Medical Sciences Commons^™

Anatomy And Function Of Vasopressin Receptor 1a-Expressing Neurons In The Limbic Thalamus, David Joseph Kahn

Theses and Dissertations

The vasopressin (Avp) system modulates social behavior through region-specific and sex-dependent mechanisms, yet the role of Avp receptor 1a (Avpr1a) signaling in the thalamus has remained largely unexplored. This dissertation examined the distribution and functional contributions of Avpr1a-expressing neurons across the mouse thalamus using a combination of genetic labeling, anatomical quantification, and chemogenetic manipulation. Mapping of Avpr1a-expressing neurons revealed a presence in most thalamic nuclei, with highest densities in the anterior thalamic nuclei and midline nuclei. Notably, Avpr1a-expressing neuron densities did not mirror previously described patterns of Avp innervation, and no sex differences in Avpr1a-expressing neuron density were observed. Chemogenetic …

Mapping The Neuroexposome: Integrative Analysis Of Dementia Risk Factors Through Multi-Omics And Environmental Profiling In The Egyptian Population., Mai Ahmed Saadzaghloul Othman

Theses and Dissertations

Background: Dementia represents one of the most pressing public health challenges of the twenty-first century, with the global burden projected to reach 153 million cases by 2050. Egypt, as the most populous Arab nation, faces a corresponding rise in age-related diseases, yet comprehensive data from low- and middle-income countries remain severely limited. The neuroexposome framework, integrating genetic susceptibility, environmental exposures, and metabolic alterations, offers a powerful strategy to characterize the complex interplay between internal and external risk factors for Alzheimer's disease (AD) and Alzheimer's disease Related Dementias (ADRD).

Objectives: This thesis aimed to: (1) examine the distribution of APOE alleles …

Determinants Of Corporal Punishment And Severe Physical Punishment In Egypt: A Mixed-Methods Analysis For Child Protection Policy, Marwa Moustafa Nassef

Theses and Dissertations

Corporal punishment (CP) and severe physical punishment (SPP) remain a major public health, child rights, and child protection policy concern. In Egypt, despite legislative reforms, survey-weighted analysis of the 2021 Egypt Family Health Survey (EFHS) 2021 (CAPMAS, 2022) reveals prevalence rates of 60.5% for CP and 27.4% for SPP among children aged 1–14 (author’s calculations using EFHS-2021, n=7623), yet evidence distinguishing the determinants of routine corporal punishment from escalation to severe physical punishment remains limited in low- and middle-income contexts. Guided by Bronfenbrenner’s ecological framework, this mixed-methods study identifies key drivers of CP and its escalation to SPP among Egyptian …

Environmental And Pharmacological Modulation Of Opioid-Mediated Behavioral Effects In Rats, Corinne Ann Gallagher

Theses and Dissertations

Opioid Use Disorder (OUD) and opioid-associated overdoses continue to pose significant burden to US healthcare systems—both financially and in lives lost. It is imperative to identify risk factors which may predispose vulnerability to OUD development, which could aid in discovery of new therapeutic strategies for susceptible populations. This dissertation investigated the impacts of two such risk factors which modulate opioid-induced reward and behavioral effects: adolescent stress and the adulteration of illicit opioids by xylazine. In Chapter 2, we examined the effects of acute adolescent stress on oxycodone self-administration in rats, and the potential involvement of the locus coeruleus in these …

Investigating Tau Pathology In The Retina And Anterior Segment Structures Of The Eye In A 3-Nitropropionic Acid–Induced Tauopathy Mouse Model, Mohamed Sayed Ahmed Abdel-Kader Qasem

Theses and Dissertations

Background and Objectives: Alzheimer's disease, the most prevalent neurodegenerative disorder in older adults, is characterized by accumulation of hyperphosphorylated tau and amyloid-beta (Aβ) plaques in the central nervous system. Given the retina's shared embryological origin with the brain, its direct neural connectivity via the optic nerve, and similarities in vasculature and age-related degeneration patterns, retinal pathology may serve as an early, non-invasive biomarker for Alzheimer's disease. This study employed 3-nitropropionic acid (3NP) as a pathway-specific tauopathy model driven by mitochondrial dysfunction. The study particularly aimed to investigate whether retinal and corneal tau pathology reflects underlying tau-related neurodegeneration triggered by …

Managing Multi-Drug Resistance: An Evolutionary Game Theory And Optimal Control Approach, Shukhrat Nasrulloev

Theses and Dissertations

Multi-drug resistance is an evolutionary process in which treatment eliminates sensitive cells, allowing resistant clones to dominate. This thesis investigates this process using a framework integrating population dynamics, evolutionary game theory, and optimal control theory. We develop a two-population logistic growth model describing competition between drug-sensitive and drug-resistant cells under treatment, construct dose-dependent payoff matrices and replicator dynamics to characterize evolutionary competition, and derive a critical drug level D_crit = (r_S - rR)/(dS - d_R) at which resistant cells gain a fitness advantage. An optimal control problem is formulated via Pontryagin's Maximum Principle to identify schedules …

Metabolic Syndrome Beyond Diagnostic Criteria: Population-Scale Integrative Metabolomics Characterization, Marwa Talal

Theses and Dissertations

Background: Metabolic syndrome (MetS) is a complex cluster of interrelated metabolic abnormalities associated with elevated cardiometabolic risk. While diagnosis is based on well-established five clinical criteria, these may overlook early or atypical metabolic alterations. Large-scale metabolomic profiling offers an opportunity to identify biochemical signatures of MetS beyond diagnostic bias and to evaluate their relative importance across different presentations of the syndrome.

Methods: Data from 117,147 UK Biobank participants were analyzed in a cross-sectional design. High-throughput NMR quantified 75 circulating metabolites, for. Univariate analyses, MetS subtype stratification, and elastic net models with SHAP interpretation were applied to assess feature …

Development Of A Practical Lu-177 Activity Calibration Protocol For Clinical Nuclear Medicine: Dosimetric Impact Analysis And Implementation Tools, Azam Almolaiki

Theses and Dissertations

Lutetium-177 (Lu-177) is widely used in radionuclide therapy, where accurate activity measurement prior to administration is essential for safe and effective treatment delivery. However, variability in dose calibrator response due to measurement conditions and source geometry remains a practical challenge in routine clinical settings. This study presents a practical clinical calibration strategy under real-world constraints for Lu-177 activity measurement using standard nuclear medicine instrumentation. A vial-based approach was implemented using a well-type ionization chamber (Capintec CRC-15R) to evaluate measurement repeatability, temporal stability, and geometry dependence. All measurements were performed under consistent conditions with appropriate decay correction applied using the physical …

Cb1 Allosteric Modulation: Preclinical Insights Into Therapeutic Potential And Misuse Liability, Mohammed A. Mustafa

Theses and Dissertations

Cannabinoid type-1 (CB1) allosteric modulators represent a promising approach to modulate CB1 receptor signaling by binding to distinct receptor sites, without producing adverse cannabimimetic and dependence-related effects associated with Δ9-tetrahydrocannabinol (THC) and other CB1 agonists. This dissertation investigates the pharmacological, behavioral, and dependence-related profiles of CB1 allosteric modulators for their therapeutic potential and misuse liability. Presented here, the chiral CB1 positive allosteric modulator (PAM) ZCZ011 was resolved into its R- and S-enantiomers and characterized across in vitro and in vivo assays. Both enantiomers enhance CB1 agonist activity and produce intrinsic effects in vitro. Behaviorally, they produce antinociceptive effects in the …

Novel Piperidone And Bispidine Derivatives: A New Approach In Cancer Therapy, Lereen Khaled Youssry

Theses and Dissertations

Cancer remains the second leading cause of death worldwide. As a result, scientists have been trying to find novel therapeutic approaches that target specific metabolic pathways selective to tumor cells. In this study, two novel piperidone and bispidine derivatives, organic molecules that target polyamine metabolism, were synthesized, and their potential cytotoxic, antioxidant and anti-inflammatory effects were investigated. Polyamines are naturally occurring metabolites that were reported to be in excess at cancer cells and were accounted for tumor proliferation, invasion and metastasis. Accordingly, the novel piperidone and bispidine derivatives were expected to disrupt tumor growth and progression via up-regulation of key …

Effects Of Stressor Exposure And Locus Coeruleus Opioid Signaling On Coping And Anxiety-Like Behavior In Rats, John Arthur Tkaczynski

Theses and Dissertations

Stress is a physiological state of altered neuroendocrine signaling and heightened indices of behavioral vigilance and arousal in response to threatening stimuli. This project aimed to investigate the adaptations to stress that occur in the noradrenergic locus coeruleus (LC) and how these changes affect stress coping behavior. We began by investigating how adolescent restraint and predator odor stress affects coping when presented with a secondary noxious stimulus in the defensive shock probe burying task one week following stressor exposure, finding that stressed male rats demonstrate a more active coping response and stressed female rats demonstrate a more passive coping response, …

Mechanisms Underlying Estrous Cycle-Dependent Changes In Incubated Cocaine Craving, Erin Elizabeth Wannen

Theses and Dissertations

Cues associated with cocaine use are one of the most common relapse triggers and understanding what promotes cue-induced cocaine craving and relapse is a critical question in the field. Human studies have shown that these measures are impacted by fluctuations in ovarian hormone levels, as higher levels of estradiol promote cue-induced cocaine craving in women while higher levels of progesterone reduce craving in both sexes. Enhanced or incubated cue-induced cocaine seeking or craving also changes across the rodent reproductive (estrous) cycle as levels of estradiol and progesterone fluctuate, with enhanced seeking behavior observed during the estrus stage of the cycle. …

Developing A Small Molecule To Inhibit Hsf1 Expression In Cancer And Evaluating Natural Genetic Variation In Small Molecule Toxicity., Michaela Kendal Foley

Theses and Dissertations

Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines …

Exploring The Effects Of Serotonin And Selective Serotonin Reuptake Inhibitors On The Neurological, Behavioral, And Cardiovascular Systems Using The Animal Model Of The Syrian Hamster (Mesocricetus Auratus), Ariana Vianey Hinojosa

Theses and Dissertations

Serotonin is a neurotransmitter widely recognized for its role in neuropsychological processes, particularly in regulating mood, cognition, and emotional responses. However, its influence extends beyond the central nervous system (CNS), playing a crucial role in various physiological functions, including metabolism, the gastrointestinal system, reproductive processes, and cardiovascular regulation. As a key modulator of homeostasis, serotonin contributes to maintaining equilibrium within these systems, ensuring proper function and response to environmental stimuli. Despite its well-documented effects on mood and behavior, the broader physiological implications of serotonin remain less understood, particularly in the context of its interactions among neural, behavioral, and cardiovascular systems. …

Investigating The Effects Of Sex And Estrous Cycle On The Incubation Of Cue-Induced Oxycodone Craving, Bhumiben Pradipkumar Patel

Theses and Dissertations

The overprescription and misuse of opioids like oxycodone has played a significant role in the ongoing opioid crisis. While effective painkillers, drugs like oxycodone are also reinforcing and often misused. While sex and ovarian hormones can impact the analgesic effects of these drugs, the impact of these factors on oxycodone reinforcement are not fully understood. This relationship between ovarian hormones and opioid reward is further complicated by the fact that opioid use can disrupt ovarian hormone levels and produce reproductive cycle irregularities. Using a rat model of drug craving and relapse vulnerability, we found that chronic oxycodone exposure produced reproductive …

Activation Of Basal Forebrain Afferents Following Systemic Inflammation, Alexis Morgan Blas

Theses and Dissertations

Sepsis is a large-scale immune response typically due to an imbalance of pro- and anti-inflammatory responses due to some type of infection or insult. Around 1.7 million adults in the United States will develop it each year, making it the leading cause of increased morbidity and mortality in hospitals. Sepsis can lead to many different symptoms, one of which is delirium. Delirium is a mental state of confusion and disorientation and involves delusions, hallucinations, memory issues, and most commonly inattention. Delirium is more prevalent in older individuals which leads to further complications and a higher likelihood of development of long-term …

Evaluating Dry Air Personnel Decontamination Of Methyl Salicylate As A Chemical Agent Surrogate In Extreme Cold Environments To Reduce Airborne Risks Using A Manikin, Lance E. Campbell

Theses and Dissertations

This research investigated a mobile air shower as an alternative to water washing for personnel chemical decontamination in Arctic environments, where traditional methods like disrobing and rinsing are impractical. Interest in Arctic operations has grown with recent U.S. military focus on strategic advancements by Russia and China, yet research on air shower effectiveness for chemical decontamination remains limited. This study examined whether a commercial off-the-shelf air shower could effectively decontaminate methyl salicylate (MES), a surrogate for chemical warfare blister agents, from a manikin outfitted in military cold-weather gear. Researchers used a ppbRAE 3000 photo-ionization detector to measure MES concentrations following …

Mir-125a-3p And Its Targets: Promising Biomarkers For Ovarian, Liver, And Breast Cancers, Offering A Beacon Of Hope For More Effective Diagnosis And Treatment Strategies, Eman Kamaleldien Anwer

Theses and Dissertations

Cancer is a worldwide health problem with various genetic and epigenetic alterations, resulting in disease heterogeneity. Effective diagnostic, therapeutic, and monitoring markers have been determined recently; however, new diagnostic, prognostic, and therapeutic markers are needed. MicroRNAs (miRNA), short non-coding RNAs, have a highlighted role in cancer progression, migration, and programmed cell death. Our study aims to investigate the significance of miR-125a-3p and its downstream targets in breast (BRCA), hepatocellular (HCC), and ovarian (OVCA) malignancies and their possibility as diagnostic biomarkers and targets for therapeutic agents. Bioinformatics and online tools were used to determine the miRNA-predicted downstream targets, analyze GEO datasets, …

Identification Of Novel Genetic Biomarkers Linked To The Prodromal Stage Of Parkinson’S Disease (Pd) Patients, Marwa Tawfik Badawy

Theses and Dissertations

Background and Objective: The early diagnosis of neurodegenerative diseases, such as Parkinson's disease (PD), is particularly challenging because symptoms appear only after significant neuronal damage has already occurred. This study is utilizing variant call format (VCF) analysis to identify genetic variants and novel genes that could serve as early prognostic markers for prodromal PD. Materials and Methods: Data were sourced from the Parkinson's Progression Markers Initiative (PPMI), focusing on prodromal patients with gVCF data from the 2021 cohort. The study included 304 participants, comprising 100 healthy controls, 146 individuals with prodromal genetic indicators, 21 individuals with prodromal hyposmia, and 37 …

Behavioral And Neuroactivational Correlates Of Psychosocial Stress-Induced Cocaine Seeking In The Rat, Nicole Hinds

Theses and Dissertations

Abstract Nicole Maria Hinds BEHAVIORAL AND NEUROACTIVATIONAL CORRELATES OF PSYCHOSOCIAL STRESS-INDUCED COCAINE SEEKING IN THE RAT 2024 Molecular Cell Biology & Neuroscience Doctor of Philosophy Cocaine Use Disorder is characterized by a high risk for relapse that can persist over extended periods of abstinence. Psychosocial stressors are well-established to promote drug craving and relapse in humans but have rarely been employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not yet been thoroughly explored. This project aimed to identify brain regions recruited during psychosocial stress-induced cocaine seeking in rats, with a …

Attacking Diabetes One Day At A Time, Kyla Duncan

Theses and Dissertations

The "Attacking Diabetes One Day at a Time" initiative targets the growing concern of public health, type 2 diabetes, among under-reserved communities. This comprehensive care program emphasizes the importance of prevention through education, improving lifestyles, and access to care. Based on insights from the Self-Care Management Theory, this initiative seeks to provide individuals with sound, culturally tailored strategies that reduce disease risk and help them manage healthy lifestyles. Major components include educational workshops, and resource navigation. The success of this program, from community engagement through evaluation on a phased implementation plan, is guaranteed. The expected outcomes of this work will …

Lis1 Depletion In Adult Mouse Projection Neurons Causes Neurodegeneration And Severe Neurological Phenotypes, Anne Ventrone

Theses and Dissertations

Proper LIS1 function is crucial for human brain development, as mutations in LIS1 lead to lissencephaly, a severe neurodevelopmental disorder caused by defective proliferation, differentiation and migration of neural precursors. Our understanding of LIS1's functions after brain development is limited. LIS1 regulates cytoplasmic dynein 1 (dynein), an essential microtubule motor protein in cell division and migration, but also a cellular transport motor. We previously showed that tamoxifen (TX)-induced global knockout of LIS1 using a Cre/Lox system (Act-Lis1iKO) in young adult mice results in severe neurological defects and rapid lethality. This strongly supports LIS1's critical post- developmental role, but the underlying …

Establishing A Conventional Linac-Based Electron Flash Beam, Justin Defrancisco

Theses and Dissertations

Problems: A rediscovered radiotherapy technique, FLASH, involves increasing the dose rate to >40 Gy/s. For a given dose, FLASH is shown to decrease the normal tissue complication probability without affecting the tumor control probability. More preclinical studies are necessary to confirm and enable these desirable properties on humans. Current preclinical investigations have diverse constraints, requiring FLASH apparatuses with flexible parameters and accurate control. However, there are limited FLASH platforms available, the existing ones are costly. Our institution is not in possession of any such infrastructure. Even if available, dosimetry and beam control in FLASH are extremely lacking. There is …

Development Of A Mediation Model Of Pain Cognition In Adult Patients With Sickle Cell Disease, Daniel M. Sop

Theses and Dissertations

Pain is a hallmark of Sickle Cell Disease (SCD), a genetic hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusion, and organ damage. While acute vaso-occlusive crises (VOC) have been extensively studied, the mechanisms underlying chronic pain and its interplay with brain function remain unclear. This dissertation investigates the relationships between cerebral blood flow (CBF), fluid cognition, and pain sensitivity in adults with SCD, utilizing advanced imaging techniques and validated assessment tools.

Arterial spin labeling (ASL) and functional magnetic resonance imaging (fMRI) were employed to measure CBF and brain activity, respectively. Pain sensitivity was assessed using the Pain Sensitivity Questionnaire (PSQ), and …

Enhancing Clinical Trial Matching In Molecular Diagnostics: Using Natural Language Processing And Clustering Approaches In Hematological Malignancies, Gillian Fanning

Theses and Dissertations

Clinical trial matching is a critical component of personalized medicine, particularly in the management of hematologic malignancies. At Virginia Commonwealth University (VCU) Health, the Molecular Diagnostics (MDX) Lab produces somatic variant reports and recommends clinical trials based on the presence of clinically significant mutations. However, the current manual trial recommendation process is time-intensive and lacks scalability.

This study introduces a computational framework to streamline and standardize clinical trial matching using natural language processing (NLP) and unsupervised clustering. Trial brief descriptions were analyzed to extract frequent terms, and trials were grouped based on term similarity using joint dimensionality reduction and clustering. …

Rare Variant Analysis Of Electronic Health Record-Defined Major Depressive Disorder In The All Of Us Research Program, Stephen Emil Vieno

Theses and Dissertations

The underlying pathogenesis of MDD remains poorly understood, with multiple competing hypotheses regarding its exact etiology. As a heterogeneous disorder with relatively low heritability, large-scale genome-wide association studies of MDD have relied on increasingly large sample sizes to identify common genetic variants associated with the disorder. However, the rare variant genetic architecture of MDD is still largely unknown. The aim of the present analysis was to use the AoU—a United States-based biobank that integrates healthcare records from over 50 healthcare systems and possesses whole genome sequencing data for participants—to perform a gene set–based analysis of MDD. This analysis presented several …

Scopolamine-Induced Modulation Of Serotonin And Dopamine Transporters Activity: Behavioral And Molecular Insights Into Rapid Antidepressant Action, Deepak Karunakaran

Theses and Dissertations

Major depressive disorder (MDD) affects over 350 million individuals worldwide and is characterized by profound dysregulation of serotonin (5-HT) and dopamine (DA) systems that govern mood, reward processing, and motivation. The serotonin transporter (SERT) and dopamine transporter (DAT), both dynamically regulated through phosphorylation, serve as critical determinants of synaptic monoamine signaling. Despite decades of therapeutic development, current antidepressants require 4-6 weeks to achieve efficacy, and approximately one-third to half of patients develop treatment-resistant depression. The emergence of rapid-acting antidepressants like ketamine represents a paradigmatic shift, demonstrating symptom relief within hours; however, ketamine's therapeutic potential remains constrained by abuse liability, dissociative …

Ecological And Pathological Applications Of The Heat Shock Response, Taylor Rae Stanley

Theses and Dissertations

The heat shock response (HSR) is a cytoprotective stress response pathway that regulates cellular proteostasis. The HSR is an evolutionarily conserved pathway that is essential for normal cellular functioning. Here, we explore the broad ecological and pathological impacts of the HSR. In an ecological context, we perform gene level analysis of the transcriptomes of two closely related sunfish. We found that the more invasive bluegill sunfish has gene expansions in two HSR gene families, the HSP70 family and the HSP90 family compared to the redear sunfish. These gene expansions were also observed in several other teleost fish species and were …

Regulation And Function Of The Rna-Binding Protein Khsrp During Neuronal Development, Regeneration And Axonal Injury Response, Courtney Nicole Buchanan

Theses and Dissertations

Axons, which extend long distances from neuronal cell bodies, rely on localized mRNA translation to swiftly respond to extracellular stimuli and physiological states. This work investigates the mechanism underlying the RNA-binding protein KHSRP’s, axonal mRNA translation and regulatory pathways involved in neuronal growth and regeneration. Our results indicate that KHSRP deletion in mice leads to upregulation of growth-associated mRNAs linked to neuronal morphology and function, resulting in increased axon growth and altered memory consolidation. Indicating a critical role for KHSRP in neuronal development and function through post-transcriptional regulation (Chapter 2). Additionally, we show there is a rapid increase in axonal …

Role Of Customized Visual And Multifactorial Interventions In Preventing Falls Among Individuals With Visual Impairment In South India, Ramya S

Theses and Dissertations

Falls are the second leading cause of unintentional injuries and extensively studied among the elderly. Hence, intervention studies for falls prevention are restricted to the elderly with or without visual impairment (VI). Even among studies with VI, strategies for treatable VI are widely explored. Hence this study aimed to understand falls and interventions that may reduce falls in all the age groups especially among those with untreatable VI.

This mixed methods study included identification of subjects aged ≥ 18 years with VI from clinical records of Medical Research Foundation, Chennai and details of previous history of falls were enquired over …