara (reproductively bimodal) were cleared & stained to reveal bone development. Photographs (high magnification, calibrated to size) were used to obtain measurements of lengths of the body, humerus, femur, skull and lower jaw, and of ossified portions of limb bones. Percent ossification was scored for targeted skull bones. Results were analyzed using general linear models and revealed …

Rotary Pump Speed Modulation To Produce Pulsatile Flow And Ventricular Volume Unloading., Connor Joseph Smith

Electronic Theses and Dissertations

Background: Continuous-flow (CF) left ventricular assist devices (LVADs) have gained widespread clinical acceptance as a treatment option for advanced heart failure (HF); however, they have also been associated with an increased risk of adverse events, including gastrointestinal bleeding, aortic insufficiency, and hemorrhagic stroke. It has been hypothesized that the increase in adverse event incidence may be due in part to diminished vascular pulsatility and high shear stress when CF-LVADs are operated at fixed speeds. Previous studies have shown that pump speed modulation generates greater levels of pulsatility in rotary pumps than when operated at fixed speeds. The objective of this …

Exploring An Outdoor Experiential And Pyd Program's Influence On Youth In A Residential And Day Treatment Program, Rebecca Durbahn

Electronic Theses and Dissertations

This dissertation explores the process and examines the outcomes of youth participating in a positive youth development adventure-based intervention Challenge By Choice (CBC) with outcomes of youth receiving treatment as usual in a residential and day treatment program. This dissertation aims to build on the growing body of literature on outcomes associated with PYD theoretical models and AET approaches. Specifically, the proposed dissertation asks: Is there a difference in externalizing behavioral outcomes for youth who participate in CBC as compared to peers of similar age/behavioral baseline who receive only treatment as usual?

To answer this research question, a mixed methods …

Trace Element Analysis Of Human Dentition From The Elite Meroitic Cemetery At Sedeinga, Sudan To Determine Dietary Consumption And Cultural Behaviors, Tiffany Lee

Electronic Theses and Dissertations

Minimal research has been conducted on the human skeletal remains from this site, and this research is aimed toward adding knowledge of the Nubian culture for the period between the 1st c. AD to the 4th c. AD, particularly focusing on answering the following questions: 1) Was intra- individual variation present in dietary consumption or cultural behaviors based on elements found within an individual's multiple molars after analysis; 2) Was an inter-individual variation apparent, based on developmental age through permanent molars, that indicated a distinction between dietary consumption against all individuals; and 3) Based on known medicinal and cosmetic use …

Comparison Of Muscle Physiology And Performance Outcomes From Either Relative Intensity Or Repetition Maximum Training, Kevin Carroll

Electronic Theses and Dissertations

The main purpose of this dissertation was to compare performance and physiological outcomes of between a repetition maximum (RM) and a relative intensity using sets-and-repetitions (RI_SR) resistance training (RT) program in well-trained lifters. Fifteen subjects underwent RT 3 d·wk^-1 for 10-weeks in either a RM group (n=8) or RI_SR group (n=7). The RM group achieved a relative maximum each day while the RI_SR group trained based on percentages. Testing included percutaneous needle biopsies of the vastus lateralis, ultrasonography, unweighted (g to assess within and between-group alterations. RI_SR from pre-to-post yielded statistically significant increases in …

Investigating The Interaction Of Monoamines And Diel Rhythmicity On Anti-Predator Behavior In An Orb-Weaving Spider, Larinioides Cornutus (Araneae: Araneae), Rebecca Wilson

Electronic Theses and Dissertations

Circadian rhythms are ubiquitous among organisms, influencing a wide array of physiological processes and behaviors including aggression. While many neurophysiological mechanisms are involved in the regulation of aggressive behaviors, relatively few studies have investigated the underlying components involved in the interplay between circadian rhythms and aggression. Spiders are an ideal model system for studying circadian regulation of aggression as they are ecologically both predators and prey. Recent studies have revealed a nocturnal orb- weaving spider Larinioides cornutus exhibits a diel and circadian rhythm in anti-predator behavior (i.e. boldness) that can be manipulated by administration of octopamine (OA) and serotonin (5- …

Role Of Ataxia-Telangiectasia Mutated Kinase In Cardiac Autophagy And Glucose Metabolism Under Ischemic Conditions, Patsy Thrasher

Electronic Theses and Dissertations

Ataxia-telangiectasia mutated kinase (ATM), a serine/threonine kinase primarily located in the nucleus, is typically activated in response to DNA damage. Individuals with mutations in ATM gene develop a disease called Ataxia telangiectasia (AT). These individuals are more susceptible to ischemic heart disease and metabolic disorder. Our lab has previously shown that ATM plays a critical role in β-adrenergic receptor (β-AR) - and myocardial infarction (MI)-stimulated myocyte apoptosis and cardiac remodeling. This study tested the hypothesis that ATM plays a critical role in cardiac autophagy and glucose metabolism following MI and ischemia, respectively. Early during MI (4 hours after its onset) …