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The Role Of The Mechanical Environment On Cd117+ Endothelial Cell Angiogenesis, Patrick Link

Theses and Dissertations

Angiogenesis is a complex process coordinating cell migration, proliferation, and lumen formation. Changes to the microenvironment regulate angiogenesis through mechanotransduction and cytokine signals. In pulmonary hypertension, something in the process becomes abnormal, resulting in changes to the microenvironment and the formation of a glomerulus of dysfunctional capillaries, called a plexiform lesion. Endothelial cells, expressing CD117 (CD117+ EC clones) increase in the plexiform lesions of pulmonary hypertension, independent of pro-angiogenic VEGF signaling. We hypothesize that the mechanical environment and the macromolecular composition of the extracellular matrix, both, contribute to the aberrant angiogenesis. When we changed the mechanical environment, we changed the …

Embryonic Stem Cell-Derived Exosomes Increase The Antiproliferative Activity Of Doxorubicin In Breast Cancer, Alexander M. Hirsch

Theses and Dissertations

The field of cancer research has grown immensely in recent decades and has led to a better understanding of the causes of the disease, as well as greatly improved treatment for various types of cancers, especially breast cancer. One of the most effective treatments involves the chemotherapeutic drug doxorubicin (DOX). DOX is an effective tool against all types of breast cancer, especially against triple negative breast cancer. However, DOX causes adverse side effects that include damage to the heart and skeletal muscle, particularly above specific cumulative doses. Recent evidence suggests that embryonic stem cell-derived (ES) exosomes, nanoscale extracellular vesicles that …

A Hybrid Molecule Of Melatonin And Curcumin For Therpeutic Use In Pulmonary Fibrosis, Varsha V. Nair

Theses and Dissertations

Pulmonary fibrosis (PF) is a serious lung disease, as its life expectancy is only 3-5 years upon occurrence and more than 50 % of the cases are idiopathic, i.e., unknown cause. Two drugs, pirfenidone (PIR) and nintedanib, have recently been approved; however, their efficacies are moderate without evidence of prolonged survival. While this is primarily due to our insufficient knowledge about key PF pathogenesis, inductions of oxidative stress and transforming growth factor-b1 (TGF-b1) have been suggested in PF lungs. Hence, anti-oxidative melatonin (MEL) and curcumin (CUR) have been studied yet their efficacies remain moderate without clear understanding about the mechanisms …

Endogenous Opioid Peptides And Brain Development: Endomorphin-1 And Nociceptin Play A Sex-Specific Role In The Control Of Oligodendrocyte Maturation And Brain Myelination, Esraa M. Mohamed

Theses and Dissertations

Myelin is an extensive cell membrane produced by oligodendrocytes to ensheath neuronal axons in the central nervous system with the primary goal of maximizing the efficiency of electrochemical impulse transmission. During brain development, oligodendrocytes differentiate into myelin forming cells in a tightly regulated process which makes them vulnerable to multiple insults. Previous results from the laboratory showed that the timing of oligodendrocyte differentiation and rat brain myelination were altered by perinatal exposure to buprenorphine and methadone, opioid analogues used for treating pregnant addicts. The mechanism by which these opioids exerted their effects involved two opioid receptors, the μ-opioid receptor (MOR) …

Cellular And Molecular Mechanisms Of Collective Migration In Facial Branchiomotor Neurons, Jane K. Rebman

Theses and Dissertations

The directed migration of neurons is influenced by multiple guidance cues, that may include soluble attractive chemotactic factors and cell-cell contact mediated collective migration. The nature of these neuron-neuron interactions and their integration with chemotaxis remains unclear. Contact inhibition of locomotion (CIL), a process whereby cells undergoing a collision cease their migration towards the colliding cell, has been identified as a driving force behind the collective migration of several cell populations in vivo, but has not been described for neurons in the central nervous system. We have established that Cadherin2 (Cdh2), a cell adhesion molecule, mediates the physical interactions …

Axon Initial Segment Integrity In Aging And Traumatic Brain Injury, Mazen M. Gouda

Theses and Dissertations

According to the Center for Disease Control’s (CDC) report to the Congress, there are 2.2 million emergency department visits; 80,000 hospitalizations; and 50,000 deaths each year due to traumatic brain injury. Adults 65 years and older account substantially for the majority of the hospitalization and deaths. Over 70% of the traumatic brain injuries of the older adults are classified as mild to moderate; however, even with these milder injuries, older adults present with a significantly higher morbidity and mortality compared to all other age groups (LeBlanc et al., 2006). With that in mind, it seems essential to develop a deeper …

Fluoxetine Attenuates Mast Cell Function By Targeting Purinergic Signaling, Tamara T. Haque

Theses and Dissertations

Mast cells are tissue resident, innate immune cells that provide protection against parasitic and bacterial infections and venom poisoning. Mast cells also play a pathogenic role in atopy and allergic diseases. Atopy and allergic diseases are increasing in the developed world and are predicted to continue to increase at an alarming rate. Current treatment options include corticosteroids, anti-histamines, anti-IgE and avoidance of allergen. These interventions have limitations: some patients are steroid resistant; anti-histamines have low efficacy since they need to be administered early during allergen exposure; and anti-IgE is costly. Thus there is a clinical need for new treatment options. …

Latent Growth Model Approach To Characterize Maternal Prenatal Dna Methylation Trajectories, Dana Lapato

Theses and Dissertations

Background. DNA methylation (DNAm) is a removable chemical modification to the DNA sequence intimately associated with genomic stability, cellular identity, and gene expression. DNAm patterning reflects joint contributions from genetic, environmental, and behavioral factors. As such, differences in DNAm patterns may explain interindividual variability in risk liability for complex traits like major depression (MD). Hundreds of significant DNAm loci have been identified using cross-sectional association studies. This dissertation builds on that foundational work to explore novel statistical approaches for longitudinal DNAm analyses. Methods. Repeated measures of genome-wide DNAm and social and environmental determinants of health were collected up to six …

The Effects Of Notch Signaling On Functional Recovery Following Traumatic Brain Injury, Jyoti Lodha

Theses and Dissertations

2.5 million people sustain a traumatic brain injury (TBI) annually in the United States. Although there is potential for functional recovery following TBI, there is no definitive treatment to improve recovery after TBI. Our lab has shown that TBI enhances an endogenous neurogenic response in the subventricular zone and hippocampus. TBI-induced neural stem cells (NSCs) can integrate into regions such as the hippocampus and olfactory bulb. Although the mechanism behind TBI-enhanced neurogenesis remains unknown, the Notch signaling pathway has been implicated as a regulator in the maintenance and survival of NSCs.

This thesis explores the effects of Notch pathway manipulation …

Illumination Of The Golgi Apparatus Of Pathogenic And Nonpathogenic Naegleria Species, Tyler M. Poe

Theses and Dissertations

In this study, Naegleria fowleri, a pathogenic amoeba and the causative agent of Primary Amebic Meningoencephalitis (PAM), was utilized to determine the presence or absence of classically conserved Golgi molecules featured in the expression of a Golgi apparatus. Previous studies concluded no Golgi expression via light microscopy and transmission electron microscopy, but a recent report on Naegleria gruberi indicated the presence of dispersed Golgi tubules. Non-pathogenic species of the Naegleria genus such as Naegleria gruberi 30540 and Naegleria lovaniensis 30569 were utilized in Western immunoblot analysis compared to reduced whole-cell lysate proteins of two strains of N. fowleri and …

Analyzing Interactions Between Methcathinone Analogs And The Human Monoamine Transporters, Vy Nguyen

Theses and Dissertations

Psychostimulants elicit their psychological and behavioral effects through interactions with the monoamine transporters. These compounds are classified as either substrates or reuptake inhibitors, depending on their mechanism of action, and have varying potencies at the three human monoamine transporters, hDAT, hSERT, and hNET. Substrates and reuptake inhibitors also have distinct electrophysiological signatures: reuptake inhibitors cause hyperpolarization in HEK293 cells stably expressing the monoamine transporters, whereas substrate transport mediates a depolarizing current. Recent studies have shown that substrate-mediated depolarization is sufficient to activate L-type calcium channels, a characteristic which has been used to develop a novel calcium assay which uses calcium …

Molecular Targets Of Psychedelics And Their Role In Behavioral Models Of Hallucinogenic Action, Hiba Z. Vohra

Theses and Dissertations

Psychedelics are a subset of hallucinogenic drugs that exert their characteristic effects through agonist activity at the serotonin receptor 2A (5-HT_2A). In this study, I aimed to characterize the modulatory role of the metabotropic glutamate subtype 2 receptor (mGluR2) in the 5-HT_2A-specific rodent model of hallucinogenic action, head-twitch response (HTR). Secondly, I aimed to explore if 5-HT_2A agonist-induced deficits in prepulse inhibition (PPI) of the startle response, an additional model of hallucinogenic action, could be produced in mice. Though 5-HT_2A agonist-induced PPI deficits, which represent interruptions in normal sensorimotor gating, have been described in …

Eralpha Isoforms Modulate The Tumorigenicity Of 24r,25(Oh)2d3 In Estrogen-Responsive Cancer, Anjali Verma

Theses and Dissertations

Over 200,000 cases of breast cancer are diagnosed every year. Nearly 20% of these patients supplement their diets with some form of vitamin D. This high frequency of vitamin D supplement use may be due in part to research suggesting that cancer patients with higher serum vitamin D₃ levels have better prognoses than patients with low serum vitamin D_3. However, double-blind clinical trials on the efficacy of vitamin D₃ supplementation in breast cancer have been inconclusive. A recent meta-analysis showed evidence of reduced cancer recurrence in patients taking vitamin D₃ supplements who had ‘estrogen receptor positive’ …

Cyclophilin A As A Molecular Switch Regulating Prolactin Receptor Mediated Signaling, Mammary Tumorigenesis And Metastasis, Shawn Hakim

Theses and Dissertations

Prolactin (PRL) and its receptor (PRLr) have been implicated in the development and progression of human breast cancer. PRL activates its receptor and induces activation of proximal Janus kinase 2 (Jak2) for signal transduction. Here, we sought to determine the role of PRLr-associated peptidyl-prolyl isomerase, cyclophilin A (CypA), in modulating structure/function relationships of the PRLr. It was demonstrated that CypA mediated PRL-induced conformational change of the CFP- and -YFP tagged forms of the PRLr cytoplasmic-tail, whereas CypA inhibition by NIM811 (N-methyl-4-isoleucine cyclosporin) or knockdown blocked the conformational change of the PRLr assessed by Fluorescence Resonance Energy Transfer (FRET) signal or …

Preconditioning Of The Tumor Microenvironment By Means Of Low Dose Chemotherapies For An Effective Immunotherapy Of Breast Cancer, Hussein F. Aqbi

Theses and Dissertations

Breast cancer mortality is mainly due to distant recurrence of the disease arising from dormant tumor cells established by cancer therapies. Patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting …

The Role Of Cellular Aging In The Regulation Of Free Fatty Acid Induced Cellular Inflammation By Liver X Receptor Alpha, Charles S. Schwartz

Theses and Dissertations

Purpose: This study examined the impact of an acute bout of exercise on LXRα mRNA expression in isolated PBMCs from aerobically fit middle-aged males, and its associations with cellular inflammation. Furthermore, association between cellular age and LXRα were investigated. Methods: LXRα mRNA, plasma free fatty acids, IL-6, and MCP-1 responses were quantified following acute moderate intensity exercise and throughout recovery. To examine LXRα’s associations with cellular inflammation, PBMCs were stimulated with palmitate. Finally, telomere length was quantified as an indicator of cellular age. Results: LXRα mRNA expression was reduced at 90 minutes of recovery and did not influence systemic inflammation. …

Modulation Of Autophagy And Senescence To Enhance The Response To Therapy In Triple Negative Breast Cancer, Liliya Tyutyunyk-Massey

Theses and Dissertations

Abstract

Although great strides have been made over the decades in development and optimization of anti-cancer therapies, even highly effective drugs often fail to completely eliminate tumors. Residual tumor cells can enter into a state of dormancy for prolonged periods of time but eventually are able to regain proliferative capacity and reemerge as chemotherapy-resistant disease. Because recurrent disease is a leading contributor to patient’s mortality, it is paramount to identify strategies for effectively destroying residual tumor cells.

Cytotoxic drugs and ionizing radiation are used as standard therapies in a variety of cancers. These modalities induce apoptosis, autophagy and senescence. Senescence …

Eternal Enemies, Or Incidental Encounters? Structure And Patterns Of Interspecific Killing In Carnivora, Tor G. Bertin

Theses and Dissertations

Lethal interactions between carnivorans (interspecific killing) may influence their population dynamics, behavior, and other important aspects of their ecology. In this study, I expand upon previous research on the broad-scale patterns of interspecific killing in Carnivora (Palomares & Caro 1999, Donadio & Buskirk 2006) with a greatly expanded dataset (inclusion of scat and stomach data and more intensive sampling of the literature), and suggest avenues for future research. While like previous studies, I found a positive effect of relative body size between killer species and killed species on the likelihood of forming a killing interaction, I failed to find evidence …

An Investigation On The Role Of Β-Arrestin 2, Protein Kinase C And Sex On The Mechanism Of Morphine Tolerance In The Mouse Ileum, Karan Hitesh Muchhala

Theses and Dissertations

Opioids such as morphine are frequently used in the clinic to treat pain. However, the perennial bane of chronic opioid use is the rapid development of tolerance to the analgesic effects but delayed development of tolerance to the respiratory depressant and constipating effects. As constipation is one of the most common opioid-related adverse effects in humans, it is important to delineate mechanisms that drive opioid tolerance in the ileum and lack of it in the colon. The overarching goal of this thesis was to investigate mechanisms of morphine tolerance in the ileum by comparing the mechanism of morphine tolerance in …

Kings In The Direct Product Of Digraphs, Morgan Norge

Theses and Dissertations

A k-king in a digraph D is a vertex that can reach every other vertex in D by a directed path of length at most k. A king is a vertex that is a k-king for some k. We will look at kings in the direct product of digraphs and characterize a relationship between kings in the product and kings in the factors. This is a continuation of a project in which a similar characterization is found for the cartesian product of digraphs, the strong product of digraphs, and the lexicographic product of digraphs.

Stat5b And Stat5 Tetramers Are Essential For Ige-Mediated Mast Cell Function, Kasalina N. Kiwanuka

Theses and Dissertations

Signal Transducers and Activators of Transcription (STATs) are latent transcription factors that mediate several cellular responses. This protein family consists of seven members, STAT1 – 6 including two closely related molecules, STAT5a and STAT5b, that show 96% amino acid sequence homology and are critical for lymphoid, myeloid and erythroid cell development and function. Activated STAT proteins dimerize and translocate to the nucleus, where they bind to high-affinity DNA motifs to modulate gene expression. We recently identified STAT5b as the critical regulator of IgE-mediated cytokine production in mast cells. STAT5b knockout (KO) cells show decreased sensitivity to IgE-mediated passive systemic anaphylaxis …

Phenotypic Characterization Of Pnpase Mutation And Overexpression In C. Elegans, Brian J. Hur

Theses and Dissertations

PNPase, polynucleotide phosphorylase, is a multifunctional exoribonuclease protein with 3` terminal oligonucleotide polymerase activity. Coded by the PNPT1 gene, the protein is associated with mitochondrial homeostasis and functions as a possible target for cancer therapy. In this study, C. elegans was used to investigate the effect of mutation and overexpression of pnpt-1, the gene that encodes PNPase. It was determined that two specific mutations in pnpt-1 did not affect PNPase expression nor did they produce deleterious phenotypes that affected polycistronic transcript accumulation or ROS production. Creation of a stable overexpression model was achieved through Fusion PCR. However, different transgenic …

Testing For Cryptic Diversity And Inference Of Population Structure In The Cosmopolitan Hoplonemertean Emplectonema Gracile (Nemertea), Paul L. Delaney Iv

Theses and Dissertations

Emplectonema gracile (Johnston 1837) is a hoplonemertean of marine intertidal hard-bottom communities and is distributed throughout the Northern Hemisphere. Although possessing a planktonic larval stage in its life history, the range of such cosmopolitan marine invertebrate species is often explained by cryptic speciation and anthropogenic transport. The purpose of this study is to test for possible cryptic species using mtDNA markers (COI and 16S rDNA) and to investigate population structure in E. gracile over a portion of its geographic range using mtDNA markers and ddRADseq nuclear SNP data. The results of both phylogenetic- and tree-based species delimitation revealed that E. …

Cultivating A Democratic Community In The Elementary Art Classroom, Kelly Fergus

Theses and Dissertations

Cultivating a more socially just, democratic classroom community is a best pedagogical practices qualitative case study. This study is designed to explore how three Virginia elementary art teachers define and create a democratic classroom community, inside their art rooms, through the implementation of various instructional strategies within the physical, social-cultural, and pedagogical spaces of their classrooms. Such instructional strategies may include a shift in power dynamics, student-centered art, choice-based art, and a big idea/real-world issue-orientated curriculum (ex: visual culture, social justice, democratic pedagogies). Each of the three selected participants were interviewed and asked to describe their classroom practices as well …

Pharmacological Assessment Of Adjuncts To Enhance Mu-Opioid Receptor Agonist Antinociception In Male Rhesus Monkeys: Does One + One = Three?, Jeremy Cornelissen

Theses and Dissertations

Mu-opioid receptor (MOR) agonists are effective agents for pain management, but are also limited by a number of undesirable effects. One approach to enhance the therapeutic effects and minimize the undesirable effects of MOR agonists may be to combine MOR agonists with an adjunct targeting a different receptor system. This targeted medical approach, known as “combination therapy”, aims to augment the desired effects of the MOR agonist (i.e. antinociception) and/or diminish the undesirable deleterious side effects of the MOR agonist. This dissertation investigated the utility of this approach in an assay of thermal nociception and schedule-controlled responding in male rhesus …

Examining Sleep And Family Functioning In Pediatric Craniopharyngioma Using Ecological Momentary Assessment, Nour Al Ghriwati

Theses and Dissertations

Craniopharyngiomas are among the most common brain tumors in children and are associated with greater rates of sleep problems compared to other pediatric cancers. However, research examining sleep among youth with craniopharyngioma has been limited by a reliance on retrospective reports or sleep studies. Families also play a crucial role in children’s adjustment following a pediatric cancer diagnosis, yet remarkably little is known about transactional associations between family functioning and sleep in pediatric cancer. This study examined cross-sectional and daily associations among family functioning, affect, and sleep difficulties for youth with pediatric craniopharyngioma using retrospective reports and ecological momentary assessment …

Molecular Pharmacology Of Non-Phyto-Cannabinoid Approaches For Treatment Of Neuropathic Pain, Nadejda A. Blajkevich

Theses and Dissertations

Approximately twenty million people in United States have some form of peripheral neuropathy. It has been shown that the CB₂ cannabinoid receptor is upregulated when there is peripheral nerve injury and activating the CB₂ receptor produces anti-inflammatory effects that translate to a reduction in signs of “neuropathic pain” in animal models. Elevating endogenous cannabinoids by inhibiting degradative enzymes has also been used to reduce neuropathic pain signs in laboratory animal models of pain. We hypothesize that the molecular pharmacology of these two approaches can be leveraged to optimize CB₁/CB₂ activation to improve non-phyto-cannabinoid treatments for …

The Effect Of Quercetin In Periodontal Inflammation, Sara Holden

Theses and Dissertations

Purpose: To determine the effect of Quercetin, a plant based over the counter flavonoid, on periodontal inflammation in a murine model of periodontitis.

Methods: Periodontitis was induced in age and gender matched mice (C57BL/6) using ligatures on the left side of the maxilla and right side was left un-ligated as baseline control. The animals received daily Quercetin gavage or Phosphate Buffered Saline (PBS) starting 5 days prior to ligation which continued throughout the experimental protocol. Micro-computed tomography (micro CT) imaging was used to determine alveolar bone loss. Real Time quantitative (qRT) PCR was used to determine level of gingival tissue …

The Dirt Of Development: Nature's Role In Social-Emotional Development And Parent-Child Connectedness, Hayley Johanna Lindsey

Graduate Theses, Dissertations, and Problem Reports (ETD)

The purpose of this study was to examine associations between nature connectedness, parent-child connectedness, and the development of prosocial behavior. Nature connectedness pertains to the strong emotional affinity towards the natural environment and is linked with happiness, stress reduction, and good health. Prosocial behavior refers to actions or behaviors done with the intent to help others. This study consisted of 467 parent-informants that gathered information on the parent’s nature connectedness, the child’s nature connectedness, the parent-child connectedness, and the child prosocial behavior. Gaps in the literature were addressed by analyzing the role that parent nature connectedness has in predicting child …

The Environmental, Social, And Economic Benefits Of Blue Green Infrastructure In An Urbanized Area, Joseph L. Oguns

Graduate Theses, Dissertations, and Problem Reports (ETD)

At present, it is evident that there is a shift from rural to an urban settlement which results in high demand for residential buildings and other urban infrastructure. Blue – Green Infrastructure (BGI) is a system of using blue (water) and green (nature) to address urban and environmental challenges. The purpose of this study is to evaluate the environmental, social, and economic benefits of blue-green infrastructure in an urbanized area in Pittsburgh, Pennsylvania, USA. The study involves the utilization of Geographic Information System (GIS) to determine water quality level resulting from nonpoint source pollution through acquiring elevation data; watershed; and …