Published ETD Collection

Permanent URI for this collectionhttps://hdl.handle.net/2152.3/2

Browse

Recent Submissions

Now showing 1 - 20 of 842
  • Item
    Ehrlichia chaffeensis Activates Notch Signaling Through SLiM Mimicry to Inhibit Apoptosis
    (May 2022) Patterson, LaNisha LaTice 05/07/1989-; Jere Mcbride; Thomas Smith; Andres Oberhauser; Gracie Vargas; Joya Chandra; Spyros Artavanis-Tsakonas
    Ehrlichia chaffeensis is a small, obligately intracellular gram-negative bacterium, and the etiological agent of human monocytotropic ehrlichiosis (HME), an emerging, life threatening tick-borne zoonosis. E. chaffeensis infects mononuclear phagocytes and has evolved molecular strategies to reprogram the host cell involving secreted effectors that interact directly with the host cell targets. Recently, we have shown E. chaffeensis evasion of innate defenses of the macrophage involve activation of Wnt, Hedeghog and Notch signaling pathways. Interestingly, the E. chaffeensis tandem repeat effector, TRP120, has been shown to interact with host proteins important for activation and regulation of conserved signaling pathways including Wnt, Notch and Sonic Hedgehog. In this study, we investigated the molecular interactions and functional implications of Notch activation during E. chaffeensis infection. The objective of this research project is to identify the SLiM ligand mimetic in E. chaffeensis TRP120 and the functional implications of TRP120 Notch activation. Two aims were originally proposed to investigate this hypothesis. Aim 1 was to elucidate the molecular interactions required for TRP120 Notch activation. Aim 2 was to investigate the role of E. chaffeensis Notch stabilization of XIAP and inhibition of caspase activation. Based on the evidence collected during my research, I have concluded that a TRP120- TR Notch SLiM memetic motif directly binds Notch-1 at a region containing the LBD to activate Notch signaling. TRP120 Notch activation results in an anti-apoptotic program involving inhibitor of apoptosis proteins (IAPs) that inhibits caspase activation for intracellular survival. We demonstrate sequence homology between TRP120 and Notch ligands and determined that the TRP120-TR shares significant identity with known Notch ligands. We determined direct interactions between TRP120 and NECD recombinant protein containing ligand interaction domain, EGFs 1-13. We further defined the TRP120-TR domain as being capable of Notch activation and have defined the TRP120 Notch SLiM memetic motif required for Notch activation. Furthermore, we determined a direct correlation between Notch activation and inhibition of apoptosis linked to an increase in XIAP expression during E. chaffeensis infection. Increased XIAP levels correlated with increased NICD levels during E. chaffeensis infection and after TRP120 Notch ligand mimetic peptide treatment. Additionally, increased XIAP expression was consistent with increased pro-caspase levels. siRNA knockdown or inhibition of XIAP with small molecule inhibitor significantly increased apoptosis and Caspase-3, -7 and -9 levels and decreased ehrlichial load. This investigation reveals a mechanism whereby E. chaffeensis repurposes Notch signaling to stabilize XIAP and inhibit apoptosis. Understanding the molecular basis of Ehrlichia-Notch ligand mimicry is important for understanding the survival strategies of intracellular pathogenesis. Defining such interactions may lead to the development of novel therapeutics that target host-pathogen protein-protein interactions. The proposed study is highly significant in revealing a molecular mechanism whereby obligately intracellular pathogens, with small genomes and limited protein effectors, have evolved moonlighting proteins and molecular mimicry to rewire conserved signaling pathways and cellular functions to ensure persistent infection and survival. The identification of a short linear motif found within a non-canonical Notch ligand gives more insight into the underlying molecular mechanisms of aberrant Notch activation and may therefore lead to therapeutic approaches for diseases by which constitutively activated Notch signaling leads to disease onset and progression. Understanding Notch activation during E. chaffeensis infection will allow for the development of agents targeting critical steps of Notch signaling to inhibit infection and survival in the macrophage.
  • Item
    The Impact of Acculturation on Quality of Life in African American Women Living with A Lung or Colorectal Cancer Diagnosis
    (August 2022) Garner, Danya Tymon
    The purpose of the proposed pilot study was to explore potential relationships between acculturation, selected demographic characteristics and perceived quality of life in African American women who have been diagnosed with and received treatment for colorectal or lung cancer. There is limited research examining potential cultural and demographic factors related to the ability to cope and maintain quality of life. A descriptive, exploratory research design was used for this study and utilized three surveys to gather data including the African American Acculturation Scale-Revised World Health Organization Quality of Life Instrument – BREF, and a Demographic Data Form. A total of 15 African American women who had been diagnosed with lung or colorectal cancer during the past five years were recruited for this pilot study. Data were analyzed using descriptive statistics including measures of central tendency, interquartile ranges, variance, and standard deviation as well as tests of differences, Mann Whitney U, and linear regressions. A statistical significance of α < .05 was the standard used for this research. Results of the research study provided baseline data about the impact of American women with colorectal or lung cancer . Published results will assist in filling the existing gap in research literature.
  • Item
    Elucidating Mechanisms of Immunity to Nipah Virus Infection through Generation of Attenuated Viruses and a Single-Cycle Vectored Vaccine
    (December 2021) Foster, Stephanie Leigh
    Nipah virus (NiV) is an emerging paramyxovirus that has caused outbreaks with high case-fatality rates in South and Southeast Asia. Mechanisms of NiV virulence are poorly understood, and there is no licensed vaccine nor treatment. Accessory proteins produced from the NiV P gene through co-transcriptional gene editing (V and W) inhibit multiple molecules in the type-I interferon (IFN-I) induction and response pathways to modulate the host innate immune response to NiV infection. Previously, ferrets infected with a recombinant NiV (rNiV) lacking V survived an otherwise lethal NiV challenge via an unknown mechanism. Mutation of the V gene of the related canine distemper virus prevented binding of V protein to melanoma differentiation-associated protein 5 (MDA5) and attenuated virulence in an otherwise lethal ferret model. The NiV V-MDA5 binding site and the effects of blocking this interaction on virulence were previously unknown. The work described here identified amino acid I414 in NiV V as a critical residue for binding to MDA5 through co-immunoprecipitation/western blot and IFN-β dual luciferase reporter assays in a plasmid overexpression system. Subsequently, rNiV lacking the ability to bind to MDA5 and signal transducer and activator of transcription 1 (STAT1) were recovered, characterized in cell culture with and without IFN-I pretreatment, and used in an experimental infection model in ferrets. Interestingly, 25% of ferrets infected with the rNiV lacking V survived challenge with a higher virus dose than in previous studies, while 75% of ferrets infected with a rNiV lacking the ability to bind to MDA5 and STAT1 survived. These experiments identified MDA5 and STAT1 together as important targets for NiV virulence. Additionally, previous NiV vaccine candidates have shown efficacy against NiV challenge in a variety of animal models, but no virus-vectored vaccines have been tested for efficacy shortly prior to challenge, as in an outbreak scenario. Therefore, a vesicular stomatitis virus-vectored NiV vaccine was rescued and tested in African green monkeys. Animals were protected from lethal challenge with NiV when the vaccine was given seven or three days prior. The vaccine is non-replicative and yet works rapidly in a single dose with no adjuvants. Combined, the experiments described here will advance understanding of NiV virulence and development of effective vaccines against this deadly infection.
  • Item
    Aging Skeletal Muscle Plasticity in Exercise and Injury
    (May 2021) Brightwell, Camille R.
    Sarcopenia—progressive loss of muscle mass and strength—diminishes quality of life and longevity. In addition to progressive atrophy, older adults exhibit impaired regeneration after muscular injury. Activity of muscle stem cells, termed satellite cells, is dysregulated with aging which impairs skeletal muscle remodeling and limits plasticity of aged muscle. Aim 1 (Chapter 2) of this dissertation seeks to clarify the debated requirement of satellite cells for overload-induced hypertrophy in aging muscle via a common surgical overload model, with the original hypothesis that while aging satellite cells contribute to overload-induced hypertrophy to mitigate sarcopenia, growth can occur in the absence of satellite cells via expansion of the myonuclear domain. In light of Aim 1 results demonstrating no overload-induced hypertrophy in aging skeletal muscle with surgical overload, Aim 2 (Chapter 3) examines the efficacy of a novel and translatable murine resistance exercise model to elicit satellite cell expansion with myonuclear accretion and hypertrophy in aging skeletal muscle, with the hypothesis that this novel exercise model would result in expansion of the satellite cell pool along with hypertrophy not observed in old mice with the surgical overload model. Indeed, PoWeR (Progressive Weighted wheel Running) elicited hypertrophy in old mice, likely supported by a robust angiogenic response in hind limb muscles. Lastly, Aim 3 (Chapter 4) examines the efficacy of a novel NNMT inhibitor to enhance regeneration of aging skeletal muscle after injury by enhancement of satellite cell proliferation and fusion to myofibers, confirming the hypothesis that NNMT inhibition would rescue age-related deficits in satellite cell activity to promote superior regeneration of muscular injury of old mice.
  • Item
    Investigation of ARNT isoform-specific regulation of AHR signaling
    (May 2021) Bourner, Luke
    The aryl hydrocarbon receptor nuclear translocator (ARNT) is alternatively spliced into two distinct isoforms, isoform 1 and 3. Although ARNT is found to be critical in immunity, xenobiotic, and hypoxic response, ARNT isoform-specific function has yet to be investigated. We previously demonstrated that primary lymphocytes express both of these isoforms, however malignant T cells overexpress ARNT isoform 1 to promote cell viability. In this study, we find that the ARNT isoforms have opposing roles in aryl hydrocarbon receptor (AHR) signaling, as ARNT isoform 1 suppresses AHR activity, whereas ARNT isoform 3 is needed for AHR target-gene transcription. Furthermore, to explore this suppressive role, we investigated a unique modification specific only to ARNT isoform 1 – phosphorylation of serine 77 (S77). We determined that phosphorylation at S77 is initiated following AHR activation and is critical for the augmentation of AHR-target gene transcription. These results further highlight the importance of investigating ARNT isoform-specific function and reveal an essential role of ARNT isoform 1 phosphorylation in AHR signaling. Collectively, these findings increase our understanding of a complex regulatory mechanism by which ARNT regulates AHR signaling, further aiding in the comprehension of their roles in immunity and supporting the potential of targeting ARNT alternative splicing as a means of therapeutic intervention in hematological diseases and malignancies.
  • Item
    A novel GC-MS/MS assay for the measurement of 2-hg enantiomers and the utility of 2-hg enantiomer levels as a biomarker for IDH mutant gliomas
    (May 2021) Strain, Shinji Kenneth
    The isocitrate dehydrogenase (IDH) gene has recently been identified to be mutated in gliomas, a malignant brain tumor. Mutant IDH (IDHmut) produces the oncometabolite, (R)-2-hydroxyglutarate (R-2-hg), resulting in a significant increase of intracellular concentrations above physiological levels. However, a lack of correlation between circulating 2-hg levels and IDH status has been observed. This is likely due to the lack of discrimination from the enantiomer of R-2-hg and (S)-2-hydroxyglutarate (S-2-hg). S-2-hg is also normally made in the body but can increase to levels comparable to R-2-hg during hypoxic and acidic conditions. Thus, it is important to differentiate between R-2-hg and S-2-hg to determine the utility of R-2-hg as a biomarker. Furthermore, the current mass spectrometry (MS) methods available for the separation and detection are lacking. Current assays use laborious methods that can result in interconversion of enantiomers during sample preparation, and since low-resolution mass spectrometry instruments have been utilized, incorrect characterization of 2-hg MS data has occurred. A novel chiral gas chromatography-tandem mass spectrometry (GC-MS/MS) assay was developed which improves upon current methods. The assay utilizes a simplified ethyl acetate extraction, separates 2-hg enantiomers using a chiral column which avoids racemization, and quantifies 2-hg enantiomers using stable-isotope dilution MS. Using 2-hg isotopologues, unique EI fragmentation pathways for both 2-hg and the 2-hg lactone have also been described resulting in the ability to simultaneously detect both 2-hg and 2-hg lactone enantiomers. The assay was then validated and serum 2-hg levels from healthy patients were measured, establishing a new, comprehensive reference range for normal levels of each enantiomer. Differences in basal levels of 2-hg enantiomers were observed between races but not sex. Finally, serum levels of 2hg enantiomers were measured in patients with and without IDHmut gliomas. An increase in R-2hg levels was observed for a number of patients with growing IDHmut gliomas, however, not all patients with IDHmut gliomas had an increase in R-2-hg levels. Increased S-2-hg levels were also observed in patients who received prior chemotherapy/radiotherapy. Further work is needed to fully understand circulating 2-hg enantiomer biology, but the work presented herein takes a significant first step in providing the tools and framework for understanding the clinical utility of R-2-hg as a biomarker for IDHmut gliomas.
  • Item
    Novel Biomarkers within Extracellular Vesicles for the Identification of Traumatic Brain Injury
    (May 2024) Tang, Zifeng Tony 1989-; Szczesny, Bartosz; Motamedi, Massoud; Micci, Maria; Zhao, Yingxin; Bossmann, Stefan
    Traumatic brain injury (TBI) is defined by the National Institute of Neurological Disorders and Stroke (NINDS) as “…external physical forces cause damage to the brain, whether from impact, penetrating objects, blast waves or rapid movement of the brain within the skull”. According to the most recent CDC data, there were roughly 214,000 TBI-related hospitalizations and 70,000 TBI-related deaths in 2021. The current diagnosis of TBI includes a neurological exam such as Glasgow Coma Scale (GCS) and imaging tests (CT, MRI). However, these modalities have several limitations, including inter-rater reliability, inconsistencies in diagnosis, and lack of predictive prognosis, all of which highlights the complex pathophysiology of this disease process. Thus, there is an urgent need for identification of novel methods for an early detection and quantitative monitoring of TBI. In this project, we investigated extracellular vesicles (EVs) in blood plasma as a potential source of novel TBI biomarkers. Key characteristics of EVs, including the protection of the packaged cargo that reflects processes occurring in the cell of origin and their ability to cross the blood-brain-barrier (BBB), make them a highly valuable source of biomarkers. We subjected 10–12-week-old C57BL/6J male mice to moderate/severe TBI using the pre-clinical, closed head, weight drop model followed by EVs isolation from blood plasma at multiple time points post injury. We detected time-dependent qualitative and quantitative changes in the biophysical properties of EVs. Furthermore, we discovered TBI induced changes in specific EVs subpopulations of microglia/macrophage CD11b+ and astrocyte ACSA-2+ vesicles post-injury. These temporal dynamics of EVs are also reflected in both mitochondrial DNA content, nuclear DNA content, and brain-derived cellular markers NFL, GFAP, and Iba1. Additionally, we combined a global mass spectrometry proteomics approach with biostatistical analysis and computational Graph Neural Network (GNN)-based modeling to discover a panel of potential novel biomarkers for the detection and severity of TBI. Lastly, we confirmed the dynamic release of mtDNA and its fragments in EVs from neurons using an in-vitro TBI model and EVs derived from glucose oxidase stressed retinal pigment epithelial cells, respectively. Together, our findings indicate that a combination of DNA quantity, SAA, and CFD proteins in EVs may be used as diagnostic tools for the rapid, accurate assessment of TBI detection and its sequelae.
  • Item
    A Naturalistic Inquiry of the Experiences of Women Diagnosed with Gestational Diabetes
    (December 2023) Mandia, Diana; Dr. Adrian Juarez (axjuarez@utmb.edu); Dr. Carolyn Phillips (Retired); Dr. Patricia Blair; Dr. Monique Pappadis; Dr. Sandra Lee
    Gestational diabetes, hyperglycemia that develops in pregnant women with no prior history of diabetes, affects 2% to 10% of all pregnancies in the United States (Centers for Disease Control and Prevention [CDC], 2022). About 50% of women with GDM go on to develop T2DM, and babies of women diagnosed with GDM also are at increased risk of developing T2DM later in life (CDC, 2022). Effective management of GDM requires women to change their health behaviors related to diet, exercise, and medication adherence. Although some studies have examined the experiences of women who have been diagnosed with GDM in other parts of the world, there is a need for research that explores the experiences of women with GDM living in the United States. The current study utilized Naturalistic Inquiry [NI] (Erlandson et al., 1993; Lincoln & Guba, 1985) to explore and describe the experiences of women diagnosed with gestational diabetes [GDM] in a previous pregnancy and were living in the United States. Data collection took place in the form of one-on-one interviews via Zoom Video Conference with women diagnosed with GDM in a previous pregnancy currently living in the United States. Study data consisted of interview data and participants’ demographic data. Interview data was analyzed using Erlandson et al.’s (1993) interpretation of Lincoln and Guba’s (1985) approach to inductive data analysis. Data analysis revealed three major categories: 1) Finding Out About the Gestational Diabetes Diagnosis, 2) Mastering GDM, and 3) Life After GDM. The implications of the study’s findings pertain to nurses and other healthcare providers who help care for pregnant women diagnosed with GDM. Women with GDM need more information about GDM risk factors, how to incorporate GDM recommendations into their daily lives, mental health resources, and whether having had GDM posed long-term risks for themselves and their children.
  • Item
    Nurse Educators' Perspectives and Experiences with Clinical Judgment
    (December 2023) Rosen, Chelsey Lynn 1992-; Richard, Patricia (plrichar@utmb.edu); Rounds, Linda (lrounds@utmb.edu); Martin, Darlene (damartin@utmb.edu); Prochaska, John (joprocha@utmb.edu); Bosenbark, Margaret (margaret.bosenbark@bswhealth.org)
    Sound clinical judgment (CJ) is an essential skill every nurse needs to care for individuals competently and safely. Over the last two decades, nursing education has struggled to sufficiently prepare and develop students’ CJ, despite various educational and curricular changes. This study utilized a Naturalistic Inquiry approach to explore prelicensure nurse educators’ perceptions and experiences with teaching and evaluating nursing students’ CJ to gain essential insight to educators’ perceptions of this education deficit. Eight prelicensure nurse educators participated in this study, recruited through the memberships of the National League for Nursing (NLN). Data saturation was evident after six participants. Four main categories emerged from the data: Making Sense of Clinical Judgment, Efforts to Foster Clinical Judgment in the Classroom and Clinical Setting, Perceived Challenges for Nurse Educators Related to Clinical Judgment, and The Next Generation National Council Licensure Examination (NGN) Impact. The findings indicate nursing education needs to agree on a definition and utilization of a CJ model to help teach. The findings also indicate creating an active learning environment, using simulation, and educators actively posing questions to students are strategies used to foster CJ in the clinical and classroom settings. The data from this study also reveals prelicensure nurse educators’ perceived challenges to teaching and evaluating students’ CJ and their perceptions on the new changes to licensure examination. The findings from this study support and add to the accelerating body of literature on nursing CJ and lay the groundwork for future research on fostering nursing students’ CJ
  • Item
    Location, Location, Location: Assessing the Role of Context in Moderating the Relationship Between Childhood Adversity and Mental Health Burden
    (December 2023) Nguyen, Amanda 1994-; Peek, Kristen M. (mkpeek@utmb.edu); Pappadis, Monique R.; Prochaska, John; Mehta, Neil; Al Snih, Soham; Buschmann, Robert
    Adverse childhood experiences (ACEs) have profound mental health implications throughout the life course. While literature has focused on individual risk factors for ACEs and their burden on health, there are social and physical environmental contextual factors outside the individual that have been overlooked in studies of childhood adversity. This dissertation sought to understand how environmental context (social and physical environment) moderates the relationship between prior ACE exposure and mental health by using the 2015 Behavioral Risk Factor Surveillance System (BRFSS) and County Health Rankings. By using the BRFSS and the County Health Rankings, this dissertation assessed ACE burden and mental health as well as examined participants’ context at the county level. The goals of this dissertation are to: (1) explore how to define context using social and physical contextual variables, (2) evaluate if context can act as an effect modifier in the relationship between childhood adversity on mental health, and (3) assess if there are racial/ethnic differences on how context moderates ACE burden on mental health. The results of this proposal shed light on how certain aspects of context can buffer the burden of ACEs on mental health, and these results can be used as evidence for allocation of funds to help alleviate the ACE burden at the county level.
  • Item
    Essays on the impact of housing insecurity and other socioeconomic factors on health-related outcomes among Medicare beneficiaries during the Great Recession
    (December 2023) Hernandez, Monica; Mehta, Neil (nemehta@utmb.edu)
    While previous recessions have informed much of our modern-day fiscal policy, they have informed less of relevant housing or healthcare policies focused on preventing or mitigating the effects of housing insecurity during economic crises. In this dissertation, I drew from nationally representative Health and Retirement Study (HRS) data to evaluate the role of housing insecurity on healthcare and health outcomes among Medicare beneficiaries ages 65+ during the Great Recession (2008-2012). In Paper 1, I assessed associations between housing insecurity and foregone medication due to cost. Findings indicated a greater odds of foregone medication among individuals experiencing onset versus persistent housing insecurity, suggesting that unexpected acute economic shocks leave households with little time to adapt and lead to forced trade-offs in basic needs. Guided by the disparities literature, in Paper 2, I examined racial differences in foregone medication among non-Hispanic White (NHW) and Black (NHB) beneficiaries during the 2008 Recession peak to evaluate the extent to which housing insecurity and predisposing, need-based and enabling factors within Andersen’s healthcare utilization model explained the Black-White racial difference. Findings indicated statistically significant associations between race and foregone medication that were explained with the addition of non-housing wealth. These findings suggest wealth was a stronger driver of racial disparities in foregone medication than housing insecurity during the Recession. Guided by stress-health frameworks, in Paper 3, I examined the association of housing insecurity with depressive symptoms among Medicare beneficiaries during the Recession and further assessed the extent to which Andersen’s factors explained this relationship. Findings indicated that baseline housing insecurity had a positive yet insignificant effect on average depressive symptoms during 2008-2012, however, this relationship became negative and significant with the addition of baseline wealth and tenure status, suggesting the strong confounding effect of these variables on the role of housing insecurity on depression. In summary, the three papers fill important gaps in our understanding of the health effects of the Great Recession, including the extent to which housing insecurity was associated with foregone medication due to cost and depression as well as how patterns in forgone medication differed by race and other socioeconomic characteristics.
  • Item
    Examining Nurses' Moral Distress, Acts of Moral Courage, and Influence of Ethical Climate in Caring for COVID-19 Patients During the Pandemic
    (May 2024) Willcott, Emily; Martin, Darlene (damartin@utmb.edu)
    The problem of interest was the nurses in the United States (U.S.) and their moral actions taken in the care of COVID-19 patients. Since March 2020, the U.S. has recorded over 103 million COVID-19 cases and over 1.1 million COVID-19 deaths (CDC, 2023). Healthcare workers comprised nearly 1.2 million of the cases and 2,500 of the deaths (CDC, 2023). Nurses’ moral stances in response to pandemic pressures varied. Nurses were seen acting morally courageous by sacrificing themselves for the care of their patients, and yet a handful of nurses abused their licenses and made unethical decisions by falsifying vaccine cards. Nurses experienced unprecedented stress, leading to experiences with moral distress, but there is limited literature regarding nurses’ moral responses to moral distress during their care of COVID-19 patients. Examining the hospital environment incited by the pandemic as well as see how nurses responded to moral distress in the hospitals was imperative.
  • Item
    Investigating Mechanisms of Nucleoside Reverse Transcriptase Inhibitor Induced Sensory Neuropathy
    (August 2021) Bush, Keegan Michael
    The success of antiretroviral therapy (ART) has generally improved the survival of HIV-infected patients. However, patients on ART whose HIV disease is well controlled show peripheral sensory neuropathy (PSN), supporting the idea that the ART may cause PSN. Although the nucleoside reverse transcriptase inhibitors (NRTIs) used in the ART are thought to contribute to PSN, the mechanisms underlying the PSN induced by NRTIs are unclear. This is partly due to the lack of a good model for mechanistic investigations. In this study, we developed a Drosophila model and modified a mouse model of NRTI-induced PSN that recapitulates the salient features observed in patients undergoing ART: PSN and nociception sensitization. Furthermore, through modified expression screening of both genomic and mitochondrial genes we have identified several effectors that inhibit or exacerbate the NRTI-induced PSN phenotype. The most promising candidate identified was nicotinamide mononucleotide adenylyltransferease (NMNAT) which at increased levels inhibits the NRTI-induced PSN and nociception sensitization in our model. Further characterization revealed that ubiquitous upregulation of catalytically competent NMNAT was required for its neuroprotection against NRTI-induced PSN. From this, we utilized the Drosophila and mouse models to investigate the effects of NAD+ precursor coadministration with NRTI. The mouse model allowed for extended testing from which we determined vitamin B3 exhibits potential to both inhibit and rescue NRTI-induced PSN. Therefore, our models developed here provide a robust platform to elucidate the pathogenic mechanisms of painful PSN induced by chronic exposure to NRTIs, and our findings provide insight into the effectors of NRTI-induced PSN and potentially provide vitamin B3 as a readily implementable, accessible, and inexpensive cotreatment with ART that could improve the quality of life for patients.
  • Item
    Pediatric Nurses' Perceptions of Bedside Shift Report
    (December 2020) Norton, Juanita Teresa
    Nursing bedside shift report (BSR) is a form of nursing shift report that may be used to involve pediatric patients and their families in discussions about their plan of care. According to Healthy People.gov (Office of Disease Prevention and Health Promotion, 2020) in the ten years between 2007 and 2017, there has only been a 1.2% increase in the number of people who reported that health care providers included them in decisions about their health care, to the extent they wanted to be involved. The bulk of research focusing on BSR has been conducted on adult patient units or with nurses who care for adult patients. Adult patient care nurses’ perceptions of the benefits and challenges of using BSR have been explored (Jeffs, Cardoso, et al., 2013), in addition to issues that may have contributed to nurses’ not fully implementing BSR (Small & Fitzpatrick, 2017). There is a significant gap in the literature that looks at BSR’s utilization on pediatric nursing units and there is a lack of studies that aim to understand the perceptions of pediatric nurses who use BSR for nursing shift report. This study utilized Naturalistic Inquiry (NI), first introduced by Lincoln and Guba (1985) and further developed by Erlandson et al. (1993), to explore and describe pediatric nurses’ perceptions of BSR. Participants were recruited using purposive and snowball sampling resulting in a total of twelve pediatric nurses who worked on pediatric general medicine nursing units. Data collection and analysis for this study was ongoing and iterative beginning with the first participant interview utilizing a bio-demographic questionnaire and semi-structured interviews. Rigor was established by using Lincoln and Guba’s criteria as described by Erlandson et al. Findings from the study raised the question of whether BSR is the right form of nursing shift report for all patient populations. While nurses in the current study agreed with the underlying principles of BSR they also identified some issues with utilizing BSR on their pediatric units that frequently required them to modify BSR practices. Repeated modifications of BSR practices could easily lead to an erosion of those practices.
  • Item
    Neuroplasticity, Neurorehabilitation, and New Hope for Brain-Injured Persons
    (December 2020) Anhalt, Carole Stewart
    In the last twenty-five years, treatment for Traumatic Brain Injury (TBI) has stagnated, which has relegated many TBI survivors to permanent disability or premature death. The reasons for this stagnation are arguably historical. In the mid nineteenth century, Paul Pierre Broca established localization theory, which holds that certain cognitive functions are located within specific areas of the brain. The cultural adoption of localization theory ultimately led to brain mapping in the late nineteenth and early twentieth century, still in use today, which attempts to physically map the purported area of the brain where certain cognitive functions occur. In the twentieth century, a nihilistic attitude developed among physicians concerning the possibility of successful treatment of TBI, which is chronicled in first person TBI patient narratives analyzed in this dissertation. Therapeutic nihilism toward TBI continued and was exacerbated when the evidence-based medicine paradigm was developed and culturally adopted by the medical establishment and clinical researchers in the 1990s. In 2017, the Lancet Neurology Commission argued that the culture of evidence-based medicine and a lack of recognition of the complexity and heterogeneity of TBI by medical professionals and researchers has led to the stagnation of TBI treatment in recent decades. The Commission has advocated for a precision-based medicine (individualized) and multidisciplinary approach to TBI treatment. In the last half of the twentieth century, evidence began to emerge validating neuroplasticity, the idea that the human brain can heal after insult or injury, and treatments can now be individualized based upon neuroplastic principles that provide hope for the brain injured.
  • Item
    Impulsivity: Psychometrics of impulsivity in adolescents and links to adolescent risk behaviors
    (December 2020) Le, Donna Jean
    The purpose of this dissertation was to extend the theory of impulsivity and adolescent risk behaviors. Impulsivity is commonly measured with the Barratt Impulsivity Scale (Fossati, Barratt, Acquarini, & Di Ceglie, 2002; Patton, Stanford, & Barratt, 1995). However, the psychometrics and performance of the measure is understudied in adolescent populations in the U.S. The studies in this dissertation used data from Dating It Safe, an ongoing, longitudinal study of adolescent behaviors of a large, high school-based sample of 894 ethnically and socioeconomically diverse adolescents (mean age of 17 years in 2012, Wave 3). The psychometrics of the BIS-11-A (Fossati et al., 2002) is assessed in the current sample of high school adolescents. Then, an adapted 28-item BIS-11-A was used to determine the association of impulsivity with two understudied adolescent risk behaviors, prescription medication misuse and reproductive coercion. The purpose of examining impulsivity with these risk behaviors was to test the performance of impulsivity measures in this sample of adolescents, as well as determine whether impulsivity is a related factor in prescription medication misuse and reproductive coercion. In Aim 1, a two factor, 28-item BIS-11-A was the best fitting factor structure for the current study sample. Aim 2 determined patterns of a risk behavior, prescription medication misuse from adolescence to early adulthood, and examined the association between prescription medication misuse and impulsivity. Aim 3 examined the relationship between impulsivity and reproductive coercion perpetration and victimization and found no significant relationship. Reproductive coercion behaviors may require more planning and forethought. Exploring the performance of the BIS-11-A provides more psychometrics for the measure in adolescents in the U.S. and provides insight on impulsive behaviors as a risk factor for substance use and intimate partner violence.
  • Item
    Brother, Help Thyself: The Construction of a Gay and Bisexual Men's Health Movement before HIV/AIDS
    (August 2020) Jones, Wilmon Dwayne
    This project traces the formation and development of a gay and bisexual men’s health movement before HIV/AIDS (1981-1996). The project is an effort to consider the lives and contributions of gay and bisexual men between the Second World War and the HIV/AIDS period. The creation and management of health and clinical programs formed by and directed toward gay and bisexual men are examined. There is particular attention given to the Whitman-Walker Clinic in Washington, DC, and to similar clinical and community outreach programs in selected urban communities in North America. Through archival research methods, the project addresses the intersection of postwar science, public health, and biomedicine with human sexuality, gender, class, and race. This draws from research and publications in a number of humanities and social science disciplines to critique health politics and activism in response to medical discrimination, health disparities, and the pathology of homosexuality. The work of philosophers Michel Foucault and Guy Hocquenghem offers insights into a larger context of sexuality and Western political and health social movements. The project is intended to place the gay and lesbian health movement alongside the histories of the women’s health movement and African American health initiatives of the postwar decades. This work contributes to a growing dialogue among historians about this overlooked period of medical history and establishes new points of intersection between gay health activists and the association of disease to this stigmatized population.
  • Item
    Interrogation of Neuromedin U Receptor 2/Neuromedin U as a Novel Therapeutic Target for the Treatment of Obesity
    (December 2020) Sampson, Catherine M
    Obesity is a growing public health concern, with 42.4% of the adult population considered obese. Obesity has many comorbidities associated with it, including diabetes, cancer, and heart disease. These comorbidities increase the likelihood of mortality and increase the individual medical costs of the obese population. Obesity is a disease commonly characterized by an overconsumption of energy dense foods leading to an increase in adiposity. The rate at which obesity is growing has demanded a better understanding of the disease and better pharmacotherapies. Currently, the pharmacotherapies available to treat obesity have modest efficacy which highlights the need for more effective pharmacotherapies to treat obesity. The identification of key neural pathways that play a role in food consumption have helped highlight the Neuromedin U Receptor 2 (NMUR2) as a promising target that can regulate body weight and food intake. NMUR2 is activated by the endogenous ligand, Neuromedin U (NMU), which then causes a downstream signaling cascade that leads to neuronal activation or inhibition. This dissertation aims to explore the role of the NMUR2/NMU signaling complex in vitro and identify the physiological role of NMU when examined in the neural pathways in which regulate food intake and body weight. Once identifying NMU as a mediator of food intake and body weight, we then explored the effect of small molecule NMUR2 agonists and their ability to decrease body weight, adiposity, and improve metabolic measures in diet induced obese animals.
  • Item
    The Impact of Powassan Virus and Borrelia burgdorferi Coinfection in Ixodes scapularis Ticks
    (August 2020) Hart, Charles E
    Ticks (Order: Ixodida) are hematophagous arthropods that transmit a number of medically significant pathogens. Two of these include Powassan virus (POWV) and the spirochete Borrelia burgdorferi, both of which are transmitted by Ixodes scapularis in the northern parts of the United States. Powassan virus can lead to neuroinvasive illness with a high fatality rate. B. burgdorferi causes Lyme disease, a potentially long-term infection of the joints, heart and brain. B. burgdorferi is present in 20-70% of ticks, while POWV is present in less than 5%. This suggests the possibility that most ticks capable of transmitting POWV are coinfected with B. burgdorferi. The existence of negative or synergistic interactions between ticks are unknown, though, as are unique consequences of dual disease. Field surveillance was conducted in endemic areas to ascertain the baseline rates of both pathogens and the rate of coinfection, and to gain an insight into the environment where the pathogens are present. B. burgdorferi was common in New York and Connecticut, while POWV was detected at a low rate, primarily in the form of Deer Tick virus (POWV Lineage II) but also in I. scapularis as a non-Lineage II strain. Coinfection was limited by the rate of POWV. Laboratory analysis of the pathogen interaction was performed to assess possible inhibition or synergistic effects that could influence their shared sylvatic cycles and to assess the risk of human co-exposure. It was determined that ticks can harbor both pathogens, and that the presence of B. burgdorferi enhances viral replication in the midgut and accelerates dissemination to the salivary glands. Transcriptome analysis suggests this response is caused by enhancement of anti-Borrelia responses in the midgut and suppression of POWV-induced metabolic changes in the salivary glands. No change was noted in the microbiome. Dual infection was studied in a murine model. A lethal model of POWV infection was developed for C3H mice, the primary model of Lyme disease. Dual infection did not attenuate the response to POWV, although the expression of some cytokines was enhanced by dual infection. Additionally, Powassan virus replication was noted in the heart, suggesting a potential interaction role in Lyme carditis.
  • Item
    Investigation of the interplay of yellow fever virus structural protein epitopes and genetic diversity
    (August 2020) Davis, Emily H
    Yellow fever virus (YFV), a mosquito-borne flavivirus, is responsible for the disease yellow fever (YF), which is characterized by hemorrhagic fever and multiorgan failure. The disease is prevented by a live attenuated vaccine (LAV), strain 17D, that was derived from serial passage of the wild type (WT) strain Asibi in chicken tissue. The mechanism of attenuation of 17D is incompletely understood. This dissertation investigates the contribution of the envelope (E) protein in YFV attenuation through its role in genetic diversity, tissue tropism and recognition by WT and vaccine specific antibodies that bind E protein. Using infectious clones (i.c.) of both Asibi and 17D viruses, structural chimeras with swapped prME, E protein domain III (EDIII) and single site mutations at each of the residues that differ between WT and vaccine strain in structural proteins were generated. Using these chimeras, the determinants of focus morphology were mapped to residues E-52 and E-380. E-305 was shown to be critical to the increased multiplication kinetics of 17D virus compared to Asibi. Genotypic stability was investigated using Illumina deep sequencing methods and it was shown that the E protein contributes to the differences seen in the genotype of Asibi and 17D viruses, whereas M protein does not. Despite this, prME was not shown to contribute to YFV susceptibility to the antiviral Ribavirin. Tissue tropism was correlated with WT and vaccine epitopes as residues in EDI were critical to viscerotropism and WT mAb recognition and residues within EDIII were shown to be critical to neurotropism and vaccine mAb recognition. It was found that the attenuating processes of 17D were not comparable to the JEV SA14-14-2 LAV. This is unsurprising due to the empirical nature of legacy LAVs and suggests there are many mechanisms that could be employed to generate future flavivirus LAVs. Overall, the role of E in the attenuation of 17D seems to rely on several critical residues (E-52, E-170, E-305, E-325 and E-380) many of which contribute the net positive charge of the 17D virion.