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Austere Lives: Afro-Caribbean Geographies of Political Austerity
No full textAustere Lives traces the racialized, classed, and gendered fallouts of the entrenchment of neoliberal austerity in the long 1980s across the North Atlantic. Through reading the epistolary memoirs of Black, Caribbean-descended subjects who were socialized into the logics of neoliberal austerity as children, the dissertation explores how this transformative era’s commencement of a new iteration of racial capitalism ushered forth our political present. Contributing to existing academic and popular culture reckonings with both the legacies of the long 1980s and also austerity as an everyday lived experience, Austere Lives utilizes epistolary memoir as historiographical method as well as textual object to situate the literary autobiographical among these debates.Despite the authors’ geographic separation and individual differences, they all exhibit similar sober, stoic, skeptical, and anti-romantic sensibilities vis-à-vis the inevitability of racial capitalism’s futures, in which Black bodies will always be in peril. Metaphorically and affectively animated by the contours of austerity as a state policy that strips resources from vulnerable populations - justified by rationales of moderation and economic scarcity - I term the emergent mentality of these memoirists political austerity. The dissertation maps how political austerity differently manifests through these authors’ narratives of their childhoods in the 1980s, foreclosing citizenship and the potential to belong in their countries of birth. Resisting this tragedy, however, are simultaneously produced alternative versions of Black sustainment and relief grounded in community kinship structures, which I term their alternative attachments. Taken together, the chapters of Austere Lives traverse multigenerational Afro-Caribbean Canadian, US, British, and Australian geographies of Black immigrant placemaking from the postwar, end of empire mass migrations to the children these authors took heed to write to several generations later. </p
Spectroscopic Investigation of Protein Dynamics and Small Molecule Binding in PGRMC1 and Fe-S Clusters using Biomimetic Models
No full textIron-containing proteins are essential for processes such as respiration, metabolism, and signaling, relying on cofactors like heme and iron–sulfur (Fe–S) clusters to enable redox reactions and catalysis. Heme proteins (e.g., hemoglobin, cytochrome P450s) mediate oxygen transport and drug metabolism, while Fe–S proteins support electron transfer and carbon fixation.My dissertation focuses on Progesterone Receptor Membrane Component 1 (PGRMC1), a single-pass transmembrane protein involved in steroid signaling, membrane trafficking, and drug metabolism. Overexpressed in cancers, PGRMC1 contributes to chemoresistance, yet its heme binding and protein interactions remain unclear. Using site-directed mutagenesis and spectroscopy, we probed the roles of Tyr113 and Cys129 in heme-induced dimerization and oligomerization. Mutants Y113F and C129S revealed how specific residues govern coordination geometry and dimer stability. UV–vis, EPR, fluorescence, and computational modeling identified distinct coordination states and stoichiometry, showing that heme binding drives dimerization via π-stacking and axial ligation, potentially modulating PGRMC1’s interaction with cytochrome P450s. I further reconstituted full-length PGRMC1 into MSP-based nanodiscs composed of POPC and POPS, mimicking the endoplasmic reticulum membrane. Nanodiscs, validated by SDS-PAGE, SEC, AFM, and DLS, provide a detergent-free platform to study membrane protein structure and interactions.Additionally, I investigated [NiFe3S4]-containing ferredoxins using variable-field Mössbauer spectroscopy, revealing temperature-dependent spin-state equilibria and magnetic interactions. Together, these studies elucidate how heme modulates PGRMC1 structure and function while highlighting the broader significance of metalloproteins in cellular processes, drug resistance and catalysis.</p
Prognostic Awareness and Quality of Life in Patients with Advanced Cancer: Moderation by Anxiety, Age, and Cancer Type
No full textBackground: Prognostic awareness, the understanding of incurable illness, is essential for advanced cancer patients to make informed treatment and end-of-life decisions. Yet, no consensus exists on how to assess it. The Prognostic Awareness Impact Scale (PAIS) measures three domains: cognitive acknowledgment, emotional coping, and adaptive response. While prognostic awareness may cause distress and reduce quality of life (QOL), findings are inconsistent. Examining each domain separately may explain these mixed results.Aims: Guided by a multidimensional framework, this study investigates how different aspects of prognostic awareness affect patient-reported QOL and whether relationships vary by cancer type, anxiety, or age.Methods: We conducted a secondary analysis with a subsample (n = 395) from a cross-sectional study of 632 patients with metastatic solid tumors at Massachusetts General Hospital (2019–2022). Cancer types included breast (23%), gastrointestinal (27.6%), genitourinary (24.3%), and lung (25.1%). Patients completed surveys assessing prognostic awareness (PAIS), anxiety (HADS), and QOL (FACT-G). Analyses tested associations between prognostic awareness domains and QOL, with moderation by cancer type, anxiety, and age.Results: Emotional coping correlated strongly with QOL (r = .52, p Conclusion: Emotional coping and adaptive response, rather than cognitive acknowledgment, are linked to better QOL. These findings highlight the importance of integrating prognosis emotionally and behaviorally to support well-being.</p
Molecular Mechanisms and Polyunsaturated Fatty Acid Sensitivity of Cardiac Ion Channels
No full textThe cardiac action potential is generated by sodium and calcium channels, which depolarize the membrane, and potassium channels that repolarize the membrane. Loss of function of potassium channels hERG and KCNQ1/KCNE1, which generate IKr and IKs currents, are the most common cause of Long QT Syndrome (LQTS). LQTS is an arrhythmia disorder predisposing individuals to ventricular fibrillation and sudden cardiac death, characterized by delayed repolarization and prolonged QT interval. Some polyunsaturated fatty acid (PUFA) analogs are KCNQ1/KCNE1 activators that could reduce QT interval and lessen LQTS risks. To understand PUFA analog effects on hERG channels, I tested DHA-glycine and LIN-glycine on Xenopus oocytes expressing hERG channels, showing these PUFAs do not affect hERG channel activation, inactivation or recovery. We evaluated the arrhythmia-associated mutation R231C in KCNQ1/KCNE1 channels, measuring voltage sensor movement and ion permeability in oocytes expressing WT and R231C-mutated channels. We propose S4 is in the intermediate-activated state in both KCNQ1 R231C and KCNQ1/KCNE1 R231C channels. Finally, this project investigates structural details of KCNE1-induced rearrangements when the modulatory subunit binds KCNQ1. We mutated residue K285 on the S5-P loop and examined mutation effects on channel sensitivity to PUFA analogs with and without KCNE1 using Two-Electrode Voltage Clamp electrophysiology. The mutation causes PUFA analogs to have different effects on conductance and voltage dependence in KCNQ1 alone versus KCNQ1/KCNE1 complex, suggesting the S5-P loop changes conformation when KCNE1 binds KCNQ1. Overall, this work aims to understand the complex pharmacological interactions between PUFA analogs and potassium cardiac ion channels, and also to investigate the role of mutations and KCNE1 in modulating channel function.</p
Shots at Success: A Mixed Methods Study of Barriers and Facilitators to Long-Acting Injectable Antiretroviral Treatment (LAI-ART) at Florida Syringe Service Programs (SSPS)
No full textPeople who inject drugs (PWID) face significant barriers to HIV care, yet long-acting injectable antiretroviral therapy (LAI-ART) offers a promising alternative to daily oral regimens. Syringe service programs (SSPs) may be uniquely positioned to deliver LAI-ART, but implementation in these settings remains underexplored. This convergent mixed-methods study examined the acceptability and feasibility of LAI-ART across three Florida SSPs by identifying multilevel barriers and facilitators. Quantitative data from 203 SSP clients living with HIV showed strong interest in LAI-ART, especially among younger participants and those who recently used methamphetamine, though many were excluded by viral suppression requirements. Qualitative interviews with SSP staff (n = 7), guided by the Consolidated Framework for Implementation Research (CFIR), revealed operational challenges, medication storage, staffing, cost, and lack of planning, alongside facilitators such as team collaboration, peer outreach, and alignment with harm reduction values. Findings suggest that while LAI-ART is acceptable to clients and staff, successful integration will require tailored strategies like expanded eligibility, mobile delivery, and sustainable reimbursement models. This study highlights the potential for SSPs to expand HIV treatment access for PWID and provides implementation guidance to support equitable scale-up.</p
Developing Oligonucleotide Combinations for Neurological Disorders
No full textOligonucleotides are short nucleic acid polymers that have emerged as a novel class of therapeutics, showing clinical success in the past decade due to advances in chemistry. However, their broader clinical application remains limited by delivery challenges, restricted tissue distribution, and lack of polypharmacology. While many are addressing delivery and distribution, few have explored how different oligonucleotides work in combination or how to design single oligonucleotides that act on multiple targets. This is especially relevant for neurological disorders, most of which are polygenic.In the first part of this dissertation, I investigated how single-stranded antisense oligonucleotides (ASOs) with different mechanisms act in tandem. Using ASOs that upregulate SCN1A mRNA, I demonstrated synergistic mRNA upregulation. This is clinically significant, as SCN1A deficiency causes Dravet Syndrome (DS), a severe childhood epilepsy. Upregulating SCN1A is a promising treatment for DS.In the second part, I explored combinations of small interfering RNAs (siRNAs) to reduce amyloid beta (Aβ) and phosphorylated tau (p-tau)—hallmarks of Alzheimer’s Disease (AD). This led to the discovery of key effects involving mTOR signaling and the development of a siRNA combination targeting APP and MAPT to reduce both Aβ and p-tau.Lastly, I developed a novel method to chemically link two oligonucleotides into a single, multi-targeting molecule. Altogether, my dissertation lays the groundwork for designing next-generation, multi-targeting oligonucleotide therapeutics.</p
Exploring the Influence of Peripheral Macronutrient Utilization in Regulating Metabolism-Fueled Tumorigenic Glioblastoma Stem Cells
No full textMetabolic rewiring of cancer stem cells plays a pivotal role in promoting tumorigenicity and recurrence in glioblastoma (GBM), making tumor recurrence inevitable. The presence of glioblastoma stem cells (GSCs) is a major factor behind the poor prognosis of GBM. Despite trimodal therapy, surgical resection, temozolomide chemotherapy, and radiotherapy, GSCs often invade into eloquent brain areas, become unresectable and resistant to treatment, promoting recurrence. GSCs leverage the postoperative wound healing period to invade into critical brain regions, making therapeutics less effective due to the inability to seek and destroy these GSCs. The recurrent nature of GBM negatively impacts conventional treatment strategies leading to a growing need for alternate therapeutic strategies. In this dissertation, we demonstrate a linear relationship between metabolic substrate utilization, stemness, and tumorigenicity in GBM. Transcriptomic analyses of patient derived GSCs and using known inhibitors of metabolic substrate utilization indicated that fat utilization fuels stemness and tumorigenicity of GSCs. We identified a distinct stemness-driven genomic difference between recurrent and newly diagnosed tumors, emphasizing the role of metabolism in fueling recurrence. Through metabolic studies in the patient derived GSCs, we were able to establish that the GSCs majorly rely on utilizing fatty acids by performing fatty acid oxidation (FAO), while depending less on glucose or glutamine oxidation for their energy requirements. We were able to determine that inhibiting the preferred metabolic substrate utilization, i.e., FAO, in GSCs by knocking out CPT1A contributes to a remarkable change in stemness potential and a significant reduction in the tumorigenic potential of the GSCs. we study the effect of a non-invasive and non-pharmacological intervention by utilizing a low carbohydrate high fat diet (LCHFD) in delaying and/or stopping proliferation of GSCs, with an aim to leverage this understanding to answer the clinically unmet needs. </p
Deep Learning for Predicting Cancer Prognosis
No full textAccurate cancer prognosis is critical for personalized treatment but remains challenging due to high-dimensional, heterogeneous biomedical data and limited sample sizes. This dissertation proposes a novel deep learning framework integrating supervised contrastive learning (CL) and a semi-supervised mean-teacher model, both optimized for survival prediction via the Cox proportional hazards loss.First, we apply supervised CL to whole-transcriptome gene expression data across 19 cancer types from The Cancer Genome Atlas (TCGA). This approach yields compact, biologically meaningful embeddings that significantly enhance the concordance index (c-index) and risk stratification compared to traditional methods. Notably, the model exhibits robust out-of-distribution generalization on external CPTAC and DKFZ cohorts without retraining.To improve robustness and leverage unlabeled data, we introduce a semi-supervised mean-teacher architecture. By enforcing student-teacher consistency using the proposed Cox loss, this approach achieves a increase in c-index over supervised baselines. Incorporating a large unlabeled external BRCA cohort further elevates the TCGA BRCA prognostic c-index to 0.89.The framework is subsequently extended to multimodal analysis by integrating diagnostic whole-slide images (WSIs). We developed a pipeline to automatically segment tumor regions and encode features using pre-trained models, including ResNet and DINOv2. These WSI features are fused with genomic data via a mutual attention mechanism, yielding an additional 5% improvement in the c-index over the unimodal model.This dissertation presents a unified semi-supervised, multimodal framework that synergizes gene expression and imaging data. The resulting methods and open-source tools establish a scalable foundation for next-generation precision oncology, effectively bridging advanced deep learning with clinical practice.</p
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
Evaluation of Statin Use, Drug Interactions, and their Associations with Lipid Changes in People with HIV
No full textPeople with HIV (PWH) have a greater risk for cardiovascular disease (CVD) than the general population. Managing cholesterol levels with medications known as statins (hydroxymethylglutaryl-coenzyme A reductase inhibitors) effectively prevents CVD by reducing low-density lipoprotein (LDL) cholesterol and certain systemic inflammation indices.This dissertation utilizes data from the Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS) to 1) estimate the prevalence of statin use among PWH, compare it with people without HIV (PWOH), and evaluate the factors affecting statin use for both PWH and PWOH; 2) evaluate the association between statin use and LDL changes at follow-up and determine whether this association differs between PWH and PWOH; and 3) evaluate the longitudinal association between statin use (and types) and LDL changes over time among PWH, and examine the interactions between statins and antiretroviral therapy (ART) regimens in relation to LDL changes over time.We found that the prevalence of statin use was 39% (95% CI: 36–42%) among PWH and 37% (95% CI: 33–42%) among PWOH. After accounting for confounders, PWH were more likely to use statins than PWOH. Among PWH only, non-Hispanic Black adults were less likely to use statins than non-Hispanic white adults. Furthermore, statin users were more likely to meet a ≥30% LDL reduction goal than non-users and this association was not moderated by HIV status. Also, atorvastatin and rosuvastatin were associated with the lowest LDL levels over time, and we observed lower LDL levels over time for atorvastatin users on protease inhibitor-based therapy compared to atorvastatin users on integrase strand transfer inhibitor (INSTI)-based therapy.This dissertation, based on real-world data, emphasizes that while the use and effectiveness of statins for achieving desired LDL outcomes may be comparable between PWH and PWOH, significant racial/ethnic differences exist. The findings provide insights that can inform preventive cardiovascular care for people with HIV receiving ART