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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
Investigation of OR51E1 Expression and Signaling in Prostate Cancer and Beyond
No full textProstate cancer is a leading cause of cancer-related death among men, highlighting the need to identify novel molecular targets and signaling pathways. This thesis investigates olfactory receptor 51E1 (OR51E1), a G protein-coupled receptor expressed in prostate tissue, as a potential contributor to prostate cancer biology. A membrane-based GTPγS trypsinolysis assay in LNCaP cells was employed to examine receptor-mediated signaling following activation by the putative agonist EN2. Although technically challenging, this approach represents an initial effort to define downstream G-protein coupling in this context. Complementary transcriptomic analyses of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) datasets revealed consistent upregulation of OR51E1, along with the related receptor OR51E2, in prostate tumors compared to normal tissue. Elevated expression of these receptors was also observed in several other cancer types, underscoring their potential biological relevance beyond the prostate. Together, these findings provide early insight into the role of ectopically expressed olfactory receptors in cancer and establish a foundation for future studies of noncanonical GPCR signaling in tumor progression.</p
Graph Neural Networks and Uncertainty Estimation in Healthcare: Advancing Patient-Specific Clinical Predictions
No full textDiverse clinical data, encompassing electronic health records, genomic profiles, and medical imaging, encode complex relationships between clinical variables, patients, and outcomes. Graph-based learning provides a natural framework for modeling these relationships, but effective representation learning in the face of data heterogeneity and the need of reliable uncertainty estimates for high-stakes clinical predictions remain open challenges. This dissertation develops a novel machine learning framework that integrates graph neural networks for relational modeling, multimodal learning for comprehensive data fusion, and Gaussian process-based uncertainty estimation for reliable predictions across two critical clinical tasks: sepsis onset prediction and breast cancer molecular subtype classification. This framework employs multimodal learning strategies to fuse information beyond structured EHRs, including temporal and relational dependencies from the MIMIC-IV dataset for sepsis and clinical, multi-omics, and imaging data for breast cancer. Spectral-normalized graph transformer convolution layers extract structured representations, while a random feature-based Gaussian process layer captures and quantifies predictive uncertainty. Integrated gradients provide interpretable attributions across temporal features, offering insight into global and patient-level prediction drivers. Uncertainty-aware modeling enhances reliability, providing well-calibrated confidence estimates that support clinical decision-making. This research demonstrates that the novel combination of graph-based learning, multimodal data fusion, and uncertainty estimation significantly improves predictive modeling in healthcare by addressing key challenges in data integration, representation learning, and uncertainty quantification. Future work will explore scaling multimodal integration, improving real-time inference, and extending interpretability methods to support clinician-centered deployment.</p
"This printing blood": Reproductive Materialities in Early Modern English Literature
No full textThis dissertation examines the language of reproduction in early modern literary and non-literary texts by centering a shared vocabulary of liquidity and fluidity. This fluid language is found in Classical texts such as Ovid’s Metamorphoses which were formative in the early modern classroom and consistently appears in genres including the sonnet sequence, lyric poetry, medical texts, agricultural manuals, and recipe books. Chapter 2 examines reproductive language in William Shakespeare’s Sonnets and Philip Sidney’s Astrophil and Stella sequence, finding that the fluid vocabulary destabilizes the poetry’s portrayal of literary production. Chapter 3 applies a similar fluid reading to the language of patronage verse letters by John Donne to his female patron, the Countess of Bedford. The chapter argues that the language employed in this genre hinges on the understanding of the female body as fluid. Chapter 4 reads misogynist manuscript lyric together with woman authored receipt books to examine the portrayal of the reproductive female body as both corrupt and erotic. Bodily fluids are central to interpreting the status of the body and exerting control over it. Chapter 5 reads the dairy as a site of reproductive female labor, centered around milk and its physical and interpretive possibilities, rooted in cheesemaking as a common metaphor for pregnancy. Ending with a reading of Hester Pulter’s childbirth poetics, this dissertation centers women’s bodies in creative narratives that often elide their lived experiences in metaphorical representations. </p
Vascular Contributions and Cerebral Microstructure in Ethnically Diverse Individuals with Varying Cognitive Status using Advanced Diffusion Magnetic Resonance Imaging
No full textDementia is a significant public health challenge, with research indicating greater risk in Hispanic adults. Macrostructural MRI studies suggest the vascular contribution to dementia may be more pronounced within the Hispanic population than the neurodegenerative. However, advanced diffusion MRI is sensitive and specific to brain microstructural integrity associated with cognitive decline and may better detect and characterize ethnic variation in MRI biomarkers of dementia. While advanced diffusion MRI has recently become implemented in clinical studies of brain health and dementia, there is insufficient representation of Hispanic individuals. This dissertation addresses this gap in literatures by using advanced diffusion MRI to better characterize brain microstructural integrity in an ethnically diverse cohort. We report ethnic variation in the relationship between brain microstructure and cognition and found the importance of these relationships varied by ethnicity within each sex group. A stronger association was found for advanced diffusion MRI metrics in the hippocampus in non-Hispanic adults, while the vascular contribution was suggested to be stronger in Hispanic participants. Furthermore, sex-specific analysis revealed microstructural integrity in the hippocampal, amygdala, and cerebral cortex were strongest in non-Hispanic women and Hispanic men, while the vascular contribution was more pronounced in Hispanic women. We also found advanced diffusion MRI models were sensitive and specific to detecting and characterizing this variation. This study adds to the literature by presenting a precision medicine approach to characterizing potential interventional biomarkers of dementia. Further research is encouraged to study these advanced diffusion MRI models in larger and more ethnically diverse cohorts for better outcomes for people of all backgrounds. </p
Reducing Harm Among Harm Reductionists: A Scoping Review of Harms Experienced by Peer Service Navigators in Harm Reduction Settings
No full textPeer service navigation has strong evidence of enhancing health outcomes across various healthcare settings, with the potential to play a critical role in harm reduction settings by providing accessible, stigma-free care to people who inject drugs, who often experience both health-related harms associated with injection drug use and barriers to care. Due to the dual identity of being both service providers and individuals with lived experience of substance use, peers face unique occupational harms, including high-stress occupational environments and burnout. This scoping review examines the experiences and harms encountered by peer service navigators working within harm reduction settings. Using a pre-defined search strategy. A comprehensive search across five electronic databases identified 6,470 studies eligible to be screened, with 63 studies ultimately eligible for full-text review, and four studies included. Data was extracted using a structured coding template, describing key study characteristics, and guided by the Axis of Nested Hierarchies framework, categorizing findings into above water (e.g., organizational and societal) and underwater (e.g., individual and biological factors) themes, as well as recommendations for action and research. All studies reported both benefits and harms in the above water domain (e.g., social connection and workforce harms), while Two of the four articles documented underwater benefits (e.g., reciprocal learning and recovery maintenance), and three of the four articles documented underwater harms (e.g., recovery maintenance, personal resource strains, and vicarious/dual trauma). All four studies provided recommendations for action (e.g., targeted support, retention, and bolstered benefits) and research (e.g., peer perspectives and longitudinal workforce outcomes). This review highlights the urgent need for interventions supporting peer service navigators in harm reduction settings. To best support public health priorities, additional research is needed to identify longer-term, structural leverage points.</p
Expanding Regulatory Cells in GVHD Target Tissues: In Vivo Administration of TL1A-Ig Fusion Protein and IL-2
No full textThe current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD), includes long-term pharmacological immune suppression, by which unwanted toxic side effects may accompany. Targeted allo-regulatory immunotherapies may serve to replace pan-immunosuppression. Investigations to manipulate regulatory cell populations to orchestrate transplant immune regulation are of value. Previous studies involving in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with the targeting of the IL-2 high-affinity receptor, CD25, with IL-2, resulted in transient but marked (~>30%) Treg expansion in donor mice spleen and lymph node that allowed for sufficient cell numbers for adoptive transfer to recipient mice, mediating suppressive activity with measurable effect. To further delineate the novel in vivo Treg expansion using TL1A-Ig in combination with low-dose IL-2 (IL-2LD) and its impact on the regulation of GVHD, these studies are analyzing alterations of recipient GVHD target organs at the cellular and microbiome level before and early post-transplant. TL1A-Ig+IL-2LD pretreatment induced a Treg expansion, persisting early post-aHSCT, leading to diminished GVHD and improved transplant outcomes. The expansion was accompanied by increased frequency of stable and functionally active Tregs, as evidenced by in vitro assays using cells from primary GVHD target tissues. In contrast to the infusion of donor Treg cells, the strategy developed here resulted in immunosuppressive target tissue environments in the recipient before receiving donor alloreactive T cells and successful preservation of GVL responses. Results of this study should allow for the harnessing of better adaptive cellular immunotherapy designed to manipulate regulatory cellular compartments of the recipient for GVHD, circumventing the need to produce large numbers of ex vivo manipulated Tregs and providing translational approaches to improve aHSCT outcomes. </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 and Evaluation of a Single Session Intervention for Parent Distress Tolerance
No full textInterventions for child internalizing and externalizing disorders increasingly utilize parent-directed approaches that rely on caregivers to facilitate treatment skills. However, parents experiencing emotional difficulties and their children demonstrate less benefit from child treatments compared to parents with greater emotion regulation capacity. Improving parent emotion coping may be key to increasing child treatment efficacy. Parents may also be unlikely to prioritize their emotion coping over their child’s due to limited resources and/or other significant time and cost burdens related to seeking their own services. The current study sought to develop and test a single-session intervention (SSI) for parent distress tolerance (DT) using a mixed-methods design. The current study used rapid qualitative analysis to inform the development of a SSI focused on parent DT. The SSI, named Parents THRIVE, was then compared to a control SSI using a randomized-controlled trial (RCT) with N = 55 parents of children 6-17 years old. Measures were collected before and two-weeks after receiving the SSI. Following the RCT, participants who received Parents THRIVE completed qualitative interviews. Results showed significant group differences from baseline to post-treatment in the DT appraisal subscale such that, controlling for baseline parent experiential avoidance, Parents THRIVE participants reported improvements in appraisals of distress while participants in the control condition reported decreases in their appraisal DT. Results also showed trending group differences over time in depression, favoring the Parents THRIVE condition. SSIs that focus on single mechanisms of change can offer a fast, free, digital, and potentially effective approach to helping parents improve their capacity to tolerate distress and may enhance their ability to benefit from child treatments. Future directions should utilize feedback obtained from participants to improve and further test the SSI as a stand-alone and adjunctive intervention for parents experiencing emotional distress.</p
TransAfroAmericas: Confronting and Debunking Myths of Whiteness in Brazil, the United States, and Colombia
No full textWith the formal abolition of slavery in the second half of the nineteenth century, white supremacy promoted several forms of racism in different parts of the Americas. In my dissertation, I look at the historical moment between the 1910s and 1950s, interweaving the works of three Black writers: Lima Barreto (1881-1922) from Brazil, Langston Hughes (1901-1967) from the United States, and Manuel Zapata Olivella (1920-2004) from Colombia. Drawing on Maurice Berger’s concept of “myths of whiteness” and Charles Mills’ idea of the racial contract, I examine how these authors used first-person narratives in colonial languages (Portuguese, English, and Spanish, respectively) to develop anti-colonial projects. To do so, I coin and develop the expression “TransAfroAmericas” to name the system of Black individuals that have challenged white supremacy in the “new world” since the sixteenth century. Within this system, I advocate for a multifaceted representation of race, developing the plural notion of “Blacknesses.” Based on an intersectional approach beyond the oft-studied constructions of gender, race, and class, I focus on three less-studied social markers: disability, sexuality, and nationality. In this reading, I consider the racialized components of the medical discourse of sanity and madness in Brazil, the white-based discourse of heteronormativity in the United States, and the exclusionary discourse of the American dream in Colombia. Thus, I analyze Barreto’s "Diário do hospício" written as a Black psychiatric patient institutionalized in an asylum, Hughes’ ambiguous expression of sexuality in his autobiographies "The Big Sea" and "I Wonder as I Wander," and Olivella’s accounts as a Black Colombian traveling in the United States in "He visto la noche.