It Takes A Muscle: Wholes, Holes, And Other Voids, Saar Shemesh

Theses and Dissertations

IT TAKES A MUSCLE¹

In the BELLY of the BEAST, the HUMAN

in the deep end of a SWIMMING POOL

in a GRAVE, looking up/out from within

at the base of a CRATER, ABYSS, PIT

the room as a CRADLE, INCUBATOR

architecture as MOTHER MOULD.²

____________________________

¹ Title is borrowed and abbreviated: Spectral Display, “It Takes A Muscle To Fall In Love,” 1982.

² For what American-English delineates as ‘mold,’ British-English uses ‘mould’ and is more specific in its technicality. The former doesn’t distinguish in spelling between mold (fungus) and mold (mould). I’m not particularly a fan of …

Modulating Ketamine’S Locomotor Activating And Reinforcing Effects Through Drug Combinations, Tegshjargal Baasansukh

Theses and Dissertations

Major Depressive Disorder (MDD) affects approximately 280 million people worldwide. The standard of care for pharmacological treatment of MDD has been monoaminergic antidepressants (MAA). However, MAAs have serious clinical limitations including a relatively slow onset of action and up to 40% of patients failing to respond and being diagnosed as “treatment resistant”. Ketamine, an N-methyl-D-aspartate antagonist, was originally approved for use as an injectable anesthetic. In addition, ketamine has been shown to rapidly improve depressive symptoms in patients with treatment resistant depression. In 2019, (S)-ketamine was approved as a nasal spray (Spravato®) for patients with MDD and treatment-resistant depression in …

Using Molecularly Imprinted Polymers For The Selective Extraction Of Analytes, Haley A. Mulder

Theses and Dissertations

Sample preparation is a critical steps in bioanalysis. Traditional methods such as solid-phase extraction and liquid-liquid extraction are laborious and ultimately incapable of properly separating target analytes from matrix and interferents. The co-extraction of these components interferes with the analytical instrument’s ability to properly detect and quantitate analytes. Molecularly imprinted polymers (MIPs) are synthetic polymers that have been “imprinted” with a template analyte in a co-polymer system. MIPs are capable of selectively extracting analytes from complex biological matrices and can be employed in off-line, benchtop extractions or for on/in-line instrument extractions. MIPs offer faster and more selective sample preparation, leading …

Biotic Characteristics Of Managed And Unmanaged Coastal Dunes In The Outer Banks, North Carolina, Andrew E. White

Theses and Dissertations

Under future climate change and sea level rise scenarios, Natural and Nature-Based Features (e.g., dunes) that protect coastal habitat and infrastructure will be exposed to increased wave energy and storm surge. Understanding how these forces will impact coastal dunes is necessary for their continued use as protective features. Coastal dunes develop through feedback between vegetation and sediment deposition, a process complicated by species-specific growth rates and responses to burial. Wave flume studies have tested the effects of dune vegetation on erosion and found multiple plant organs across several functional types to be important for resisting erosion. Although dune building and …

Mechanisms And Treatment Of Pain-Depressed Behavior In Male And Female Mice, Clare M. Diester

Theses and Dissertations

One of the largest discrepancies between preclinical and clinical assessment of pain and analgesia is the type of behavioral endpoint used. Although most preclinical research has historically focused on drug effectiveness to block reflexive withdrawal behaviors stimulated by a noxious stimulus, increasing evidence shows that drug-induced restoration of pain-depressed behaviors provides increased clinical translation with decreased susceptibility to false-positives. Accordingly, the first portion of this dissertation designed a behavioral battery that featured pain-depressed behaviors as well as more conventional pain-stimulated behaviors for testing candidate analgesics in male and female mice. The main findings are as follows. (1) Intraperitoneal injection of …

The Role Of Irf-1 In Spontaneous Mouse Glioma, Aakash B. Vaidya

Theses and Dissertations

Glioblastoma Multiforme has been shown to be one of the deadliest primary brain cancers. One of the reasons why GBM is so deadly, is a unique immunosuppressive tumor microenvironment that promotes GBM growth and progression. Both astrocyte and microglia have been implicated in immunosuppression. In this study, we explored the role of Interferon Regulatory Factor 1 (IRF-1) in astrocytes and glioma cells on the growth of spontaneous glioma tumors. IRF-1 is regulated by the JAK/STAT pathway and induces expression of Programmed death ligand 1 (PD-L1). PD-L1 downregulates immune responses to glioma. We found that IRF-1 had no effect on spontaneous …

Targeting Bcl-2 Family Proteins In Therapy Induced Senescent Cancer Cell Models, Wade Cook

Theses and Dissertations

Non-small Cell Lung Cancer (NSCLC) originates from numerous different cell types in the lungs and is among the deadliest of cancers. Head and Neck Squamous Cell Carcinomas (HNSCC) are derived from the mucosal membranes of the oral cavity, pharynx, and larynx. Both NSCLC and HNSCC are predominately caused by tobacco smoke inhalation and as such mutations in the tumor suppressor gene TP53 are common. Since similarities exist in the root cause of NSCLC and HNSCC, they may also share similarities in treatment methods. Cisplatin is a platinum-based DNA damaging agent that has been used as a cancer chemotherapy for decades. …

Evaluating Population Genetic Structure And Potential Genomic Signals Of Natural Selection In A Migratory Songbird (Protonotaria Citrea), Tyler A. Hohenstein

Theses and Dissertations

In this study I attempted to further resolve the population genetic structure in the Prothonotary Warbler (Protonotaria citrea), and conducted an outlier SNP analysis and exploratory gene ontology analysis to investigate potential ongoing natural selection in the species. This analysis of population structure confirms previous work by DeSaix et al. (2019), where weak population structure was observed between eastern sites along the Atlantic Coastal Plain, and western sites in the Mississippi Alluvial Valley, possibly due to a genetic discontinuity across the Appalachian Mountains. I conducted two forms of outlier SNP analyses, a principal component analysis (PCA)-based approach to identify SNPs …

Alternatively Spliced Csf3r In Human Health And Disease, Borwyn A. Wang

Theses and Dissertations

Elevated alternative colony stimulating factor 3 receptor (CSF3R) isoforms are observed in myelodysplastic syndromes (MDS) and other myeloid neoplasms, but their role in driving disease progression has not been fully explained. In this study we report on the role of an MDS-associated splicing factor SRSF2 and its effects on the production of Class III and Class IV CSF3R isoforms and granulopoiesis. Class IV add-back in Csf3r-null mice showed impaired neutrophil differentiation with increased number of CFU-G, which largely consisted of metamyelocytes, while Class III showed greater dysgranulopoiesis accompanied by dysmorphic neutrophils. Alternative CSF3R isoforms were elevated in …

Coupled Structure-Function Responses To Disturbance: High Structural Complexity Resistance Supports Primary Production Resistance, Kerstin M. Niedermaier

Theses and Dissertations

The capacity of forests to resist structural change and retain material legacies–the biotic and abiotic resources that persist through disturbance–is crucial to sustaining ecosystem functioning after disturbance. However, the role of forest structure as both a material legacy and feature supporting carbon (C) cycling stability following disturbance has not been widely investigated. We used a large-scale disturbance manipulation to ask whether LiDAR-derived canopy structures as material legacies drive 3-year responses of NPP to a range of disturbance severity levels. As part of the Forest Resilience Threshold Experiment (FoRTE) in northern Michigan, USA we simulated phloem-disrupting disturbances at a range of …

Changes In Physical Activity And Relationships To Submaximal Exercise Capacity And Cardiac Function During Breast Cancer Therapy, Moriah P. Bellissimo

Theses and Dissertations

Background: Breast cancer (BC) survivors are at high risk for heart failure due to curative cancer therapies. In non-cancer populations, physical activity is a first line treatment for preventing cardiovascular disease. This study examined whether more physical activity was associated with better submaximal exercise capacity and cardiac function during the first three months of cancer therapy.

Methods: Participants included 223 women with stage I-III BC before therapy and after three months of undergoing treatment and 126 controls. Leisure time physical activity was reported using the Godin Sheppard leisure time exercise questionnaire. Cardiac function was assessed by cardiac magnetic resonance, and …

Advancing Forest Structure-Function Relationships: Linking Above- And Belowground Structure To Soil Respiration, Laura J. Hickey

Theses and Dissertations

Variation in the soil-to-atmosphere C flux, or soil respiration (Rs), is influenced by a suite of biotic and abiotic factors, including soil temperature, soil moisture, and root biomass. However, whether canopy structure is tied to soil respiration through its simultaneous influence over these drivers is not known. We assessed relationships between measures of above- and belowground vegetation density and complexity, and evaluated whether Rs is linked to remotely sensed canopy structure through pathways mediated by established biotic and abiotic mechanisms. Our results revealed that, at stand-scale, canopy rugosity–a measure of complexity–and vegetation area index were coupled to soil respiration through …

Estimating Weighted Panel Sizes For Primary Care Providers: An Assessment Of Clustering And Novel Methods Of Panel Size Estimation On Electronic Medical Records, Martin A. Lavallee

Theses and Dissertations

Primary Care is on the frontlines of healthcare, thus they see the most diverse set of patients. In order to achieve high functioning primary care, a practice must establish empanelment, the pairing of patients to providers. Enumeration of empanelment, or estimating panel sizes, helps ensure that the demands of the patients demand the supply of providers and optimize the balance of primary care resources to improve quality of care. Further we can adjust panel sizes by using patient-level data on healthcare utilization and complexity extracted from the electronic medial record to determine the amount of care or burden of work …

Therapeutic Injectable Iron-Chelating Hydrogels, Debbie Campbell-Rance

Theses and Dissertations

ABSTRACT

Therapeutic Injectable Iron-Chelating Hydrogels for Improved Central Nervous System Regeneration

By

Debbie S. Campbell-Rance

A dissertation submitted in partial fulfillment of the requirements of the degree of Doctor of Philosophy at Virginia Commonwealth University 2021.

Director: Xuejun Wen, M.D., Ph.D., AIMBE Fellow, Alice T. and William H. Goodwin Jr. Endowed Chair Professor in Regenerative Medicine, Institute for Engineering and Medicine, Department of Chemical and Life Science Engineering

Severe traumatic brain and spinal cord injuries are major global public health and socioeconomic problems in terms of mortality and morbidity. Currently there are two main lines of treatment under development for …

The Injury-Induced Neurogenic Response And The Role Of Notch1 In Regulating This Process, Nicole M. Weston

Theses and Dissertations

Traumatic Brain Injury (TBI) is a prevalent problem with an estimated 5 million people suffering from chronic cognitive impairments long after the injury. Following TBI there is a series of pathophysiological changes in the brain including neurogenesis, an important response linking endogenous repair and regeneration. The dentate gyrus (DG) of the hippocampus is a primary neurogenic region within the adult brain where neural stem and progenitor cells (NS/NPCs) reside. Studies using rodent models have shown that cognitive recovery after TBI is associated with new neurons generated from the DG. Thus far, in studies examining post-injury neurogenesis, the regulatory mechanisms, functional …

Modification Of Culture Medium And Identification Of Microbial Contaminants For Improved In Vitro Propagation Of Freshwater Mussels, Raquel M. Wetzell

Theses and Dissertations

In vitro propagation efforts play an essential role in conserving and restoring threatened freshwater mussel populations by circumventing the need for a fish host. Across a broad range of taxa, transformation is induced with an artificial M199 medium and rabbit serum. However, such formulation may not be sufficient in culturing critical species with more specific physiological requirements. In this study, multiple serum mixtures were tested to improve in vitro transformation of two freshwater mussel species: yellow lampmussel (Lampsilis cariosa) and tidewater mucket (Atlantaconcha ochracea). These species were selected because they parasitize similar fish host species but …

Quantifying Contributions Of Climate, Geography, And Gene Flow To Divergence: A Case Study For Three North American Pines, Constance E. Bolte

Theses and Dissertations

Long-lived species of trees, especially conifers, often display weak patterns of reproductive isolation, but clear patterns of local adaptation and phenotypic divergence. Discovering the evolutionary history of these patterns is paramount to a generalized understanding of speciation and the processes that confer population persistence versus those that compromise adaptive potential under rapidly changing environments. Forest trees have long generation times and low migratory potential making them especially vulnerable to population fragmentation and reductions of genetic diversity due to insufficient tracking of niche optima and adaptational lags. Within clades of the genus Pinus, evolutionary histories appear to be riddled with hybridization …

Structure-Based Drug Discovery And Development Of Protein Structure Prediction Tools Using An Empirical Force Field, Noah B. Herrington

Theses and Dissertations

Traditional drug discovery has rapidly accelerated thanks to development of computational molecular modeling. The crucial component that these computational studies hinge upon is having a well-defined, and energetically favorable structure. Structures of proteins and ligands that meet these criteria are important for accurately simulating models used to study drug binding. To demonstrate the role of accurate structure simulation in the study of these events, this thesis presents, first, a story examining the problem of accurate structure modeling of ionizable residues within protein structures, specifically aspartic acid, glutamic acid, and histidine. I present our method, which uses the HINT force field …

The Transcription Factor Nfe2l2a Is Required For Development Of Hematopoietic Stem Cells In The Zebrafish Embryo, Sivam Bhatt, Teerth Patel, Madeleine Seputro, Anubhav Thapaliya, Erich Damm

UROP Posters

Hematopoietic Stem Cells (HSCs) are the self-renewing population of cells that generate all erythrocytes and leukocytes over the lifetime of a vertebrate organism. HSCs are also the therapeutic units of curative bone marrow transplants used in the treatment of blood malignancies and in gene therapy for genetic blood disorders. In all vertebrate embryos, HSCs originate from the floor of the embryonic dorsal aorta during the endothelial to hematopoietic transition. Nascent HSCs will bud into the blood vessel and be carried to maturation sites by the embryonic blood flow. Despite the curative potential of HSC transplants in blood disorders, this approach …

Comparison Of Free Versus Encapsulated Drugs On 3t3 Differentiation, Simon H. Friedrich, Gabriel Volpe

UROP Posters

The scope of this project was to design, synthesize and test targeted nanoparticles containing hydrophobic and hydrophilic drugs that promote browning in adipose tissue. For hydrophilic drugs the use of liposomes and their hydrophilic core is more useful than the PLGA nanoparticles which have hydrophobic cores. The inhibition of the FOXO1 pathway and modulation of autophagy in adipose tissue can promote browning of white adipose tissue, or an energy burning state where excess energy is burned as heat instead of stored in the cell. If successful, these drugs would offer an alternative treatment for obesity where changes to the patient's …

Determining Effective Treatment Regimens For Breast Cancer Using Combined Immunotherapy And Chemotherapy In Vivo, Akhila R. Kunuthuru, Laura Graham, Harry D. Bear Md, Phd

UROP Posters

Breast cancer has the highest incidence rate of all cancers globally in women, and those of African descent, especially West African females, face higher rates of triple-negative breast cancer (TNBC), a more aggressive form of breast cancer. Immunotherapy for breast cancer is a relatively new treatment option, and research is ongoing to identify the best combination treatments for increasing survival of those diagnosed with TNBC. Eganelisib (IPI-549: a PI3K-gamma inhibitor that works to shift M2 macrophages to M1 to augment T cell function) with other combinatory treatments has shown promising results in reducing tumor growth and increasing survival in mice. …

Observing Gravitropism In Brassica Rapa Roots, Trang Ly, Maya O'Callagham, Lan Poeschl, Adil Saeed, George Zorn

UROP Posters

The objective of this experiment is to observe the effect of gravitropism on the orientation of Brassica rapa (B. rapa) roots. Specifically, amyloplasts that reside at the bottom of root tips act as gravity sensors. As plants are disturbed from upright orientation, roots automatically grow according to the downward pull of gravity. It is hypothesized that as the angle of rotation increases, the angle of root growth is inversely proportional. Five plants containing four seeds of B. rapa were grown over the course of 10 days. Each plates, aside from the control, were rotated once 90°, 80°, and 270° to …

Human Papillomavirus 16 E2 Regulates Host Cell Pathways Important For Cancer Progression And Treatment Sensitivity Which May Contribute To Cancer Outcomes, Christian Fontan

Theses and Dissertations

Human papillomaviruses (HPVs) are causative agents in around 5% of all cancers, including cervical and oropharyngeal. A feature of HPV cancers is their better clinical outcome compared with non-HPV anatomical counterparts. In turn, the presence of E2 predicts a better clinical outcome in HPV-positive cancers; the reason(s) for the better outcome of E2-positive patients is not fully understood.

Previously, we demonstrated that HPV16 E2 regulates host gene transcription that is relevant to the HPV16 lifecycle in N/Tert-1 cells. One of the genes repressed by E2 and the entire HPV16 genome in N/Tert-1 cells is TWIST1. In these studies, we demonstrate …

Bioinformatic Pipeline For Determining Terminal Repeats In The Human Cytomegalovirus Genome Assembled With Pacbio Long Read Sequences, Ahmed Al Qaffas

Theses and Dissertations

Human Cytomegalovirus (HCMV) is a member of the betaherpesvirinae subfamily of the Herpesvirus family. HCMV infection is common among adults worldwide, with an estimated seroprevalence of 66 to 95%, depending on the geographic region (Zuhair et al., 2019). Although most of the virus genomic content has been studied extensively, the terminal repeating region sequences remain understudied. Two main challenges hindered the study of the region: a) limitations of sequencing technologies; and b) misassembly of the repeats due to its complex nature. Here I show a novel bioinformatics pipeline that takes advantage of PacBio's long reads to resolve the challenges mentioned …

Protein Structure And Interaction: The Role Of Aromatic Residues In Protein Structure And Interactions Between Pyridoxine 5'-Phosphate Oxidase/Dopa Decarboxylase, Mohammed H. Al Mughram

Theses and Dissertations

Naturally developed proteins are capable of carrying out a wide variety of molecular functions due to their highly precise three-dimensional structures, which are determined by their genetically encoded sequences of amino acids. A thorough knowledge of protein structures and interactions at the atomic level will enable researchers to get a deep foundational understanding of the molecular interactions and enzymatic processes required for cells, resulting in more effective therapeutic interventions. This dissertation intends to use structural knowledge from solved protein structures for two distinct objectives.

In the first project, we conducted a bioinformatics structural analysis of experimental protein structures using our …

Behavioral Screening And Chiral Bioanalysis Of Emerging Stimulant-Type Drugs In Rats, Tyson R. Baird

Theses and Dissertations

The epidemic of drug use in the United States and elsewhere in the world has resulted in tragic loss of life and substantial economic costs. Novel psychoactive substances (NPS) are one of the contributors to this problem, and the lack of information about many of these drugs compounds their risk. This dissertation proposes a strategy to use intracranial self-stimulation (ICSS) as a behavioral screening tool to assess emerging drugs of abuse for their abuse potential in order to generate a proactive threat assessment. A series of stimulant-type drugs including methcathinone, α-pyrrolidinohexanophenone (α-PHP), cocaine, and the phenyltropane analogs of cocaine WIN35428 …

Identifying The Human Homologs Of Yeast Rab Proteins Ypt10 & Ypt11 And A Global-Scale Louse Endosymbiont Genome Variation, Nathaniel P. Smith

Theses and Dissertations

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease that causes loss of upper and/or lower motor neurons, and currently has no treatment or cure available. Over 90% of cases occur spontaneously with unknown causes, highlighting the complexity of the disease, and only 10% of cases are linked to heritable genetic mutations. Numerous ALS-linked genes are conserved through evolution, and model organisms may therefore provide opportunities to understand disease pathology at a molecular or cellular level, proving instrumental in identifying therapeutic targets. ALS subtype 8 (ALS8) is caused by an autosomal dominant P56S mutation in the VAPB gene that …

Examination Of Common And Rare Variant Genetic Architecture Of Psychiatric Disorders, Mohammad Ahangari

Theses and Dissertations

Psychiatric disorders are often heterogenous in their manifestation and genome-wide association studies have identified many common risk variants involved in their polygenic architectures with varying degrees of pleiotropy. In recent years, large-scale biobanks have also begun sequencing the genome of their participants to elucidate the role of rare risk variation in the genetic architecture of complex phenotypes, including psychiatric traits. This dissertation sought to better understand the role of both common and rare risk variation in the genetic architecture of psychiatric disorders with a particular focus on schizophrenia and alcohol problems. In the first three analyses, we focused on characterizing …

Computational Analysis Of Drug Targets And Prediction Of Protein-Compound Interactions, Sina Ghadermarzi

Theses and Dissertations

Computational prediction of compound-protein interactions generated a substantial amount of interest in the recent years owing to the importance of the knowledge of these interaction for drug discovery and drug repurposing efforts. Research suggests that the currently known drug targets constitute only a fraction of a complete set of drug targets, limiting our ability to identify suitable targets to develop new drugs or to repurpose current drugs for new diseases. These efforts are further thwarted by our limited knowledge of protein-drug (and more generally protein-compound) interactions, where only a subset of drug targets is typically known for the currently used …

Can't Stop Won't Stop: Continuing The Journey To Full Inclusivity In Freshwater Science With The Emerge Program, Amy Rosemond, Patina Mendez, Checo Colón-Gaud, Amanda Rugenski, Daniel Mcgarvey Dr., Breanna Ondich

Environmental Studies Publications

Emerge is a new, expanded effort to promote diversity within the freshwater sciences that builds upon the successful Instars program. With support from the National Science Foundation, Emerge will serve a continuum of undergraduate to graduate to early career scientists. The primary objective is a sustained and maximally inclusive community in which every Participant can build their professional network while simultaneously developing a strong sense of self- and group identity. Community building activities will include an annual, multi-day river expedition prior to the start of the SFS Annual Meeting, peer-supported participation throughout the Annual Meeting, and year-round virtual workgroups led …