Life Sciences Commons^™

Pre-Clinical Trials With Precision-Medicine Based Therapeutics In Basal-Like Patient-Derived Xenografts, David C. Boyd

Theses and Dissertations

Breast cancer treatments have improved over time, but the diseases seeing the most benefit from these improvements have the estrogen receptor, progesterone receptor, or are positive for HER2. Basal-like breast cancer tends to not have these biomarkers, which necessitates their treatment to be traditional, untargeted therapeutics which are less effective and tend to have harsh adverse effect profiles – this is an important unmet need. These studies utilize a variety of techniques, including tissue culture, viability assays, high-throughput screening, in vivo drug treatments and imaging, pathway analyses, molecular techniques such as Western blot, antibody arrays, RNA sequencing, sc RNA sequencing, …

Effects Of Hiv-1 Tat And Opiates On Gene Regulation Of Oligodendrocyte Lineage Cells: Identification Of Myrf As A Novel Target, Kelly M. Flounlacker

Theses and Dissertations

HIV-associated neurocognitive disorders remain pervasive even with increased efficacy/use of antiretroviral therapies. Opioid use/abuse among HIV+ individuals is documented to exacerbate deficits. White matter (WM) alterations (myelin pallor, volume/structural) detected by diffusion tensor imaging, are common observations in HIV+ individuals. Using transgenic mice expressing HIV-1 Tat, we examined effects of 2-6 weeks of Tat/morphine exposure on WM using genomic/biochemical methods. RNA sequencing of striatal tissue after 2-weeks revealed robust changes in mRNAs associated with oligodendrocyte populations/myelin integrity, including Transferrin, Ndrg1, and myelin regulatory factor (Myrf/Mrf), an oligodendrocyte-specific transcription factor involved in differentiation/maturation. Immunoblots conducted after 6-weeks exposure in …

Patterns, Mechanisms, And Characterization Of Carbon Cycling Stability Following Partial Forest Disturbance, Kayla C. Mathes

Theses and Dissertations

Among the most essential questions in the era of climate change is how the forest carbon (C) cycle will respond to an increase in the extent of biotic disturbances from insects and pathogens. While research has focused on stand-replacing disturbance regimes, less is known about C cycling stability following partial disturbances that produce gradients of disturbance severity. Belowground C cycling responses to disturbance are especially poorly understood, even though temperate forest soils contain up to 50% of total ecosystem C and soil respiration (R_s) accounts for more than half of temperate forest C loss. Interpreting trends and mechanisms …

Intrinsic Efficacy As A Determinant Of Opioid Effectiveness In Treatment Of Pain-Depressed Behavior, Edna Santos

Theses and Dissertations

Pain is a major public health concern that is commonly associated with behavioral depression, and a major goal in pain treatment is alleviation of pain-related behavioral depression. High-efficacy mu opioid receptor (MOR) agonists (e.g. fentanyl, morphine, oxycodone) are effective to treat pain, but their use is limited by side effects that not only endanger the patient but may also obscure analgesic rescue of pain-depressed behavior. The ongoing epidemic of opioid abuse and overdose deaths has stimulated research to discover non-opioid alternative analgesics; however, this search neglects the clinical potential of safer intermediate-efficacy MOR agonists (e.g. buprenorphine). The objective of the …

Unraveling The Consequence Of Adult Onset Sulfatide Depletion: Its Implications In Myelin And Axonal Heath In The Context Of Neurodegenerative Disease, Elizabeth Dustin

Theses and Dissertations

Multiple Sclerosis is an immune mediated disease of the CNS. MS is diagnosed through detection of demyelinated regions. However, recent studies demonstrate that Normal Appearing White Matter (NAWM) contains substantial pathology. One such pathology observed in the NAWM is the reduction of sulfatide. The proper stoichiometry of lipids in myelin acts to maintain rapid conduction velocity, provide trophic support to the neuron, and protect the axon from degeneration. We previously characterized a mouse lacking sulfatide’s synthesizing enzyme, CST through constitutive gene disruption and demonstrate that sulfide is required for proper stability of the myelin sheath. However, since MS is typically …

Interactions Between Hiv And Opioids On Antiretroviral Accumulation, The Blood Brain Barrier, And The Inflammatory Response In The Brain., Kara Rademeyer

Theses and Dissertations

The complex mechanisms related to HIV infection, neurodegeneration, and chronic neuroinflammation collectively describe neuroHIV (Hauser et al. 2007; Chang et al. 2014; Smith et al. 2014). Specifically, opioid abuse, poor penetration of antiretroviral (ARV) drugs, chronic inflammation and neuronal injury/degeneration are all implicated in neuroHIV (Fantuzzi et al. 2003; Letendre et al. 2004; Verani et al. 2005; Duncan and Sattentau 2011; Hong and Banks 2015; Simoes and Justino 2015; Olivier et al. 2018; Murphy et al. 2019; Osborne et al. 2020). For the first time, we demonstrate that morphine, fentanyl, and methadone in vivo alter the brain accumulation of ARVs, …

Plant Trait Effects On Tidal Wetland Methane Emission, Adam M. Dunn

Theses and Dissertations

High rates of carbon (C) sequestration exhibited by coastal wetlands is an important natural climate solution to global environmental change. At the same time, however, wetlands are the largest natural source of methane (CH₄) to Earth’s atmosphere, a potent greenhouse gas that influences the global climate. Wetland CH₄ emissions display high degrees of uncertainty in accounting for spatial and temporal variations in emissions due to the complex interactions between biotic and abiotic factors that influence methane production and transport, in addition to simultaneous influences from climate-driven effects on wetlands such as rapid sea level rise and increased …

Probing The Porphyromonas Gingivalis Nitrosative Stress Response Network, Alexandra Galina

Theses and Dissertations

Objective: To persist in the oral cavity, the perio-pathogen Porphyromonas gingivalis must have an efficient nitrosative stress response mechanism. To better understand how P. gingivalis responds to nitrite (NO₂^-) we must determine what genes are involved in the nitrosative stress response network.

Methods: Through genomic screening, a list of genes was generated that were hypothesized to be part of the nitrosative stress response network and believed to be involved in nitrate/nitrite metabolism or redox state of the cells. Protein coding regions were replaced with the ermF sequence by allelic exchange mutagenesis. 15 mutants were created …

Epithelial Membrane Protein 3 (Emp3b) Is A Novel Regulator Of Sympathetic Nervous System Development In Zebrafish., Jessica M. White

Theses and Dissertations

Notable progress has been made in understanding the development of the neural crest (NC). Neural crest cells (NCCs) can be divided into 4-5 subpopulations. A major lineage among trunk NC derivatives are sympathoadrenal (SA) cells, which give rise to the sympathetic nervous system (SNS). Trunk NCCs follow a ventromedial migration pathway where signals derived from the dorsal aorta instruct migrating NCCs to a SA cell fate. Defects in NC development can result in syndromes known as neurocristopathies. Neuroblastoma is one of the most common forms of pediatric cancer affecting nearly 800 infants each year in the United States (Takita et …

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

Stage-Structured Predator-Prey Interactions In A Warming World: A Case Study In Riverine Rock Pools, Andrew T. Davidson

Theses and Dissertations

Warming can impact predator-prey interactions through a variety of mechanisms. For example, warming can both alter the rate at which predators consume prey and the rate prey develop through vulnerable life stages. Thus, the overall effect of warming on consumer-resource interactions will depend upon the strength and asymmetry of warming effects on predator and prey performance. Here, we describe the consequences of these asymmetrical responses to temperature by first developing a simple stage-structured modeling framework, then applying that framework to predation of American rock pool mosquito larvae, Aedes atropalpus, by several common predators in riverine rock pools. We then …

Integrative Post-Gwas Analyses Of Psychiatric Disorders: Identifying Putative Risk Genes And Gene Sets Using Transcriptome, Proteome And Methylome Information, Huseyin Gedik

Theses and Dissertations

Genome-wide association studies (GWAS) of psychiatric disorders (PD) yield numerous loci with significant signals, but often they do not implicate specific protein coding genes. Because GWAS risk loci are enriched in expression/protein/methylation quantitative loci (e/p/mQTL, hereafter xQTL), transcriptome/proteome/methylome-wide association studies (T/P/MWAS, hereafter XWAS), which integrate information from GWAS and x-level (mRNA, protein or DNA methylation levels) coming from largest xQTL studies, can link GWAS signals to effects on specific genes. For gene level analyses, researchers use mendelian randomization (MR) methods to fine-map the association between x-levels and trait. However, none of the previous studies ever jointly analyzed XWAS of multiple …

Association Of Interpersonal Trauma And Polygenic Risk Scores With Depressive Symptoms In College Students, Rowan K. O'Hara

Theses and Dissertations

Major depression is considered a complex trait influenced by both polygenic risk factors and environmental exposures, such as childhood trauma. This study applied statistical genetic methods to calculate aggregate genetic risk for major depression to predict depressive symptoms scores in a college student sample. Data were from the Spit for Science (S4S) study in which college students from a large urban university self-reported interpersonal trauma (IPT) exposure prior to college and depressive symptoms from the past month (N = 7502; ancestry group: 20% African [AFR], 12% Admixed Americas [AMR], 10% East Asian [EAS], 49% European [EUR], 8% South Asian [SAS]). …

The Impact Of Hiv-1 Tat And Morphine On Spatial Distribution Of Drugs In The Brain., Austin M. Jones

Theses and Dissertations

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, the central nervous system (CNS) remains affected by the virus. Approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND) or neuroHIV. Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, viral replication, and potentially altering the antiretroviral concentrations within the brain.

Using a transgenic mouse that expresses the HIV-1 Tat protein, we examined the effects of Tat and morphine on antiretroviral accumulation and distribution and the effects of Tat on morphine accumulation within the brain using infrared matrix-assisted laser desorption electrospray ionization with mass spectrometry imaging (IR-MALDESI-MSI). …

Protacs – A Novel And Rapidly Developing Field Of Targeted Protein Degradation, Hannah R. Gatley

Theses and Dissertations

There is a continued need for new technology and strategies for tackling cancer and other diseases, and within the current century a novel therapeutic strategy has emerged in the realm of targeted protein degradation called Proteolysis-Targeting Chimeras (PROTACs). This technology specifically targets and degrades disease-causing proteins via the ubiquitin-proteasome system, and has seen an explosion of research and intrigue in both academia and industry over the past two decades. The diversity of PROTAC classes based on the E3 ligase recruiting ligand and the target protein allows for a universal molecular structure that can be customized for a specific target and …

Genomic Comparison Of Dba/2j And C57bl/6j Strains Of Mus Musculus And Best Practice Of Genome Alignment For Bioinformatics Analyses, Dustin J. Zeliff

Theses and Dissertations

Alcohol use disorder is known to have significant genetic components that contribute to an individual’s susceptibility to the disease. Mouse models are commonly used to study the mechanisms underlying alcohol use disorder, with C57BL/6J (B6) and DBA/2J (D2) being two of the more prominently used inbred strains. Research in the Miles Laboratory has used these two strains, and genetic panels of mice derived from them, to identify potential genes associated with variance in ethanol-related behaviors using quantitative trait loci (QTL) analysis. For example, Ninein (Nin) was identified as a potential candidate gene for the anxiolytic effects of ethanol, discovered because …

Novel Strategies In Head And Neck Tumor Therapy; Contribution Of Senescence In Therapy Response, And Resistance Development After Cisplatin Treatment, Fereshteh Ahmadinejad

Theses and Dissertations

Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local, and distant metastasis and disease relapse as well as cisplatin-induced resistance are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in both p53 wild- type HN30 and p53 mutant HN12 head and neck cancer models. We also show that tumor cells can escape from senescence both in vitro and in vivo. We further established a cisplatin-resistant cell line from HN30 parental cell line that underwent brief senescence …

A Standardized Pipeline For Isolation And Assembly Of Genomes From Symbiotic Bacteria In Whole Louse Genomic Sequence Data., Mohammad Mikail I. Bala

Theses and Dissertations

Many insects are known to harbour intracellular and heritable bacteria (endosymbionts), which provide their hosts with adaptive traits. Whole insect gDNA shotgun sequencing projects often sequence the genome of endosymbiont, in addition to the insect’s genome. There are approximately 600 whole genome shotgun libraries from insects available on the public repository (NCBI), which can be mined to obtain endosymbiont genomes. The assembly and annotation of endosymbiont genomes can contribute towards the exploration of their role as obligate symbiotic partners. However, de novo assembly of an endosymbiont genome, continues to be challenging, when the host and/or enteric bacterial gDNA is present …

Salinization Impacts On Heterotrophic Respiration, Ecosystem Respiration, And Plant Productivity In Tidal Freshwater Marshes, Kelsie J. Moses

Theses and Dissertations

Tidal freshwater marshes have preserved substantial stocks of soil carbon, which represents carbon dioxide that is no longer in the atmosphere. There is conflicting evidence in the literature about how disturbances such as sea level rise and associated wetland salinization impact the accumulation and long-term stability of this stored carbon. The goal of this experiment was to quantify how salinization impacts total ecosystem respiration and its component parts, autotrophic and heterotrophic respiration. This was a microcosm experiment using a C4 plant (Spartina cynosuroides) grown in soil derived from C3 plant matter and exposed to different salinities (0 to …

Examining Genetically-Informed Etiologic Models Of Co-Occurring Posttraumatic Stress Disorder And Recreational Cannabis Use Among College Students, Terrell A. Hicks

Theses and Dissertations

The college years encompass a period of increased risk recreational cannabis use (RCU), as well as a time of increased risk for trauma exposure and developing posttraumatic stress disorder (PTSD). Given the high co-occurrence between RCU and PTSD, and the potentially negative consequences of the two (e.g., worse academic outcomes), there is a need to understand the etiologic mechanisms of these commonly co-occurring conditions. Two primary phenotypic models exist: self-medication model (i.e., PTSD to RCU) and the high-risk model (i.e., RCU to PTSD). To date, there are two existing studies longitudinally examining the etiologic models proposed to explain co-occurring RCU …

Population Demography Of A Neotropical Migratory Songbird In The Face Of A Changing Climate, Adele Balmer

Theses and Dissertations

This dissertation investigates the population dynamics and demographic trends of the Prothonotary Warbler (Protonotaria citrea), a migratory songbird that breeds in North America during the spring and summer and overwinters in Central and northern South America. The primary objective of this dissertation is to examine the combined implications of variation in weather and individual traits on demographic traits and to project the effects of climate change on population trajectories of the Prothonotary Warbler.

The analyses conducted in this dissertation centered around female Prothonotary Warblers; however, visual identification of a nestling’s sex is impossible in most altricial bird species, …

Applications Of Urban Land Evaluation And Site Assessment (Ulesa) In Chesterfield County, Virginia, Emily Hastings

Theses and Dissertations

Urban and suburban agriculture is increasing in popularity across the United States. However, many of these farms are short-lived due to a combination of human factors (e.g., managerial, economic, cultural) and environmental or spatial factors (e.g., zoning, soil quality, distance to markets). Geospatial analysis, in the form of suitability modeling, could aid in locating suitable sites for these activities. Land Evaluation and Site Assessment (LESA) is a suitability modeling technique that generates a score for agricultural land use in traditionally rural spaces. This research explores adapting this method to encompass the complexities of placing diverse, in-ground agriculture in urban and …

Growing The Future Of Agriculture: An Examination Of Knowledge-Sharing And Community Building In The Fresh Produce And Floral Council, Oscar Guzman

Theses and Dissertations

This study examines knowledge-sharing practices within a community of practice (CoP) through a case study of the Fresh Produce and Floral Council (FPFC). The study sought to investigate how the FPFC promoted agricultural knowledge and expertise, impacted its members' social relationships and knowledge-sharing practices, communicated clear roles and expectations, and provided valuable and accessible resources. A mixed-methods approach was employed to investigate the research questions, which involved conducting a survey and utilizing descriptive statistics, frequencies, and Spearman correlations to analyze both the Likert scale and open-ended responses. The findings suggested that the FPFC has a knowledge-sharing culture promoting active participation …

Methods For Drone Trajectory Analysis Of Bottlenose Dolphins (Tursiops Truncatus), Jillian D. Bliss

Theses and Dissertations

With the increase in the use of UAS (Unmanned Aerial Systems) for marine mammal research, there is a need for the development of methods of analysis to transform UAS high resolution video into quantitative data. This study sought to develop a preliminary method of analysis that would quantify and present a way to visualize the dynamics and relative spatial distribution and changes in distribution of bottlenose dolphins (Tursiops truncatus) in the waters of Turneffe Atoll, Belize. This approach employs a previously developed video tracking program ‘Keypoint Tracking’ that enables manual tracking of individual dolphins and the creation of …

Variation In The M-Opioid Receptor (Oprm1) And Offspring Sex Are Associated With Maternal Behavior In Rhesus Macaques (Macaca Mulatta), Zachary Baron

Theses and Dissertations

A m-opioid receptor (OPRM1) single-nucleotide-polymorphism, found in both humans and rhesus macaques mediates the mother-infant attachment bond. Because mothers treat their sons and daughters differently, it is somewhat surprising that the role of infant sex has not been assessed in the context of a maternal-OPRM1-genotype-by-infant-sex interaction. The present study investigates the effect of maternal-OPRM1-genotype and infant sex on mother-infant behaviors. Over the first six months of offspring life, mother-infant behavioral data assessing attachment quality was collected twice weekly from a large number of rhesus monkey mother-infant pairs (N=161 dyads; n=64 female infants, n=97 male infants). Mothers were genotyped for OPRM1 …

The Influence Of Predation Environment On The Sensory Ecology Of Brachyrhaphis Rhabdophora, Alexandra Grace Duffy

Theses and Dissertations

Across the animal kingdom, predation is a ubiquitous and omnipresent selective agent for a variety of traits. I aimed to address gaps in our knowledge pertaining to how predation shapes animal behavior. Many species of fish naturally occur in drainages that differ in the density of predators and exhibit obvious population divergence, making them ideal study organisms to investigate predator-driven behavioral evolution. In Chapter 1, I conducted a systematic review of the literature. The purpose of this review was to determine if predation acted as a stronger or weaker selective agent on particular behavioral traits (e.g., foraging, mating, antipredator etc.) …

Understanding The Ahupua'a: Using Remote Sensing To Measure Upland Erosion And Evaluate Coral Reef Structure, Logan Kalaiwaipono Ellis

Theses and Dissertations

Under ever intensifying pressures from land use, climate change, and erosion, tropical islands are among the most vulnerable systems in the world. Terrestrial systems are weakened by intensifying land use patterns, the weakening of which is highlighted when high intensity rainfall events erode sediment and leads to sediment deposition on the marine system. The deposition of sediment on the marine system is a major stressor that can lead to weakened coral reefs and a decrease in marine resources commonly gathered for food. These interactions have led to the emergence of biocultural resource management strategies, one of which is the ahupua'a …

Of Bugs And Wildfires: Tracing The Impacts Of Changing Wildfire Regimes On Aquatic Bacteria And Macroinvertebrates Using Edna, Isabella M. Errigo

Theses and Dissertations

Human disruption of climate, habitat, and ignition has altered the behavior of wildland fire at local to continental scales. In many regions, novel fire regimes are emerging that threaten to exceed the capacity for local management to protect human wellbeing and ecosystem function. Simultaneous changes in climate, species composition, and fire management have resulted in extreme fire behavior in many regions. For the Western United States, the emerging novel fire regime consists of more frequent, severe, and intense wildfires, with annual area burned by wildfire having doubled and high-severity wildfire area having increased 8-fold since the 1980s. The impacts of …

Effect Of Climate History On The Genetic Structure Of An Antarctic Soil Nematode, Abigail C. Jackson

Theses and Dissertations

Historical climate disturbances such as glacial cycling and fluctuating stream, lake, and sea levels strongly influence the distribution and evolutionary trajectories of Antarctic terrestrial species. Antarctic invertebrates, with limited long-range mobility, including the ubiquitous sentinel nematode species Scottnema lindsayae, are especially sensitive to climate disturbances. We tested hypotheses associated with the historical geographic and population genetic structure of this species as it occurs across the McMurdo Dry Valleys (MDVs) of Antarctica. In order to reconstruct the influence of climate disturbance and ecological conditions on this species, partial mitochondrial COI gene sequences were sequenced and analyzed from individual S. lindsayae collected …

Core Microbiome To Fingerprint Dust Emission Sources Across The Western United States Of America, Detiare Lisa Leifi

Theses and Dissertations

Over the past century, dust emissions have increased in frequency and intensity due to anthropogenic influences and extended droughts. Dust transports microbes, nutrients, heavy metals and other materials that may then change the biogeochemistry of the receiving environments. The purpose of this study was to find whether unique bacterial communities may provide distinct fingerprints of dust sources in the Western USA. We collaborated with the National Wind Erosion Research Network (NWERN) to identify bacterial core communities (core) of dust from ten NWERN sites, and compared communities to location, soil, and regional characteristics. In order of importance, precipitation levels (F = …