Medicine and Health Sciences Commons^™

Bacterially-Based Immune Challenges And Trauma Elicit Terminal Investment In Male Aedes Aegypti, Molly K. Schumacher

Theses and Dissertations

Investment in life history traits such as immune function and reproduction is constrained by finite available resources. A cost-of-immunity trade-off may occur in response to infection when resources are diverted away from reproductive effort and into an immune response. Alternatively, an infected individual may enhance reproductive effort to maximize terminal reproductive success in response to the survival threat inherent to infection (terminal investment). We measured male Aedes aegypti reproductive behavior following inoculations with: living bacteria; killed bacteria as an immune elicitor; and a sham control. Mating competitiveness relative to naïve males was also determined through a binary mate choice experiment …

Cannabinoid-Mediated Epigenetic Regulation Of Immune Functions, Jessica Margaret Sido

Theses and Dissertations

The cannabinoid system consisting of exogenous and endogenous ligands as well as dedicated receptors has been proposed to play a regulatory role in immune functions. The exogenous cannabinoid Δ9-tetrahydrocannabinol (THC), one of the most widely studied marijuana derivatives, has been associated with multiple anti-inflammatory properties over the years. The majority of THC research has centered on the shift from Th1 to Th2 responses however, the complexity of inflammation has since increased. Recent studies have revealed that epigenome, Th cell subsets, and immunoregulatory cell induction, are all known to impact inflammation. In the current research, we have attempted to look holistically …

Age Related Decline In Memory: Examining The Mediation Effect Of Processing, Executive Functioning And Intelligence In Normal Adults, Jada J. Stewart

Theses and Dissertations

Multiple mediation analyses that collectively examine the prominent theories of cognitive aging (i.e., Common Cause, Processing, and Executive Decline Hypotheses) along with other cognitive domains that are sensitive to aging are rare. Moreover, having identified that cognition begins to decline as early as 30 years old, few studies have examined the mechanisms that underlie memory change among younger aging individuals. As a result, it is unclear whether relevant mediating variables have been excluded from early research on age-related memory decline, or to what extent rehabilitative strategies are applicable as early interventions for maintaining cognitive functioning into late life.

The present …

Conduction States Of The Human Dopamine Transporter, Krasnodara Cameron

Theses and Dissertations

Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic …

Dual Pi3k/Mtor Inhibition With Bez235 Augments The Therapeutic Efficacy Of Doxorubicin In Cancer Without Influencing Cardiac Function, David E. Durrant

Theses and Dissertations

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. …

Risperidone And Its Deconstructed Analogs: Functional Effects On The 5ht2ar, Sneha Shah

Theses and Dissertations

G protein-coupled receptors (GPCRs) are seven-transmembrane domain receptors that sense extracellular signal and activate intracellular signaling pathways. The serotonin 5HT2A receptor (or 2AR) is one of the GPCRs coupled to Gq proteins, activating PLC and hydrolyzing PIP2. This hydrolysis causes a diffusion of bound PIP2 away from the channel binding site resulting in G protein-gated inwardly rectifying K⁺ channel (GIRK) inhibition and a downstream stimulation of Ca²⁺ release from endoplasmic reticulum stores. Previous experiments have demonstrated that the serotonin 5HTA receptor is a target of serotonergic psychedelic drugs, such as LSD, and partially mediates the action of many …

An Association Study Between Adult Blood Pressure And Time To First Cardiovascular Disease, Yongjia Pu

Theses and Dissertations

BACKGROUND: Several studies have demonstrated the association between the time to hypertension event and multiple baseline measurements for adults, yet other survival cardiovascular disease (CVD) outcomes such as high cholesterol and heart attack have been somewhat less considered. The Fels Longitudinal Study (FLS) provides us an opportunity to connect adult blood pressure (BP) at certain ages to the time to first CVD outcomes. The availability of long-term serial BP measurements from FLS also potentially allows us to evaluate if the trend of the measured BP biomarkers over time predicts survival outcomes in adulthood through statistical modeling.

METHODS: When the reference …

The Effect Of Statins On Il-33 Mediated Mast Cell Function, Marcela Taruselli

Theses and Dissertations

This study demonstrates original findings of statin effects on IL-33 stimulated mast cells. Statins are a class of drugs used to lower cholesterol production by targeting HMG CoA reductase. These commonly prescribed drugs have been shown to be immunomodulatory. In this study, we have found that pretreatment with statins has a variety of effects on IL-33 stimulated mast cells. Atorvastatin suppresses TNF and IL-6 production, while fluvastatin significantly enhances release of these proinflammatory cytokines in BMMCs. Although they have differing effects on cytokine production, both statins lowered ST2 expression on the cell surface, decreased cell viability, and enhanced expression of …

Effects Of Hiv-1 Viral Protein Tat On The Viability And Function Of Oligodendroglial Cells, Shiping Zou

Theses and Dissertations

Myelin pallor is frequently reported in HIV patients, and can occur in the CNS prior to other evidence of disease process. Our exploratory studies showed that oligodendrocytes (OLs) are direct targets of HIV-1 Tat (transactivator of transcription). Tat induces a dose-dependent increase of intracellular Ca²⁺ level ([Ca²⁺]_i) in cultured murine OLs, which can be attenuated by ionotropic glutamate receptor (iGluR) antagonists MK801 and CNQX. The Tat-induced [Ca²⁺]_i increase leads to increased death in immature (O4⁺, MBP^-), but not mature (O4⁺, MBP⁺) OLs, over 96 …

Understanding The Function Of Dyrk1a Through Characterization Of Its Interacting Proteins, Varsha Ananthapadmanabhan

Theses and Dissertations

DYRK1A is a protein kinase encoded by a gene implicated in Down syndrome pathogenesis. Loss of DYRK1A could promote oncogenic transformation. However, the regulation and substrates of DYRK1A are not fully understood. MudPIT proteomic analysis revealed novel DYRK1A interacting proteins with poorly characterized or even unknown functions. Therefore, the aim of this thesis was to understand the function of DYRK1A through the characterization of its interacting proteins. To achieve this aim, we established stable cell lines expressing these proteins and confirmed the interactions between DYRK1A and seven candidate binding partners. Furthermore, we found that all novel DYRK1A-interacting proteins also bind …

Dysregulation Of Micrornas In Blood As Biomarkers For Diagnosing Prostate Cancer, Rhonda W. Daniel

Theses and Dissertations

Prostate cancer is the most common noncutaneous cancer among men, yet current diagnostic methods are insufficient and more reliable diagnostic markers need to be developed. The answer that can bridge this gap and enable more efficient diagnoses may lie in microRNAs. These small, single stranded RNA molecules impact protein expression at the translational level and regulate important cellular pathways. Dysregulation of these small RNA molecules can have tumorigenic effects on cells and lead to many types of cancers.

Currently the Prostate-Stimulating Antigen (PSA) is used as a diagnostic marker for prostate cancer. However, many factors can elevate PSA levels such …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Effects Of Hiv-1 Tat On The Enteric Nervous, Joy Ngwainmbi

Theses and Dissertations

More than 1.2 million people are estimated to be currently living with the human immunodeficiency virus (HIV) in the United States of America. The gastrointestinal (GI) tract is both a major target and an important component of HIV pathogenesis. The GI processes that are dysregulated during HIV infection are controlled by the enteric nervous system (ENS). Indeed, both clinical and experimental studies have implicated the ENS in HIV and simian immunodeficiency virus (SIV) pathogenesis. In addition to direct viral effects, the HIV virus also indirectly affects the GI tract via cellular and/or viral toxins released by infected cells. Trans-activator of …

Inhibition Of Mtor Signaling Protects Against Myocardial Reperfusion Injury, Acute Myocardial Infarction, Scott M. Filippone

Theses and Dissertations

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Currently, the best method of treating cardiac ischemia is early reperfusion which, itself, induces myocardial damage. The mTOR complex is a key regulator of cardioprotection against cell stressors. We hypothesized that reperfusion therapy with Rapamycin, a potent mTOR inhibitor, would reduce infarct size in adult mouse hearts. Rapamycin was administered at the onset of reperfusion following 30 min in situ LAD ligation. After 24 hours of reperfusion, myocardial infarct size and apoptosis were significantly reduced in rapamycin-treated mice compared to control. Rapamycin inhibited pro-apoptotic protein Bax and phosphorylation of …

Psychoactive Synthetic Cathinones (Or 'Bath Salts'): Investigation Of Mechanisms Of Action, Farhana Sakloth

Theses and Dissertations

Synthetic cathinones represent threatening and high abuse-potential designer drugs. These are analogs of cathinone (the b-keto analog of amphetamine (AMPH)) a naturally occurring stimulant found in the plant Catha Edulis. Methcathinone (MCAT) was the first synthetic analog of cathinone to be identified in 1987 by Glennon and co-workers and it exerted its action primarily through the dopamine transporter (DAT). Most central stimulants exert their action via monomaine transporters by causing either the release (e.g. cathinone analogs such as MCAT) or by preventing the reuptake (e.g. cocaine) of the neurotransmitter dopamine (DA) thus increasing the extracellular synaptosomal concentration of this …

High-Throughput Data Analysis: Application To Micronuclei Frequency And T-Cell Receptor Sequencing, Mateusz Makowski

Theses and Dissertations

The advent of high-throughput sequencing has brought about the creation of an unprecedented amount of research data. Analytical methodology has not been able to keep pace with the plethora of data being produced. Two assays, ImmunoSEQ and the cytokinesisblock micronucleus (CBMN), that both produce count data and have few methods available to analyze them are considered.

ImmunoSEQ is a sequencing assay that measures the beta T-cell receptor (TCR) repertoire. The ImmunoSEQ assay was used to describe the TCR repertoires of patients that have undergone hematopoietic stem cell transplantation (HSCT). Several different methods for spectratype analysis were extended to the TCR …

Mitochondrial Biogenesis And Electrical Properties Of Hpsc-Derived Motor Neurons, Laura O'Brien

Theses and Dissertations

Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) hold great promise in the fields of drug development and regenerative medicine. If iPSCs reprogrammed from patient cells replicate what is seen in vivo they may be used as a model of disease. A process that is disrupted in many neurodegenerative diseases is mitochondrial biogenesis. One of these diseases is amyotrophic lateral sclerosis (ALS), which is characterized by loss of motor neurons in the brain and spinal cord. Differentiation of hPSCs into motor neurons offers a way to study a previous unavailable cell …

Incorporation Of Molecular Diagnostics Into Medical Laboratory Science Curriculum: Clinical Facilities Expectations. An Asynchronous, Iterative, Online Delphi Study., Barbara Kraj

Theses and Dissertations

The medical laboratory science (MLS) profession is in need for published molecular diagnostics competency-based standards and curriculum. To assess their expectations of new MLS graduates, professionals performing and supervising performance of clinical molecular assays were surveyed to rate the importance of relevant cognitive and psychomotor learning objectives. A modified, asynchronous, iterative online Delphi process was utilized for assessment of consensus on the importance of the objectives. The survey was delivered through online REDCap application. Program directors of 221 MLS programs accredited by the National Accrediting Agency for Clinical Laboratory Science (NAACLS) were asked to forward the first Delphi survey to …

Investigating The Role Of Bptf In Immunoediting In Breast Cancer And Melanoma, Kristen N. Peterson

Theses and Dissertations

In this study, we explore the effects of NURF depletion on the growth of tumors in immune-competent mice. NURF depletion in tumors results in reduced tumor growth in immune-competent mice, suggesting enhanced anti-tumor immunity. Analysis of the tumor microenvironment by flow cytometry revealed a significantly elevated CD8 and progressively elevated activated CD8 phenotype in Bptf KD tumors, possibly contributing to the increase in cell death and decrease in tumor weight observed. Examination of antigen presentation was evaluated using the OT-1 and Pmel-17 models, though no significant difference in cytotoxicity was observed as measured by LDH and/or IFNγ assays. This indicates …

Axon Initial Segment Stability In Multiple Sclerosis, Suneel K. Thummala

Theses and Dissertations

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by inflammation and demyelination. In addition to these hallmark features, MS also presents with axonal pathology, which is likely responsible for the signs and symptoms of the disease. Although prominent in MS, axonal pathology is frequently considered a consequence of demyelination and not a primary event. This conclusion is consistent with demyelination inducing the loss of specific axonal domains, known as the nodes of Ranvier that are responsible for the propagation of action potentials along the axon. In contrast, we propose that axonal pathology associated with MS …

Measuring The Impact Of Recognized Patient-Centered Medical Homes (Pcmh), Rick Moore

Theses and Dissertations

This dissertation proposal seeks to understand if the increasingnumbers (density) of recognized PCMH practices incommunities affect avoidable hospitalizations related toambulatory care sensitive conditions (ACSC), as measured bythe AHRQ Composite Prevention Quality Indicators (PQI). Theresearch has two purposes: 1. Establish constructs and hypotheses to measurethe effect of the increasing numbers of NCQA-Recognized PCMH practices in communities(counties). 2. Using an outcomes-based measurement approach,investigate the relationship between growingdensities of NCQA-Recognized PCMH practicedoctors among all primary care doctors (PCD) ina community and the associated impact on theutilization of inpatient care, specifically related toACSCs, as measured by the AHRQ CompositePQIs.

The research is quasi-experimental in …

Effects Of Brain-Derived Neurotrophic Factor And Its Signaling Pathway On Sensory Neuronal Activation During Colitis, Fiza Hashmi

Theses and Dissertations

Visceral hypersensitivity is the heightened response to sensory stimuli. Visceral sensations are transmitted through primary afferent neurons in the dorsal root ganglion (DRG) and the sensitization of the neural pathway leads to modification in spinal ascending and descending neurons. The aim of this investigation is to determine the effects of brain-derived neurotrophic factor (BDNF) and its signaling pathway on sensory neuronal activation during colitis. In order to evaluate this, levels of calcitonin-gene related peptide (CGRP), a neuropeptide marker for nociceptive transmission, and phosphorylated cAMP-response element binding protein (pCREB), a molecular switch in neuronal plasticity, were studied in response to BDNF …

Characterization Of Stard4 And Stard6 Proteins In Human Ovarian Tissue And Human Granulosa Cells And Cloning Of Human Stard4 Transcripts, Aisha Shaaban

Theses and Dissertations

Progesterone is essential hormone for pregnancy, which is produced by the human corpus luteum in early pregnancy until the placenta assumes this function. Transport of the cholesterol from the outer to the inner mitochondrial membrane is the rate limiting step for the de novo synthesis of pregnenolone (the precursor to progesterone), a process mediated by STARD1. STARD1 contains a C-terminal lipid binding domain which binds cholesterol and an N-terminal domain targeting STARD1 to the mitochondrial membrane. Unlike STARD1, STARD4 and STARD6 proteins lack a mitochondrial targeting sequence; however, they can bind cholesterol and increase steroidogenesis in model systems. In this …

Goal Achievement In Young Adults With Asperger Syndrome And High Functioning Autism, Melissa Racobaldo

Theses and Dissertations

Purpose: This study aimed to evaluate perspectives of young adults with Asperger syndrome (AS) and High Functioning Autism (HFA) regarding supports and services, future goals, and confidence in their success. The goal of this study was to identify valuable supports and areas in which this support was lacking. Identifying areas of support for young adults with AS/HFA transitioning into adulthood aids in providing consistent services for successful goal achievement. The study has value among genetic counselors as the discovery of genetic etiologies of autism has led to referral of families with ASD to the genetics clinic. Methods: Young adults with …