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THE ROLE OF THE GPI-ANCHOR CLEAVING ENZYMES GDE2 AND GDE3 IN SYNAPTIC FUNCTION
No full textNeurodegenerative diseases such as Alzheimer’s Disease (AD) and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD) are characterized by progressive neuronal dysfunction, synaptic loss, and accumulation of pathological protein aggregates, leading to cognitive, behavioral, and motor impairments. Central to the pathology of these disorders is synaptic dysfunction, which disrupts neuronal communication and contributes to disease progression. As research increasingly highlights the importance of synaptic regulation and intercellular communication in maintaining brain health, novel molecular pathways involved in these processes need to be investigated. The Glycerophosphodiester Phosphodiesterase (GDE) family of proteins, specifically GDE2 and GDE3, have emerged as important regulators of neuronal and glial development and neuronal survival. GDE2 is expressed in neurons, among other cell types, and plays important roles in neurogenesis, synaptic protein maintenance and neuronal survival, with loss of function linked to key features of AD and ALS/FTD pathology. Meanwhile, GDE3, predominantly expressed in astrocytes and oligodendrocyte precursors, also regulates aspects of nervous system development and has recently been shown to release a distinct population of extracellular vesicles (EVs), although its impact on neuronal function remains unexplored.
Here, through a combination of behavioral, electrophysiological, and molecular approaches, I demonstrate that loss of GDE2 leads to behavioral deficits similar to those observed in AD and ALS/FTD models and causes abnormalities in hippocampal synaptic structure, function, and plasticity. I further show that GDE2 modulates N-methyl D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) via the PI3K-AKT-GSK3 (Phosphoinositide 3-Kinase – Protein Kinase B – Glycogen Synthase Kinase 3) signaling pathway. Lastly, I identify a distinct role for astrocytic GDE3 in early postnatal development, showing that EVs released by GDE3 are required for proper hippocampal postsynaptic function, likely through modulation of metabotropic glutamate receptor1/5 (mGluR1/5) signaling. Collectively, these findings highlight a previously unknown layer of synaptic and behavioral regulation by GDE proteins with potential implications for neurodegenerative diseases
THE DENIALIST UNCONSCIOUS: CAPITAL ACCUMULATION AND REPRESSIVE NOVUMS IN SPECULATIVE MEDIA OF CLIMATE WRECKAGE
No full textThis dissertation challenges a conventional (often assumed or unspoken) critical presupposition that narrative representations of climate wreckage necessarily oppose the articulation, circulation, and reproduction of climate denial. Analyzing contemporary science fiction (sf) novels, films, and digital games published within a window roughly delimited by The Fifth Assessment Report of the United Nations Intergovernmental Panel on Climate Change (2014), this dissertation examines the construction and repressive functions of three sf figurations, called “novums”: the ark, arcology, and geoengineering. Mobilizing a theoretical apparatus that draws upon concepts and understandings from intellectual traditions including historical and dialectical materialism; Marxist theories of political-economy and cultural production; postcolonial critiques of The Enlightenment and modernity; psychoanalysis; aesthetic and critical theory; novel, film, and game studies; and contemporary climate science and discourse, this project demonstrates that various forms of climate denial continue to flourish not despite widespread narrativizations of climate wreckage but because of many of these representations, which mediate climate wreckage in ways that repress Real climate relations and thus (re)produce denial. This dissertation argues such texts constitute a material, powerful, and growing “denialist unconscious.” This dissertation aims to contribute a critical model of the imaginary and symbolic means through which climate narratives produce denial that perpetuates the economic, political, and social relations driving the climate crisis. Such a model can play a crucial role in exposing and negating mystifications which today misdirect great amounts of intellectual and physical labor towards ultimately accelerating the crisis
“BRICKS TO STAND ON”: BEYOND BELONGING, LAYING THE FOUNDATION FOR BLACK TEACHER CANDIDATE SUCCESS
Full text linkThis mixed methods dissertation investigated the persistent racialized performance gap experienced by aspiring teachers in an online teacher preparation program. Utilizing Bronfenbrenner’s Ecological Systems Theory (EST) and framed within the transformative paradigm, the connection between culturally responsive pedagogy (CRP) and academic engagement between Black and White teacher residents (TRs) was interrogated and analyzed. The study answered three questions: (1) How does academic engagement differ between Black and White TRs? (2) What CRP practices do faculty report using, and how do Black TRs perceive these practices? (3) What is the relationship between CRP practices and the academic engagement of Black TRs?
Quantitative data was collected from both TRs and faculty using Likert-scale survey instruments and analyzed using descriptive statistics, t-tests, and a series of regression models. Although no statistically significant differences were revealed in engagement scores by race in this study, Black TRs consistently reported higher engagement across behavioral, emotional, and cognitive domains. These findings, alongside persistent academic disparities, surface points of fragility within EDU’s capacity to achieve equitable outcomes for all students. Notably, both faculty and Black TRs reported frequent use of CRP, though their definitions and perceived enactment of CRP revealed important divergences. Regression analysis revealed that diverse teaching practices significantly predicted behavioral and overall engagement among Black TRs.
Qualitative data, gathered through semi-structured interviews with faculty and Black TRs, were thematically coded and integrated using joint displays. Qualitative findings identified four core themes of CRP at EDU: a) relational engagement, b) instructional flexibility, c) critical professional skill-building, and d) reflective praxis. Black TRs communicated a strong perception of CRP, especially in relation to equity commitments and a building community. However, TRs and faculty differed in their views of CRP enactment. Faculty pointed to cultural acknowledgment, while Black TRs described these gestures as superficial, noting their lived experiences and funds of knowledge were seldom affirmed in meaningful ways.
Conducted in a period of accelerating backlash against identity-affirming practices, this research underscores the importance of examining how such practices influence engagement and equity, particularly when policy shifts risk erasing them without understanding their impact
Enhancing Model Based Value-Based Care for Surgical Treatment of Claudication
No full textPeripheral artery disease (PAD) affects over 8.5 million Americans and remains a major source of morbidity. Its prevalence continues to rise due to aging populations and increasing rates of diabetes and smoking. Claudication, the hallmark symptom of PAD, presents a key opportunity for intervention to improve mobility, quality of life, and long-term vascular outcomes.
Over the last decade, peripheral vascular interventions (PVIs) for claudication have grown markedly. However, this growth has come with increased practice variation, overuse of low-value interventions, and concerns about patient outcomes and healthcare costs. Studies have shown that early invasive treatment, unwarranted tibial procedures, and underuse of supervised exercise therapy contribute to inefficient and inequitable care. Meanwhile, value-based care models are gaining momentum, underscoring the need for better evidence to guide appropriate intervention use.
Modeling is a cornerstone of biomedical informatics and supports evidence-based decisions by simulating clinical pathways, estimating treatment outcomes, and informing guidelines. In vascular care, models can integrate patient characteristics, treatment strategies, and outcomes data to optimize care and evaluate the value of interventions.
This dissertation leverages national administrative claims data and advanced decision modeling to enhance value-based surgical care for claudication. The work is organized into three aims:
Aim 1 characterizes trends, regional variation, and system-level factors associated with PVI use from 2011 to 2022. Sub-analyses explore how market dynamics influence early and tibial interventions, and the persistent underuse of supervised exercise therapy.
Aim 2 evaluates the clinical and economic outcomes of early PVI versus initial non-invasive management using decision analysis applied to real-world data.
Aim 3 extends the analysis internationally, comparing PVI trends across countries to identify policy implications and structural differences in care delivery.
A concluding discussion highlights the broader role of informatics in transforming surgical care through decision modeling and systems thinking. Together, these studies provide a comprehensive, data-driven assessment of current practices and offer pathways to more effective, patient-centered, and cost-efficient vascular care
BRIDGE THE GAP BETWEEN ORGANIC SYNTHESIS AND BIOSYNTHESIS: REPROGRAMMING METALLOENZYMES FOR NEW-TO-NATURE REACTIVITIES
No full textAs the catalysts of nature, enzymes offer unmatched selectivity, efficiency, and sustainability, making them increasingly attractive for modern chemical synthesis. Recent advances in protein engineering techniques and mechanistic understanding have paved the way of reprogramming enzymes to catalyze reactions far beyond the chemistries in nature. This thesis focuses on the development of novel biocatalytic platforms using non-heme iron enzymes, a versatile class of metalloenzymes traditionally involved in radical-mediated hydroxylation and halogenation. Through a combination of metal center substitution, first-sphere residue engineering and directed evolution, these works expand the functional landscape of non-heme enzymes to access diverse non-natural reactivities.
In the first part of this thesis, a non-heme iron enzyme SadA was successfully reprogrammed to catalyze the Conia-ene reaction, a Lewis acid-mediated transformation widely applied in organic synthesis but previously unknown in enzymology. Through rational substitution of the native iron center with Cu(II) and subsequent directed evolution, an optimized variant was obtained with excellent yield, enantioselectivity, and catalytic efficiency. This represents the first example of biocatalytic Lewis acid mediated ene reaction, establishing a new framework for bridging enzymatic and organometallic catalysis. The second part of the thesis addresses the challenge of biocatalytic enantiodivergence, i.e. accessing both enantiomers of a product using related enzyme scaffolds. By rationally mutating the first coordination sphere of a non-heme iron enzyme HppE and substituting its metal center to copper, two complementary variants were developed offering opposite enantiomers of Conia-ene products. This work introduces a general strategy for achieving enantiodivergence in biocatalytic systems. In the third part, a non-natural N-radical hydroamination reaction was developed using a reprogrammed non-heme iron enzyme. Inspired by non-heme enzymes’ ability to activate N-F bonds and generate nitrogen-centered radicals, a tailored substrate was designed to undergo intramolecular radical cyclization to form valuable γ-lactam scaffolds catalyzed by a reprogrammed non-heme iron enzyme PAH. We anticipate these findings illustrated in this thesis would not only deepen our understandings of reprogramming metalloenzymes for non-natural functions, but also lay a foundation for the future industrial application of biocatalysis in the development and manufacturing of complex, pharmaceutically relevant molecules
Sharecropping and Surplus Life in US Southern Literature
No full text“Sharecropping and Surplus Life in US Southern Literature” shows how writers in the US South in the first half of the twentieth century represented the history of sharecropping, the predominant form of labor exploitation in Southern agriculture in the late nineteenth and early twentieth centuries. As the onset of the Great Depression and increased mechanization in agriculture led to the disintegration of the sharecropping system, a range of writers working across genres turned their focus toward the deepening poverty of the South’s rural population. While literary works on sharecropping are commonly interpreted as nostalgic records of a vanishing peasantry, I argue that these works are better understood as a contested set of literary responses to an emergent form of rural unemployment. This literary response to crisis was central to the institutional history of Southern literature, a subfield that emerged from a contestation of regional cultural identity. By situating sharecropping within the dynamics of capitalist accumulation and the history of the wage relation, I advance a new reading of the political and representational problems of race, labor, and land in Southern literature
Leveraging analytical tools to evaluate the behavior of nanoscale anthropogenic materials in environmental matrices
Full text linkThe impact of nanoscale materials in environmental matrices can be disproportionately large. Engineered nanomaterials have garnered attention as a promising tool for sustainable agriculture, as they have been demonstrated to deliver pesticides, nutrients, and other cargo of interest more efficiently than conventional methods. In plant systems, the interactions of engineered nanomaterials are influenced by many factors such as particle size, composition, surface charge and charge density, and plant composition. As more and more nanomaterials are being designed specifically for use in nano-enabled agriculture, it is important to understand the mechanisms behind their interactions. Model plant systems show promise in being a high-throughput tool to probe nanomaterial interactions with plant cell walls, which are the main barrier nanomaterials face in entering the plant cell. Using model systems to mimic the plant cell wall, we examined how nanoparticle charge, size, and solution chemistry regulate nanoparticle adsorption to and penetration through the plant cell wall. Our findings demonstrate that small, positively charged nanoparticles adsorb and penetrate most efficiently, and that calcium-induced crosslinking can selectively restrict or permit nanoparticle movement, highlighting the complexity of nanomaterial uptake in plant systems. These insights can inform the development of nano-enabled agricultural technologies while also guiding environmental risk assessments.
Beyond nanomaterials, micro- and nanoplastics (MNPs) are increasingly detected in the environment, raising concerns about their interactions with plants and potential for uptake into edible plants. MNPs can serve as vectors for plastic additives and organic pollutants, which may enter food chains through plant uptake. However, detecting and quantifying MNP movement within plant systems remains a challenge. To address this, we developed labeling strategies to track MNP accumulation in hydroponically grown plants. Our results indicate that MNP uptake is size-dependent, with preferential accumulation in roots, and that associated contaminants are also taken up into the plant and can undergo metabolic transformations.
In addition to their impact on food systems, plastic-derived chemicals also pose risks to drinking water quality. Phthalates, widely used as plasticizers in drinking water distribution systems, can leach from polyvinyl chloride (PVC) pipes and react with free chlorine present in the drinking water as a disinfectant. These reactions can generate disinfection byproducts, altering the composition of contaminants in drinking water. Understanding these processes is essential for evaluating potential human exposure and developing safer materials for water distribution.
Together, these studies highlight the complex interactions between nanomaterials, plastics, and environmental systems. By improving our ability to track material movement and transformations in environmental and agricultural contexts, we can better assess risks and design safer, more sustainable technologies
Engineering and profiling immune system components for cancer immunotherapy applications
No full textThe immune system can be a powerful force both in promoting health and in causing disease. In this work we present several strategies for leveraging components of the immune system as therapeutics and in profiling immune system components to better understand health and disease states. First, we create bispecific antibodies that can target T cells to kill cancer cells that express mutant peptides generated from somatic mutations in RAS genes. Second, we generate bispecific antibodies for treating T cell cancers based on expression of specific T cell receptor variable gene segments. Third, we engineer mammalian cells to express immunotoxin conjugates as a path towards augmenting anti-cancer cell therapies. Fourth, we develop SafeTSeqS and SafeBSeqS, methods for sequencing T cell receptors and B cell receptors respectively, and we apply these techniques for profiling immune repertoires in colorectal cancer, lymphoma, sarcoidosis, multiple sclerosis, and immune-related adverse events associated with immune checkpoint inhibition. Together, these approaches highlight the multifaceted ways in which insights into immune system mechanisms can be leveraged towards improving human health
The Case for Subsidizing GLP-1s in the United States as a Harm Reduction Strategy to Reduce Cardiometabolic Disease from Multiple Interlocking Forms of Food-Related Disadvantage
Full text linkThis paper examines the current therapeutic use of glucagon-like peptide 1 (GLP-1) receptor agonists primarily to treat Type II Diabetes and advocates for expanding the use of GLP-1s to combat other cardiometabolic conditions, like obesity. Expanding the on-label use of GLP-1s could help to ameliorate negative health outcomes associated with overweight and obesity and offer a preventative measure against the onset of Type II Diabetes. Drawing on empirical evidence, the paper then illustrates that the burden of cardiometabolic conditions like obesity and Type II Diabetes, disproportionately impacts populations that experience multiple interlocking forms of food-related disadvantage (i.e., food insecurity, lack of access to healthy food, etc.) Recent studies have demonstrated increased efficacy of GLP-1s’ ability to modulate dietary habits, which could offer a direct intervention to reduce the harms associated with experiencing food-related disadvantage. As such, there is a critical argument for increasing access to GLP-1s in communities that face food-related disadvantage as a harm reduction strategy that could subsequently reduce the burden of cardiometabolic disease. Given the exorbitant price of GLP-1s and the current landscape of health insurance across the United States, the paper concludes by explicating the need for GLP-1 subsidies to improve access to the medication for low-income populations that experience food-related disadvantage. Such subsidies can uphold distributive justice by reducing socioeconomic health disparities and mitigating the modifiable harms associated with multiple interlocking forms of food-related disadvantage
Analysis of envelope diversity in simian immunodeficiency virus infected rhesus macaques during untreated infection
No full textHuman immunodeficiency virus (HIV) establishes lifelong infection by integrating into the host genome of CD4+ T cells, forming a persistent latent reservoir. This latent reservoir in resting memory CD4+ T cells is the major barrier to HIV cure and viral eradication, even with effective antiretroviral therapy (ART). Simian immunodeficiency virus (SIV) infection in Indian-origin rhesus macaques is a powerful model to study HIV pathogenesis and reservoir dynamics due to closely related immunological and virological characteristics, replication strategies, and disease progression. A key feature of both HIV and SIV is the extraordinary genetic diversity of the envelope (env) gene, which encodes the viral surface spike protein and plays a critical role in immune escape and persistence.
To understand the diversification of the viral envelope during untreated infection, we examined the intra-host evolution of the SIV env gene in eight Indian-origin rhesus macaques infected with the SIVmac251 swarm. Using single-genome sequencing (SGS) of plasma samples obtained at multiple (6-7) time points pre-ART, we generated 4,731 high quality env sequences, coupled with 2,443 on-ART proviral sequences that were already published (Fray et al., 2023).
The analysis reveals extensive within-host viral diversification following host-specific evolutionary patterns despite being infected with the same viral stock. We hypothesize that distinct dominant mutations present in the plasma virus of each animal at the same time reflect unique pathways of escape from the host’s neutralizing antibodies. Chao1 estimator predicted thousands of unique env variants were present in each animal. Longitudinal sampling of pre-ART plasma viruses and on-ART proviral sequences uncovered continuously new variants being sampled at different time points, and same variants were rarely found. Rarefaction analysis showed that the new variants discovered had different combinations of previously observed mutations. Amino acid substitution analysis suggests that only certain amino acid positions within gp120 subunit of the envelope tolerate a restricted set of amino acid changes. Together, this work demonstrates the evolutionary constraints that are necessary to maintain the structural integrity and functionality of the envelope. These results highlight that the significant animal-specific immune driven diversity within each host is bound by evolutionary limitations