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Investigating the Interaction of Huntingtin Protein with Copper: Insights into Huntingtin Protein Aggregation Pathways and Therapeutic Implications
No full textHuntington’s Disease (HD) is a fatal, inherited neurodegenerative disease characterized by the expansion of polyglutamine (CAG; polyQ) repeat consisting of 36 or more glutamines (mhtt) in the huntingtin (htt) protein. While mhtt is broadly associated with HD severity, the depletion of wild type (WT) htt (fewer than 36Qs) is also recognized as a contributing factor to disease progression. Similarly, elevated metal levels have been observed in HD patients, however the molecular interactions of biorelevant metals (particularly, copper) with htt, and their effects on protein aggregation, remain poorly understood.This dissertation provides insight into the interaction of copper with an in vitro htt model (N171-17Q), using a combination of molecular biology, biochemical and biophysical techniques. We demonstrated that addition of equimolar or higher concentrations of Cu(II) induces time- and temperature- dependent oligomerization/aggregation of htt. Additionally, chelation assays and mass spectrometry confirm the rapid reduction of Cu(II) in the presence of N171-17Q htt and direct binding of multiple copper ions per protein revealing a complex Cu:htt speciation profile. Site-directed mutagenesis identifies specific amino acid residues as key mediators of copper binding, redox activity and aggregation propensity in htt.Together, these findings provide the first direct evidence that coordination of redox-active copper drives the oligomerization/aggregation of WT htt, independent of polyQ expansion. This work also highlights critical role of specific amino acid-metal interactions, offering a new avenue for therapeutic strategies aimed at preserving WT htt function and mitigating early aggregation. Furthermore, this study establishes a foundation for future investigations exploring how similar conditions may influence the aggregation behavior and metal binding in the pathological form of protein
Biomarkers of the Inflammatory Response Following Brain Injury
No full textBrain injury remains a devastating condition with long-lasting consequences. Brain injury triggers a cascade of pathophysiological processes that contribute to both immediate and long-term damage. Excessive inflammation disrupts the repair and regeneration of damaged neurons, accelerates neuronal degeneration, and predisposes patients to developing neurodegenerative conditions. A significant consequence of brain injury is cognitive, emotional, and physical impairments, leaving patients unable to make their own healthcare decisions. In such cases, designated proxies are tasked with making difficult decisions on behalf of the patient. The accurate prediction of functional recovery and long-term outcomes remains challenging due to the heterogeneity of the condition and individual patient factors, such as age, pre-existing health conditions, and genetic predispositions to comorbidities. Biomarkers have shown promise in identifying injury severity and providing insights into secondary injury mechanisms. There is a pressing need to identify a set of biomarkers that can be integrated into multi-modal assessments to reliably predict patient outcomes. Inflammasome proteins have gained attention as essential regulators of the neuroinflammatory response following injury, thus extensive research has been conducted to understand their roles and therapeutic potential, including biomarker potential in TBI. Inflammasomes are multiprotein complexes of the innate immune system. Upon activation, inflammasome complexes lead to cleavage of pro-inflammatory cytokines. It has been previously established that inflammasome overactivation contributes to poor outcomes following brain injury. This work in this thesis explores novel biomarkers associated with the inflammatory response in aneurysmal subarachnoid hemorrhage (aSAH) and acute brain injuries, including traumatic brain injury (TBI), subarachnoid hemorrhage, and intracerebral hemorrhage.</p
Analyzing the Effects of COVID-19 on the Catering Industry in Florida Using Machine Learning
No full textBy combining consumer spending records and points of interest (POI) data from SafeGraph and aggregating them to the block group level, this thesis investigates the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on customer traffic at restaurants in Florida. It compares changes in customer traffic patterns and recovery — including their origins (local, within Florida, and out-of-state) — across three phases: before, during, and after the pandemic. Using advanced spatiotemporal analyses, the study finds that the pandemic made restaurant customer traffic more localized and that suburban areas experienced less fluctuation and recovered more quickly than urban cores. Results from machine learning (ML) models further confirm that local neighborhood characteristics (e.g., ethnicity) remained the most important factors contributing to a restaurant’s resilience during the pandemic. Additionally, traditional economic geography determinants, such as agglomeration effects, regained importance in explaining customer traffic patterns in the post-pandemic phase. These findings suggest that although restaurant customer behavior shifted during the pandemic, locational theory continues to provide a robust framework for understanding the spatial dynamics of restaurant customer traffic.</p
Defining the Role of Vitamin B12 in the Progression of Myeloid Malignancy
No full textClonal hematopoiesis (CH) is a pre-malignant condition that can progress to myeloid malignancy, yet the factors driving this transition remain poorly defined. Elevated serum vitamin B12 levels have been associated with increased risk of myeloid malignancy in otherwise healthy individuals and at the time of diagnosis of acute myeloid leukemia (AML). However, the relationship between B12 levels and CH has not been previously established. Analysis of the All of Us research database revealed a significant association between elevated serum B12 and CH, suggesting a potential role for B12 in early myeloid disease evolution.Environmental stressors such as chronic inflammation and poor diet promote CH progression, and inflammation due to increased intestinal permeability stimulates the expansion of pre-malignant myeloid cells. Dietary one-carbon (1C) metabolites, including B12, regulate gut microbial production of short-chain fatty acids (SCFA) that strengthen gut mucosal integrity. In a Tet2-deficient mouse model of CH, high B12 supplementation either via dietary or parenteral administration elevated serum B12, induced a myeloid lineage bias, and increased circulating pro-inflammatory cytokines and responsiveness to microbial stimuli. These changes were accompanied by loss of SCFA-producing microbiota, reduced SCFA levels, and increased gut permeability. Supplementation with SCFAs reversed the myeloid bias, implicating microbiome-mediated inflammation as a key mechanism by which B12 influences CH progression.In leukemic models, high B12 increased intracellular Met, SAM, and succinate, consistent with enhanced activity of B12-dependent enzymes methionine synthase and methylmalonyl-CoA mutase. These metabolic alterations promoted DNA hypermethylation and reduced hydroxymethylation, hallmarks of myeloid transformation. Dietary supplementation with B12 and methionine accelerated leukemia development, while genetic ablation of the B12 transporter CD320 abrogated disease, highlighting B12 metabolism as a potential therapeutic vulnerability in AML.</p
Unveiling the Holistic Pain Experience: Integrating Neural Correlates, Pain Drawings, and Pain Distribution in Spinal Cord Injury Patients with Neuropathic Pain
No full textAnnually, a range of 250,000 to 500,000 new cases of spinal cord injuries (SCIs) have been documented, with approximately 60% of SCI patients experiencing the onset of neuropathic pain (NP) within the first year of injury. NP is a chronic and debilitating condition that impairs mental health and quality of life. NP has been demonstrated to disrupt the perception of body representation (BR). To investigate these BR deficits, I utilized neural correlates obtained from electroencephalogram (EEG) recordings during a laterality-judgment task. Specifically, event-related potentials (ERPs) were generated from the EEG recording to correspond to pertinent body-representation potentials. Furthermore, an exploration of the psychosocial impact of neuropathic pain was conducted, establishing associations between this impact and neural correlates. Additionally, the second aim investigated the role of pain location in BR in individuals with SCI and NP. This investigation aimed to not only shed light on the neural mechanisms underlying BR deficits but also to contribute valuable insights into how pain may change the way we see our own bodies. Moreover, by elucidating the intricate relationship between pain location and body representation in individuals with spinal cord injuries and neuropathic pain, this investigation holds the potential to inform tailored interventions aimed at alleviating both physical and psychological burdens, ultimately improving the quality of life for those affected by this challenging condition. To further investigate a holistic understanding of the pain experience, a comprehensive methodology for assessing pain drawings was developed and implemented at set time points. This method provides a quantifiable measure of intervention effectiveness, while also providing critical information about pain type, pain intensity, and pain interference.</p
Investigate the Role of ROS and RNS in Axon Degeneration
No full textFollowing injury, sensory neuron terminals rapidly degenerate before initiating regeneration. While reactive oxygen species (ROS) are known to promote axon regeneration through epidermal mechanisms, their role in axon degeneration remains unclear. A hallmark of neurodegenerative diseases is the formation of mitochondrial ROS (mitoROS), but whether mitoROS contribute to injury-induced axon degeneration was unknown.Here, I demonstrate that mitochondrial superoxide in cutaneous sensory neurons drives axon degeneration following fin amputation. Further analysis showed that reactive nitrogen species (RNS), specifically peroxynitrite, are formed by superoxide and contribute to axonal destruction. I identified putative nitration and nitrosylation sites at conserved residues in NMNAT, a key regulator of SARM1-driven axon degeneration. Modulation of ROS/RNS with the ROS scavenger NADPH significantly reduced amputation-induced sensory axon degeneration while enhancing the regeneration of cutaneous axons. Furthermore, NADPH co-administration mitigated axon degeneration under pathological conditions induced by paclitaxel, suggesting that oxidative stress-induced axon degeneration extends beyond injury models and may underlie broader neurotoxic mechanisms.To further investigate the role of ROS in paclitaxel-induced axon degeneration, I examined the expression and function of the ROS-producing enzyme Nox1 in the presence and absence of paclitaxel. Paclitaxel treatment induced a nuclear translocation of Nox1 in epidermal keratinocytes, leading to increased nuclear ROS formation and upregulation of mmp13 transcription. Sensory axon degeneration was prevented in cyba-/- mutants, which impair Nox1 activity, confirming a role for Nox-induced ROS in paclitaxel neurotoxicity. These findings suggest that ROS contribute to axon degeneration through distinct mechanisms: extrinsically via keratinocyte-mediated Nox1 signaling in paclitaxel-induced pathology and intrinsically through mitochondrial superoxide in acute injury-induced degeneration.</p
Bonnethead Shark (Sphyrna tiburo) Aggregations: Drone-Based Monitoring in Biscayne Bay, Florida
No full textBonnethead sharks (Sphyrna tiburo) form aggregations, yet the ecological and reproductive significance of these gatherings remains poorly understood. This study investigated aggregation patterns, aggregation habitat use, and reproductive behavior of bonnethead sharks in Biscayne Bay, Florida, using drone-based monitoring and hormone analysis. Drone surveys were conducted on 82 days, with a total of 1,751 bonnethead sightings recorded. Aggregations, defined as groups of five or more individuals, occurred on 56 of the 82 survey days, with the largest recorded aggregation of 117 sharks observed in August, coinciding with reported pupping season. Aggregation events were analyzed in relation to environmental variables using a generalized linear model. Results indicated that increases in water temperature increased aggregation probability by 27% and aggregation size by 16%, while human presence significantly decreased aggregation probability by 95% and aggregation size by 81%. Additionally, greater lunar illumination increased aggregation size by 164%. Drone-based behavioral observations confirmed social interactions previously described in captive bonnethead sharks and revealed rarely observed behaviors, including repeated mating attempts. To complement drone observation data, plasma samples from 91 female bonnethead sharks (collected from 2019–2024) were analyzed for 17β-estradiol, progesterone, and testosterone using enzyme immunoassays. Hormone analysis confirmed previously reported reproductive patterns in bonnethead sharks, with particularly elevated testosterone concentrations (96-170 ng/ml) detected during the sperm storage period. This study enhances our understanding of the environmental and biological factors influencing bonnethead aggregations, reinforcing the connection between aggregations and reproductive cycles.</p
The Development of an International Computational Framework to Optimize and Size Premise Plumbing Systems
No full textAccurately estimating design flow rates is essential for sizing premise plumbing components, yet prediction remains difficult because demand depends on occupancy, fixture characteristics, regional behavior, and event timing. Current design methods still rely on approaches developed in the 1940s, which studies show consistently overestimate simultaneous flow rates and lead to oversized systems. Oversizing increases capital costs, raises water age and disinfectant decay, promotes microbial growth, and reduces pump efficiency. To address these limitations, empirical, probabilistic, and stochastic methods have been explored. Stochastic models offer the greatest potential because they represent behavioral variability, but existing versions often rely on outdated assumptions, exclude key behavioral factors, or lack practical implementation pathways. This dissertation introduces a novel demand estimation framework using a stochastic event-generation model that applies events to a user-defined digital twin of a plumbing system. The work includes four components: (1) evaluation of assumptions and distributions used in existing stochastic models against regional empirical data; (2) identification of socioeconomic, demographic, and housing factors influencing water use using MGWR and OLS; (3) analysis of high-resolution datasets to determine whether consumption patterns reveal latent user populations; and (4) development of a Monte Carlo simulation that generates water-use events and routes them through the digital twin to estimate simultaneous hot- and cold-water flow rates without relying on unrealistic assumptions.</p
Electromagnetic System with Metastable Spatial-Temporal Considerations for Neural Stimulation and Recording
No full textThis dissertation presents an interdisciplinary study of wireless neural interfacing, leveraging a high spatial and temporal precision electromagnetic stimulation system for neural modulation. A novel magnetic stimulation system was designed and its feasibility validated via multiphysics modeling in COMSOL, which demonstrated that a high-frequency alternating magnetic field can induce suprathreshold electric fields in tissue to reliably evoke neural action potentials. Based on the modeling results, a custom high-frequency amplifier and air-core coil were developed and bench-tested, confirming the ability to deliver the required field strength for neural stimulation. Using an anesthetized rodent experiment, the system achieved successful in vivo peripheral nerve (sciatic) stimulation: the wireless magnetic stimulus elicited consistent neural responses, evidenced by reproducible limb motion and thereby validating contactless electromagnetic neural activation. In addition, theoretical work was undertaken to support future wireless neural recording using MENPs. This effort analyzed the magnetoelectric coupling at the neuron interface and introduced a proof-of-concept lock-in detection scheme, indicating that MENPs could function as wireless transducers for capturing neuronal signals. Overall, by bridging physics-based modeling, engineering design, and neuroscience experimentation, this work delivers a validated electromagnetic stimulation platform and establishes the foundation for next-generation, fully wireless brain–machine interfaces.</p
Estimating Aerosol-Derived Phosphorus and Iron Fluxes to the Surface Ocean: Looking Beyond Mineral Dust to Understand the Aerosol Indirect Effect on Biogeochemical Cycles
No full textWhile many factors affect climate via impacts on radiative forcing, the magnitude of impacts associated with aerosol-related processes remains the most uncertain. Two mechanisms through which aerosols impact radiative forcing have been considered in climate models and projections for decades. However, a third mechanism, the “aerosol indirect effect on biogeochemical cycles,” has only been considered in the last 15 years. This mechanism describes aerosols’ ability to impact atmospheric carbon dioxide concentrations via releasing nutrients that stimulate photosynthetic growth and/or nitrogen fixation upon deposition. For example, in the North Atlantic Ocean, mineral dust deposition releases significant amounts of phosphorus (P) and iron (Fe), which stimulate phytoplankton production, nitrogen fixation, and carbon dioxide drawdown. However, we lack definitive estimates for P and Fe bioavailability in mineral dust, and little is known about nutrient release from other aerosol types like volcanic ash. My work shows that P solubility in mineral dust deposited in the North Atlantic has declined since the 1990s due to air pollution regulations like the Clean Air Act. I also demonstrate that volcanic ash, in addition to mineral dust, can serve as a source of soluble and bioavailable P to seawater. Finally, Fe in mineral dust is nearly 10% bioavailable to marine phytoplankton, while Fe in volcanic ash is only about 6% bioavailable. I show that aerosol mineralogy and interaction with acidity prior to deposition are the dominant factors controlling aerosol Fe bioavailability. My work provides evidence that atmospheric aerosols besides mineral dust provide important fluxes of soluble and bioavailable nutrients to the North Atlantic Ocean, and the relative importance of non-dust aerosol in this region is likely increasing with air quality regulations that have reduced nutrient solubility in mineral dust.</p