Medicine and Health Sciences Commons^™

Environmental Exposures And Aging., Daniel Chris Gomes

Electronic Theses and Dissertations

In recent years, research into air pollution has shown that exposure to certain components in air pollution, primarily PM2.5 can accelerate biological aging and thereby lead to increased susceptibility to multiple diseases. We hypothesize that prolonged exposure to air pollutants can result in premature aging leading to extensive tissue dysfunction and susceptibility to diseases. To examine this, we exposed mice to PM2.5 for 9, 15, and 21 days, then measured the telomere lengths, cellular senescence, and histone methylation patterns of multiple cell types. We found consistently increased telomere attrition, cellular senescence and advanced age-consistent histone methylation patterns in groups exposed …

Development And Praxis Of Ph Drug Delivery System Contra Zika, Julissa Rodriguez

Electronic Theses and Dissertations

As the effects of global warming continue to spread throughout the world, another critical issue is slowly gaining attention in many urban tropical countries. The Emerging Infectious Diseases/ Pathogens list from the National Institutes of Health (NIH) listed the Zika virus as a potential pandemic threat. In 2015, an outbreak of Zika was noted in several South American countries until the spread reached an all-time high of 87 countries in 2017. During the outbreaks, adults affected were noted to have joint and muscle pains, fevers, and rashes. The worst cases reported would ultimately lead to Guillain-Barre symptoms. Still, pregnant women …

Metabolic Foundations Of Exercise-Induced Cardiac Growth., Kyle Fulghum

Electronic Theses and Dissertations

Regular aerobic exercise promotes physiological cardiac growth, which is an adaptive response thought to enable the heart to meet higher physical demands. Cardiac growth involves coordination of catabolic and anabolic activities to support ATP generation, macromolecule biosynthesis, and myocyte hypertrophy. Although previous studies suggest that exercise-induced reductions in cardiac glycolysis are critical for physiological myocyte hypertrophy, it remains unclear how exercise influences the many interlinked pathways of metabolism that support adaptive remodeling of the heart. In this thesis project, we tested the general hypothesis that aerobic exercise promotes physiological cardiac growth by coordinating myocardial metabolism to promote glucose-supported anabolic pathway …

Early Detection Of Atypical Motor And Neurobehavior Of Infants At Risk Secondary To Opioid Exposure: A Prospective Study, Kara Boynewicz

Electronic Theses and Dissertations

Prenatal opioid exposure has been studied in relation to infants' medical outcomes. However, large gaps exist in the literature supporting early identification of atypical neurobehavior and motor development of infants with prenatal opioid exposure. The purpose of the study was to investigate whether prenatal opioid exposure has a negative influence on a newborn infant’s neurobehavior and motor development to aid in the early identification of potential delays. Using a prospective quasi experimental design, infants motor development using the Test of Infant Motor Performance (TIMP) and neurobehavior using the NICU Neonatal Network Scale (NNNS) was assessed on 58 infants in a …

Role Of Meibum And Tear Phospholipids In The Evaporative Water Loss Associated With Dry Eye., Samiyyah M. Sledge

Electronic Theses and Dissertations

It is generally believed that the tear film lipid surface film inhibits the rate of evaporation (Revap) of the underlying tear aqueous. It is also generally believed that changes in the composition of the tear film lipid layer is responsible for an increase in Revap in patients with dry eye. Both of these ideas have never been proven. The purpose of the current studies was to test these ideas. Revap was measured in vitro gravimetrically. Lipid spreading was measured using Raman spectroscopy and microscopy. The influence of the following surface films on the Revap of the sub phase of physiologically …

Decreasing Unintentional Pregnancies For Tennesseans, Paula M. Todd

Electronic Theses and Dissertations

In 2018, 49% of all pregnancies in the United States were unintended, with women with a lower- income status being five times more likely to experience an unplanned pregnancy. Tennessee has a high rate of unintended pregnancies, particularly among the uninsured, low-income, and rural teen populations; some 22% of these unintended pregnancies end in abortion. Oral or transdermal contraceptives that are affordable and accessible for women of childbearing age can reduce unintentional pregnancies. The addressed gap in clinical practice was that contraceptives are not currently available over the counter in Tennessee pharmacies without a prescription, which necessitates a costly medical …

Machine Learning Applied To Colloidal Properties Of Perfluorocarbon Nanoemulsions For Imaging In Ards/Ali, Marco Hosfeld

Electronic Theses and Dissertations

Acute Respiratory distress Syndrome (ARDS) and Acute Lung Injury (ALI) are inflammatory lung pathologies consisting of non-hydrostatic pulmonary edema leading to hypoxia and impaired gas exchange in the lungs. ARDS/ALI is both difficult to study and treat as it is not in itself a specific pathology but rather a syndrome consisting of many pathologies that vary case by case. It is, however, consistently characterized by an explosive acute inflammatory response in the lung parenchyma leading to hypoxia. Although time has seen to an increase in the understanding of ARDS/ALI, the mortality rate remains in the range of 30-50%. For these …

Identifying The Cardiovascular Effects Of Multiple Pollutants., Katlyn Elizabeth Mcgraw

Electronic Theses and Dissertations

Cardiovascular disease (CVD) is the leading cause of death from environmental exposures. Although exposure to PM_2.5 is an established risk factor for CVD, the contribution of other hazardous pollutant exposure to CVD is less clear. Overall, this work aimed to examine the effect of pollutants with lesser documented effects on cardiovascular disease using a multi-pronged approach to exposure assessment. The three aims were to examine the relationship between county-level toxic chemical releases and CVD mortality in the contiguous United States between 2002 and 2012, to assess the relationship between individual-level VOC metabolites and vascular function, and to build multipollutant …

Heterocyclic Amines And Arylamine N-Acetyltransferase 2 Polymorphism In Pathogenesis Of Insulin Resistance., Kennedy M. Walls

Electronic Theses and Dissertations

Heterocyclic amines (HCAs) are formed when cooking meats at high temperatures or for long periods of time, and their major metabolic pathway includes hepatic N‑hydroxylation by CYP1A2 followed by O-acetylation by N-acetyltransferase 2 (NAT2). NAT2 is a highly polymorphic gene involved in metabolism of drugs and xenobiotics, and its single nucleotide polymorphisms (SNPs) produce phenotypes characterized as slow, intermediate, or rapid acetylator. Recent studies have documented associations between HCAs and insulin resistance and between certain NAT2 phenotypes and insulin resistance. In this study, we demonstrated that NAT2 activity and exposure to certain HCAs may alter cellular glucose …

Risk Factors And Trends In Antimicrobial Susceptibility Patterns In Strains Of Neisseria Gonorrhoeae Following Changes In The Cdc Sexually Transmitted Disease (Std) Treatment Guidelines – United States, 2012-2018, Niketta A. Womack

Electronic Theses and Dissertations

Antimicrobial resistant Neisseria gonorrhoeae (N. gonorrhoeae) has become a major global public health concern in the 21st century. Surveillance activities are essential in identifying risk factors in priority populations. The purpose of this study was to identify risk factors associated with and trends in antimicrobial susceptibility patterns in N. gonorrhoeae strains identified through the Gonococcal Isolate Surveillance Project (GISP). A study sample of 37,157 men was evaluated to measure adherence to changes in CDC’s STD treatment guidelines in 2012 and 2015. Data were analyzed to measure associations between independent and dependent variables by conducting bivariate and logistic regression …

Identification And Structural Characterization Functional Motifs In The Porphyromonas Gingivalis Mfa1 Short Fimbria., Mohammad K. Roky

Electronic Theses and Dissertations

Porphyromonas gingivalis is a causative agent of periodontal disease, initially colonizes the oral cavity by adhering to commensal streptococci. Adherence requires the interaction of the minor fimbrial protein (Mfa1) of P. gingivalis with streptococcal antigen I/II (Ag I/II). A peptide derived from Ag I/II peptide has been well characterized and shown to significantly reduce P. gingivalis colonization and bone loss in vivo, suggesting that this interaction represents a potential target for therapeutic intervention. However, the functional motifs of Mfa1 involved in the interaction with Ag I/II remain uncharacterized. A series of N- and C-terminal peptide fragments of Mfa1 were …

Does Circularizing Source-Separated Food Waste Present A Risk To Our Food?, Astha Thakali

Electronic Theses and Dissertations

About a third of the food produced annually is wasted. Food waste recycling can be a way to close the loop and attain a more sustainable food system, however, the system must be carefully monitored and managed to avoid the introduction and build-up of contaminants. To study the potential presence of contaminants in food waste, source-separated food waste was collected and screened for five classes of contaminants (physical contaminants, heavy metals, halogenated organic contaminants, pathogens, and antibiotic resistance genes) from two separate regulatory environments (voluntary vs mandated food separation). The regulatory environment did not affect the level of contamination, except …

Arachidin 3 Modulation Of Lipid Metabolism In Rotavirus Infections, Stormey Wisdom

Electronic Theses and Dissertations

Rotavirus (RV) can cause severe and deadly gastroenteritis in young children, infants, and immunocompromised individuals. Previous studies have shown that arachidin 3 (A3) inhibits RV replication, and that RV replication is dependent on the presence of lipids. This study investigated the alteration of lipid metabolism by A3 in RV infected HT29.f8 cells. A decrease in the RV regulation of lipid biosynthesis genes was observed with the addition of A3 using qRT-PCR. Also, immunofluorescent and histochemical staining for neutral fats, a major component of cellular lipid droplets, revealed an increased accumulation with both RV and RV+A3 when compared to no virus …

Synthesis, Characterization, And Evaluation Of Metal Complexes With Cancer Selective Anti-Proliferative Effects And Hydrogen Evolution Catalytic Properties., Nicholas Vishnosky

Electronic Theses and Dissertations

Bis-thiosemicarbazones (BTSC) and their metal chelates have properties that are useful in several different scientific fields. These systems have already received attention in major fields of biology and engineering. Hydrogen evolution reaction (HER) catalysts need to be cheap and operate under minimal overpotentials with a long lifetime. The treatment of cancer requires, novel agents that have potent cytotoxic activity against cancer cells while displaying minimal side effects. In this dissertation the modular synthesis of these bis-thiosemicarbazone systems is utilized to regulate the redox chemistry for employment in the desired sector of chemistry. The ligand and metal chelates synthesized were characterized …

Development Of A Lectin-Fc Fusion Protein With Antiviral And Anti-Cancer Activity., Matthew William Dent

Electronic Theses and Dissertations

This thesis describes the development of a novel lectin-Fc fusion protein and its antiviral and anti-cancer activity. The molecule, Avaren-Fc (AvFc), is a fusion of a variant of the actinomycete lectin actinohivin (Avaren) and the Fc region of human IgG1, and is selective for the terminal α1,2-mannose residues found at the ends of high-mannose-type glycans that can be found on the surface of certain heavily glycosylated viruses and cancer cells. Here, AvFc was found to be able to neutralize simian immunodeficiency virus as well as Hepatitis C virus with nanomolar IC₅₀ values. Furthermore, AvFc recognizes a number of cell …

A Complete Approach To Predict Biodistribution Of Nanomaterials Within Animal Species From In-Vitro Data, Edward Price

Electronic Theses and Dissertations

Smart drug-design for antibody and nanomaterial-based therapies allows for optimization of drug efficacy and more efficient early-stage pre-clinical trials. The ideal drug must display maximum efficacy at target tissue sites, but to track and predict distribution to these sites, one must have a mechanistic understanding of the kinetics involved with the individual cells of the tissue itself. This process can be tracked through biological simulations coupled with in-vitro approaches, which result in a rapid and efficient in-depth understanding of drug transport within tissue vasculature and cellular environment. As a result, it becomes possible to predict drug biodistribution within live animal …

Photoassisted Synthesis Of Complex Polyheterocycles Via Esipt-Driven Dearomative Intramolecular Cycloadditions, Dmitry Kuznetsov

Electronic Theses and Dissertations

This research is focused on the development of novel photoassisted synthetic methodologies that provide straightforward access to complex and diverse libraries of polyheterocycles from modularly assembled precursors. All methods are based on the dearomative cycloadditions between two components: (i) o-azaxylylenes, generated by the excited-state intramolecular proton transfer, and (ii) tethered arene groups.

We have demonstrated the synthetic utility of four new photoinduced processes that yield complex products amenable for post-photochemical modifications:

• [4+4] Cycloaddition of o-azaxylylenes to 1,3,4-oxadiazoles with subsequent dinitrogen extrusion. This reaction furnishes compounds outfitted with epoxide fragments, which undergo ring-openings with various nucleophiles; furthermore, the oxidized products …

The Study Of Alcoholic Liver Diseases, Seun Emmanuel Owoseni

Electronic Theses and Dissertations

Excessive alcohol consumption is the primary contributing factor in the development of alcoholic liver diseases (ALD). Nicotine contained in tobacco is a major addictive alkaloid, which enhances the effects of ALDs. The major enzyme involved in nicotine metabolism is cytochrome P450 2A5 (CYP2A5) which is produced in the liver. Alcohol can stimulate the CYP2A5 enzyme. We utilized cyp2a5-/- knockout mice in this research to examine the effects of CYP2A5.

The cyp2a5-/- mice and wild-type (WT) mice were fed liquid ethanol diet with or without nicotine to induce ALD. Nicotine enhancing effects on ALD were observed in WT mice but not …

The Effect Of Wild Blueberry Bioactives On Endothelial Cell Migration And Angiogenesis: An In Vitro Mechanistic, Genomic And Proteomic Approach, Panagiotis Tsakiroglou

Electronic Theses and Dissertations

The goal of this study is to investigate the effects of wild blueberry fractions (Anthocyanins and Phenolic acids) on vascular function and physiology. More specifically the potential effects of the above fractions and their combination in physiological concentrations on endothelial cell migration, angiogenesis, gene expression and proteins synthesis of markers related to the above processes. The objectives are to study whether anthocyanins, phenolic acids and their combinations (ACNs:PAs) affect: a) cell proliferation, b) speed of endothelial cell migration, c) angiogenesis, d) gene expression of genes critical for cell migration and angiogenesis such as RAC1, RHOA, AKT1, eNOS and VEGF and …

Macromolecule Loading On Plga Particles Through Surface Adsorption, Yiwei Wang

Electronic Theses and Dissertations

The advent of biotherapeutics have impacted the ways in which diseases are treated. In many instances development of recombinant proteins and oligonucleotides into therapeutics are slowed by poor stability of the candidate drugs. Progress has been made in using polymeric particles as carriers of macromolecule drugs. Historically the method is to encapsulate biological drugs into spherical polymeric matrices. Owing to its biocompatible and biodegradable nature, poly (d,l-lactic-co-glycolic acid) (PLGA) has been used extensively in formulating biological drugs into nano- and micro-sized particles. The development of PLGA biologic formulations, however, has been hampered by matrix acidification; the hydrolysis of the polymer …

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 …

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 …

Developing A Risk Assessment Protocol To Quantify Distribution And Uptake Of Persistent Organic Pollutants In Glacial Outflows, Kimberley Rain Miner

Electronic Theses and Dissertations

Pollutants released by industrialized nations between 1960 and 2004 have been transported northward through atmospheric processes and deposited into glaciated alpine ecosystems. Many of these chemicals retain their original structure and are absorbed into the biota thousands of miles away from where they were originally utilized. With a warming climate increasing the melt of alpine glaciers, these glaciers may be introducing growing amounts of toxins into the watershed. While studies have demonstrated the existence of resident pollutants within glaciated ecosystems, no one has developed a risk assessment to identify sources and quantity of risk posed by these compounds when released …

Synthesis Of 2,4,6-Substituted Pyrrolo[2,3-D]Pyrimidines As Potential Anticancer Agents, Si Yang

Electronic Theses and Dissertations

This thesis mainly focuses on the introduction of the background and work have been done in the areas of antifolates development, such as folate function, its three uptake mechanisms inside human cells, antifolates’ role in chemotherapy, et. al. In addition, the Structure-Activity-Relationship design rationale for the series of antifolates will also be discussed. Nevertheless, the details of synthesizing these pyrrolo[2,3-d]pyrimidines as potential antifolates have been described, including chemistry reviews on the pyrrolo[2,3-d]pyrimidine scaffold, and the challenges encountered and the solutions how to solve or improve in order to achieve better yield.

Magnetic Field-Induced Intramolecular Cyclization As A Trigger For Nanoparticle-Based Delivery Systems., Sara Katherine Biladeau

Electronic Theses and Dissertations

Magnetic nanoparticles (MNPs) are used in a variety of applications, including as agents for magnetic resonance imaging, generation of local hyperthermia, and as platforms for drug delivery. Iron-based MNPs are often coated with a shell, such as silica or gold, to increase biocompatibility for drug delivery applications. Many MNPs used for cancer therapy rely on either an internal trigger, such as a difference in pH, or an external trigger, such as light or an alternating magnetic field (AMF), to cause release of a payload, typically a chemotherapeutic drug. Internal triggers are appealing because drug release can be targeted to a …

An Analysis Of Neurogenesis In A Mouse Model Of Chemotherapy Related Cognitive Impairment, Maxwell A. Hennings

Electronic Theses and Dissertations

Cancer patients treated with adjuvant chemotherapy often experience cognitive decline following treatment. This phenomenon, often dubbed “chemo brain” or “chemo fog” is usually temporary, but for a subset of survivors, these cognitive impairments can be long-lasting (>10 years) and negatively affect patients’ quality of life, career performance, and social fulfillment. While it is unclear what neurobiological mechanisms underlie chemotherapy related cognitive impairment, the majority of the animal literature has focused on adult neurogenesis. One process important for neurogenesis is the proliferation of new neurons within the dentate gyrus of the hippocampus. It is evident that many chemotherapy agents can …

Discovery Of Pyrimidine-Based Heterocycles As Single Agents With Combination Chemotherapy Potential And As Inhibitors Of Purine Nucleotide Biosynthesis For The Treatment Of Cancer, Rishabh Mohan

Electronic Theses and Dissertations

This dissertation describes the design, synthesis and biological evaluation of monocyclic and bicyclic pyrimidine-base heterocycles as single agents with combination chemotherapy potential having both antiangiogenic effects and cytotoxic effects. This dissertation also describes selective tumor targeting with 5-substituted pyrrolo[2,3-d]pyrimidines analogs with heteroatom bridge substitution as GARFTase inhibitors.

The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization as well as for inhibition of one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), platelet derived growth factor receptor-β (PDGFRβ) and epidermal growth factor receptor …

The Role Of Nicotine, A7 Nicotinic Acetylcholine Receptors And Extracellular Matrix Remodeling In Pulmonary Fibrosis., Glenn Ward Vicary

Electronic Theses and Dissertations

The median survival for idiopathic pulmonary fibrosis (IPF) patients from diagnosis is a dismal 3 years. This condition is characterized by pulmonary fibroproliferation and excess production and disordered deposition of extracellular matrix (ECM) proteins resulting in obliteration of the original tissue architecture, loss of lung function and eventual death due to respiratory failure. The main hindrance to the development of effective treatments against pulmonary fibrosis is the late detection of its progression and is often of unknown cause. Tobacco smoke represents the most important environmental factor linked to the development of pulmonary fibrosis, with over 60% of IPF patients current …

Multipurpose Tenofovir Disoproxil Fumarate Electrospun Fibers For The Prevention Of Hiv-1 And Hsv-2 Infections., Kevin Tyo

Electronic Theses and Dissertations

Sexually transmitted infections affect hundreds of millions of worldwide. Both human immunodeficiency virus (HIV-1 and -2) and herpes simplex virus-2 (HSV-2) remain incurable, urging the development of new prevention strategies. While current prophylactic technologies are dependent on strict user adherence to achieve efficacy, there is a dearth of delivery vehicles that provide discreet and convenient administration, combined with prolonged-delivery of active agents. To address these needs, we created electrospun fibers (EFs) comprised of FDA-approved polymers, poly(lactic-co-glycolic acid) (PLGA) and poly(DL-lactide-co-ε-caprolactone) (PLCL), to provide sustained-release and in vitro protection against HIV-1 and HSV-2. PLGA and PLCL EFs, incorporating the antiretroviral, tenofovir …

Effects Of Melatonin On Heartbeat And Possible Identification Of A Melatonin Receptor In Drosophila Melanogaster, Tricia L. Vankirk

Electronic Theses and Dissertations

Chapter 1 of this manuscript is a literature review that serves as an introduction to the entire dissertation. Chapter 2 examines the effects of the melatonin injection on heart rate and rhythmicity in Drosophila melanogaster Canton-S (wild-type) pupae and pupae bearing a variety of heart mutations. Chapter 3 investigates further the possible mechanisms of melatonin’s ability to increase heart rhythmicity without significantly affecting heart rate. A melatonin antagonist, luzindole; a high-affinity melatonin agonist, 2-iodomelatonin and RNAi techniques are used to identify a possible melatonin receptor in Drosophila melanogaster.

An appendix contains a previously published manuscript detailing experiments performed at the …