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INVESTIGATION OF BLADDER CANCER PLASTICITY WITH REPRODUCIBLE COMPUTATIONAL TOOLING
No full textMuscle invasion is a critical point in the progression of bladder cancer, but it is difficult to determine if or when it will occur in a given patient. While Src — one of the first discovered proto–oncogenes — has been implicated in tumor progression for a variety of cancers, previous work has determined that Src acts as a tumor suppressor in bladder cancer. The second chapter of this thesis investigates how molecular subtypes of bladder cancer may be important for resolving this apparent paradox.
Upon muscle wall invasion, metastasis becomes a primary threat to the patient. While immune checkpoint blockade (ICB) can provide complete, durable response, it is only in a subset of patients. It has been suggested that combination therapy of erdafitinib and ICB can allow would–be non–responders to respond, but this is surrounded by conflicting evidence and little mechanistic work. In the third chapter of this thesis, we note a consistent increase in interferon signatures upon FGFR3 inhibition, but that in vivo this inhibition may not be sufficient to stimulate immune infiltration.
The behavior of cells is sensitive to their environment, complicating in vitro studies. Previous work has shown that cells take on basal characteristics when in culture, a phenotype that can be reverted to luminal when placed in vivo. During the development of the models in the previous chapter, we discovered that cells placed in vivo became more aggressive and lost markers of differentiation. We note our observations as well as preliminary mechanistic
findings.
Orchestrating the acquisition and analysis of datasets large and small from disparate sources has become the standard for modern science. Unfortunately, this often results in publications that are difficult to reproduce due to lack of sufficient (immense) detail. Reproducible science takes time, but the ‘activation energy’ can be reduced with the help of tailor–made software. In the final chapter of this thesis, I describe case studies of software I have created to aide reproducible science, and the importance of creating software for the particular as well as the general
AUTOFLURORESCENCE AS A BIOMARKER FOR SCHIZOPHRENIA AND BATTENS DISEASE: STRATIFICATION OF PATIENTS AND MOLECULAR CHARACTERISATION FOR TARGETED THERAPEUTIC INSIGHTS
Full text linkRecent evidence implicates lysosomal dysfunction as a convergent mechanism across neurological and psychiatric disorders, including schizophrenia (SZ). In a prior study, we observed lysosomal abnormalities in SZ postmortem brains. To investigate further, we conducted two lines of preliminary research. First, in human subjects, we found that lysosome pathology-driven cellular autofluorescence (AF) in lymphoblasts was associated with reduced cognitive flexibility and increased oxidative stress. Second, in mouse models, we discovered that AF levels increased when the nuclear GAPDH (N-GAPDH) stress-response cascade was activated via repeated low-dose LPS exposure. This activation led to cognitive inflexibility and AF elevation in peripheral blood mononuclear cells, which could be reversed by inhibiting the N-GAPDH pathway, highlighting a causal role. Building on these findings, we established a high-throughput platform to measure AF in blood cells. We analysed lymphoblasts from SZ patients (n = 61), healthy controls (n = 37), and Batten disease patients, a monogenic lysosomal disorder with elevated AF and cognitive impairment. A distinct subgroup of SZ patients exhibited significantly elevated AF, independent of antipsychotic treatment. This supports AF as a clinically accessible biomarker for identifying SZ patients with lysosomal pathology. By using Batten disease as a reference framework, we highlight how insights from rare diseases can illuminate mechanisms underlying heterogeneous psychiatric conditions. Our approach enables precision psychiatry by stratifying patients based on lysosomal dysfunction. AF profiling identifies biologically distinct subgroups, paving the way for targeted clinical trials and therapies beyond conventional symptom-based treatments
FOOD REGULATION AT THE INTERSECTION OF GOVERNMENT AND THE CONSUMER: EVALUATING THE OUTCOMES OF LEGAL AND REGULATORY INTERVENTIONS
No full textLegal mandates have been employed by the federal government as a means to ensure the safety, wholesomeness, and integrity of the food supply for nearly 120 years. Despite this long history, examinations of the population health outcomes of food law and regulation are lacking. Three studies were conducted to assess and expand the evidence base for the public health outcomes of food regulation in the United States.
An integrative review of food regulatory outcomes research found a moderate amount of evidence across four domains: labeling and disclosure, nutrition and product formulation, retail food safety, and manufactured food safety. Sufficient evidence was found to support a net public health benefit from labeling and disclosure laws. Only a small, conflicting body of evidence for hygiene and sanitation regulations was found, suggesting a need for additional research in this space.
Next, an analysis of the reading comprehension level of legally-mandated disclosure and labeling on food and drug labels was conducted. In many cases, the explicit text is defined by regulation and cannot be altered. A majority of label messages were found to be at a reading level exceeding the comprehension of the average adult, potentially putting important health messages out of reach of the consumer.
Last, the variability in restaurant inspection scores was examined between local health jurisdictions. If consumers are expected to use score data for risk-informed decisions, they must be able to understand the information being provided. Quantitative analysis of inspection scores reveals that significant variation in scoring exists between jurisdictions, even when comparing peer localities in the same state. Additionally, inspectional outcomes varied depending on the way in which a jurisdiction chose to report its inspection results. Consumers may be unable to interpret highly variable scores, significantly reducing the value of the inspection disclosure system.
Taken together, there is opportunity to strengthen the evidence base and improve the effectiveness of food safety and nutrition regulations, in particular by conducting retrospective reviews to evaluate outcomes. Routine assessment of interventions is a best practice and will help maximize the public health protection of the food regulatory system
A finite-dimensional functional for circle segmentation, with applications to pupil tracking
Full text linkIn this thesis we propose a novel circle tracking active contour model that directly evolves a flexible initial circle without relying on edge detection or finely tuned initialization. Two variants are introduced: a full gradient descent (R5) that jointly optimizes center, radius, and region intensity parameters, and a reduced gradient descent (R3) that computes region intensities in closed form. We present experiments on different eye images, on brain CT slices, and on approximately circular objects. The results demonstrate that R5 achieves substantially higher intersection‐over‐union (IoU) and lower center and radius errors than classical Hough transform, while requiring minimal hyperparameter tuning. The proposed circle tracking framework provides a versatile, data‐driven approach to circular object segmentation with strong accuracy and robustness
IMPLEMENTATION OF HIV TREATMENT SUPPORT STRATEGIES FOR FEMALE SEX WORKERS LIVING WITH HIV IN SOUTH AFRICA
No full textBackground. In South Africa, 62% of female sex workers (FSW) are living with HIV, with many experiencing suboptimal treatment outcomes. Antiretroviral therapy (ART) is free and widely available, but among FSW, inconsistent access and adherence limits its effectiveness. This dissertation assessed determinants and mechanisms underlying the implementation of two HIV treatment support strategies, described engagement with strategies, and characterized the role of sex worker-specific programming utilization.
Methods. This dissertation used data from the Siyaphambili Study, a trial testing two HIV treatment support strategies aimed to promote viral suppression among a FSW living with HIV in South Africa. First, we characterized strategy implementation determinants using the Consolidated Framework for Implementation Research (CFIR). Secondly, we generated mechanisms underlying strategy implementation and effectiveness using a combined CFIR/realist-informed evaluation. Next, we identified longitudinal patterns of strategy engagement using group-based trajectory modeling, describing factors associated with each engagement trajectory and the association with clinical outcomes. Finally, we identified correlates of receiving HIV care and treatment from the TB HIV care sex worker program.
Results. Twelve CFIR constructs across three domains emerged as facilitating, hindering, or having mixed effects on strategy implementation, with three constructs weakly operating distinctly between strategies. Four ‘context+mechanim=outcome’ configurations emerged: 1. Needs of FSW+relative advantage of strategy=appropriateness for FSW, 2. Work infrastructure/available resources/knowledge resources+strategy design=feasibility of implementation, 3. Partnerships/relational connections/communication+strategy complexity/adaptability=fidelity of implementation, and 4. FSW capability+FSW opportunity/motivation=strategy effectiveness. We identified four strategy engagement trajectories. A quarter of FSW were consistently engaged, and FSW in this trajectory were more likely to be older, single, on ART at enrollment, and retained and virally suppressed at 18-months. Finally, we found FSW not receiving ART care from the sex worker-specific HIV program implementing Siyaphambili were more vulnerable, at increased risk for suboptimal HIV treatment outcomes, and at risk for onward HIV transmission due to inconsistent condom use.
Conclusions. Patient-centered HIV services that address the unmet treatment needs of FSW will optimize health and support HIV epidemic control. Understanding who these strategies worked for, as well as the determinants and mechanisms in which they operated, informs future strategy design and implementation among FSW at greatest need
ENHANCING RESEARCH COMPLIANCE: A TRAINING MANUAL FOR RESEARCH ADMINISTRATORS AND CLINICAL PROFESSIONALS
Full text linkThis capstone project addresses the critical need for standardized research compliance training among research administrators and clinical professionals. With increasing regulatory complexity and evolving ethical standards, many institutions face frequent gaps in compliance education, which may result in regulatory violations, poor financial management, and compromised research integrity. This project proposes a comprehensive training manual that integrates federal regulations, institutional policies, and clinical research best practices. The training manual discusses essential topics including IRB review processes, informed consent, conflict of interest management, and research misconduct. Additionally providing SOPs, compliance checklists, and real world case studies, this resource aims to improve regulatory knowledge, promote ethical research conduct, and strengthen oversight across clinical research settings. The capstone covers the development process and practical applications, offering recommendations for future improvements in research compliance training
Establishing and Validating Novel Highly Multiplexed Antibody-Profiling Platforms Integrating Linear Epitope Reactivities and Virus Neutralization Activities to Better Understand Humoral Immunity Against Hemagglutinin Protein of Influenza Virus
No full textInfluenza A virus (IAV) is a highly contagious respiratory pathogen that affects millions of people globally each year, causing significant morbidity and mortality. Despite the widespread use of vaccines, protection against IAV remains limited by factors such as relatively low vaccine efficacy, rapid viral mutation, and the lack of broad and durable immunity. Immune responses to influenza are influenced by a range of by a range of vaccine, virus, and host factors, including virus strains in the vaccine formula and circulation, age, health status, prior exposure, and immunization history, making it challenging to design universally effective vaccines. A critical step toward improving our understanding of protective immunity is identifying the specific viral targets that elicit functional antibody responses. While neutralizing antibodies directed against the viral hemagglutinin (HA) protein are central to protection, the contribution of linear epitopes within HA to functional neutralization is not fully understood. We used data from two complementary high-throughput platforms: the InFlux neutralization assay, which uses a whole-virus barcoded HA library to assess neutralizing activity across diverse IAV strains, and the HAscan PhIP-Seq library, which profiles peptide-level antibody binding across the HA protein. By comparing these datasets, we aim to map the relationship between antibody binding to linear HA epitopes and their ability to neutralize viral infection. This integrative approach provides new insights into the functional relevance of linear epitopes in the context of vaccine-induced humoral immunity and supports efforts to develop more effective, broadly protective influenza vaccines
POLITICAL AND CORPORATE FORCES SHAPING THE EUROPEAN UNION’S CORPORATE SUSTAINABILITY REPORTING DIRECTIVE AND IMPLICATIONS ON THE FUTURE OF SUSTAINABILITY REPORTING: COMPARATIVE ANALYSIS WITH THE SARBANES-OXLEY ACT OF 2002
Full text linkThis study examines the trajectory of sustainability reporting under the European Union's Corporate Sustainability Reporting Directive (CSRD) amidst corporate and political pushback. The research problem asks: Will sustainability reporting under the CSRD follow the path of the Sarbanes Oxley Act of 2002 (SOX), becoming an and inspiring other long-term global standards, or will sustained opposition weaken its impact, leading to further regulatory rollbacks?
A mixed-methods approach was employed, including a policy comparison of SOX and CSRD, a content analysis of European Sustainability Reporting Standards (ESRS) public comment letters, and a survey of Corporate Sustainability Directors and Advisors. The policy comparison highlighted key similarities in the scope, intent, pushback, and potential impact of the two regulations. The content analysis revealed corelated relationship between stakeholder concerns regarding the CSRD and specific changes reflected in CSRD proposed amendments. The survey results indicate that while challenges exist, many organizations are committed to sustainability reporting on a voluntarily basis, citing value propositions for reporting beyond mere regulatory compliance.
The study concludes that despite pushback and amendments, the CSRD is likely to endure and help shape the future of global sustainability reporting
DISCOVERY AND CHARACTERIZATION OF NOVEL PLASMODIUM FALCIPARUM PLASMA BIOMARKERS
No full textThe increasing prevalence of the gene deletions of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) has led to widespread failures in rapid diagnostic tests (RDTs), posing a serious challenge to malaria diagnosis and control. To address this issue, this study focuses on identifying alternative plasma protein biomarkers that can serve as new RDT targets. DIA mass spectrometry was adopted to identify P. falciparum proteins in the plasma of infected patients, providing a pool of potential biomarker candidates. MutateX and AlphaFold are applied to assess the functional impact of genetic variations in these proteins, ensuring the selection of stable targets. Additionally, structural and splicing variations in stage-specific P. falciparum proteins are explored by integrating single-cell transcriptomic data with alternatively spliced protein isoforms, providing insights into their expression dynamics and suitability as biomarkers. By combining proteomics, structural modeling, and transcriptomics, this study aims to discover robust plasma biomarkers that can improve malaria diagnostics and mitigate the impact of Pfhrp2 deletions on RDT accuracy
A STUDY ON THE FUNCTION OF THE ANCIENT MIR-100 FAMILY IN CAENORHABDITIS ELEGANS
Full text linkMicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally, playing key roles in animal development. While miRNAs with single, essential targets (e.g., let-7) have been thoroughly studied, understanding miRNAs with broad, multi-target regulatory functions remains challenging. This thesis investigates the function of the highly conserved miR-51 family (miR-51Fam) in Caenorhabditis elegans, a homolog of miR-100 -the most conserved animal miRNA-, to explore its molecular targets and functional roles.
Using the powerful genetics of C. elegans, I dissected the contribution of individual miRNAs within the miR-51Fam to its overall redundant function. This analysis revealed that the miR-51Fam most likely expanded into a 6-membered family to achieve high concentrations of miRNA, required for proper embryogenesis.
To identify relevant candidate targets of the miR-51Fam, I used a combination of phenotypical analysis, conservation analysis, mRNA-sequencing, and target prediction. Candidates were enriched in processes related to the extracellular matrix (ECM) and cell signaling, including kal-1 (a cell adhesion molecule), hst-3.2 (a heparan sulfate sulfotransferase), and lin-12 (a Notch receptor). I validated these targets through disruption of miR-51Fam binding sites in their 3’UTRs, which led to upregulation of the candidates, strongly supporting their regulation by miR-51Fam.
Phenotypic analysis of binding site mutants revealed that single target mutants did not phenocopy the defects observed in miR-51Fam-deficient embryos. However, generating multiple binding site mutants using CRISPR/Cas9 led to cumulative phenotypic defects, including impaired HSN neuronal migration, egg-laying defects, and locomotion defects, resembling the phenotypes of miR-51Fam loss.
Overall, my results support a model in which the miR-51Fam regulates ECM composition and cell-cell communication through targeting of a diverse set of genes. These processes are essential for the emergence of the complexity associated to true tissues in eumetazoans. Evidence from other systems, including Pristionchus pacificus and vertebrate models, supports this hypothesis, suggesting an ancient and conserved regulatory role for miR-100.
In conclusion, this thesis provides a framework for understanding miRNAs with broad regulatory networks. The miR-51Fam emerges as a regulator of ECM biology and cell communication, raising fundamental questions about its evolutionary role in shaping tissue complexity across animals