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Equity in Mathematics: Dismantling Opportunity Gaps for 8th Grade Math Students in a Large Suburban School District
No full textLeadership and Learning in Organizations capstone projectMaplewood School District, a large suburban district committed to educational equity, continues to face persistent disparities in mathematics achievement. This capstone project examines how systemic practices, specifically math tracking, teacher placement, and educator mindsets, contribute to the underrepresentation of minoritized students in 8th-grade Algebra I. Using a mixed methods design, the study integrates three years of enrollment and state assessment data with surveys and interviews to explore these structural inequities. Findings reveal that both tracking practices and teacher perceptions significantly influence placement outcomes, with marked disparities in access to rigorous instruction for minoritized students
Machine learning is a powerful tool for linking phenotype and genotype in Saccharomycotina yeasts
No full textThe recently characterized genomes, isolation environments, and presence/absence of growth on 122 substrates and conditions from 1,154 (nearly all known) yeast species in the subphylum Saccharomycotina provide a powerful but complex dataset for studying the evolution of the genotype-phenotype map. Using a random forest algorithm on this dataset elucidated an alternate galactose-degrading pathway in yeasts, as well as linked relevant traits and genes to the ecological niches of cactophily, the floral-bee niche, and generalism/specialism. For the final part of my thesis, I used a random forest trained on these datasets as well as relevant gene sequences to predict antifungal resistance in yeasts and found that the genes and variants associated with resistance were different than those found previously clinical samples. I conclude that machine learning is a powerful tool for investigating the macroevolution of the genotype-phenotype map in fungi
The impact of benign genetic variation on clinical misclassification and overtreatment in biomarker-driven care
No full textDiagnostic biomarkers such as laboratory tests guide clinician decision-making, but interpretation relies on reference intervals and clinical decision thresholds derived from populations that may be either unrepresentative or under sample the populations to which the thresholds are applied. Traditional approaches can adjust for measurable sources of variability, such as age and sex, but a growing body of evidence indicates that individuals possess stable biomarker "set points" that are genetically influenced and not accounted for in current practice. Misalignment of clinical decision thresholds to these set points can lead to misclassification, unnecessary procedures, and extensive diagnostic uncertainty. We hypothesize that benign genetic variation underlies many unnecessary diagnostic odysseys and can be used as a risk stratification tool to reduce unnecessary testing and interventions. In the first application, we demonstrate that a benign genetic predisposition to higher prostate-specific antigen (PSA) increases the risk of urology referrals for false-positive PSA elevations. In patients undergoing prostate biopsy, genetically elevated PSA was associated with a lower likelihood of prostate cancer. In evaluations for underlying pathology in children with unexplained short stature, polygenic scores for height effectively distinguish between benign polygenic short stature and pathologic growth disorders, particularly among patients whose average parental heights do not accurately reflect their genetic predisposition. Finally, we observe that polygenic variation underlying neutrophil counts further increases the risk of benign neutropenia in patients with the Duffy null genotype. This genotype, present in two-thirds of patients of African ancestry, causes a benign form of neutropenia that can predispose patients to unnecessary bone marrow biopsies and chemotherapy modifications due to provider concerns for a low neutrophil count. Using a polygenic score, we create genotype-adjusted reference ranges for neutrophil counts, demonstrating a proactive approach to preventing inappropriate referrals. Together, these findings demonstrate the value of genetic personalization in biomarker interpretation, reducing diagnostic uncertainty and unnecessary diagnostic odysseys and interventions
Linking Early Life Stress and Psychopathology through Neural Correlates
No full textEarly life stress is thought to impact the brain, leading to alterations in normative cognitive and emotional development, which may contribute to the emergence of psychopathology. However, there is a lack of longitudinal studies examining neural measures as mediators of the relationship between early life stress and psychopathology. Furthermore, our understanding can be significantly improved by utilizing hierarchical modeling to reveal the inherent organization of early life stress and psychopathology. To this aim, the current study 1) examined whether environmental stressors (general environmental stress, family dynamics, interpersonal support, neighborhood SES deprivation, and urbanicity) derived from hierarchical modeling are associated with greater psychopathological symptoms (general psychopathology, internalizing symptoms, ADHD symptoms, and conduct problems) longitudinally, and 2) determined whether neural structures measured by regional brain volume, cortical thickness, and surface area mediate the putative association between environmental stress and psychopathology. Study 1 found that the general environmental stress factor predicted greater conduct problems and ADHD symptoms at the third-year follow-up, whereas it predicted lower general psychopathology and internalizing symptoms after controlling for baseline psychopathology symptoms. Family dynamics predicted psychopathology symptoms in all domains. Neighborhood SES deprivation predicted conduct problems specifically, whereas urbanicity showed divergent effects in predicting specific factors of psychopathology. Study 2 found that brain regions implicated in the frontal, default mode, motor, and reward processing networks mediated the relationship between early life stress and later psychopathology. Taken together, the results of this study suggest that early life stress is associated with later psychopathology and the neural substrates found in the current study may inform risk factors that underlie the development of future psychopathology
Dipeptidase-1: an old protein with new roles in shaping the tumor microenvironment and impacting progression in colorectal cancer
No full textDipeptidase-1 (DPEP1) has been mainly studied as an apically localized, kidney-specific protein that cleaves dipeptides, but there is an emerging interest for its role in colorectal cancer (CRC). DPEP1 is one of the most upregulated genes in CRC in comparison to normal colonic epithelium and has been reported to impact proliferation, invasion, and metastasis. With the recent discovery of DPEP1’s nonenzymatic function of binding neutrophils, we investigated this novel function of DPEP1 in CRC. The Coffey lab previously found that DPEP1 is preferentially upregulated in microsatellite stable (MSS) CRC that does not respond to immunotherapy due to a paucity of CD8+ T cells in the tumor proper; in marked contrast, microsatellite instability (MSI-H) CRCs have plentiful intratumoral CD8+ T cells and have a dramatic response to immunotherapy. I found that neutrophils bind CRC cells in a DPEP1-dependent manner and that DPEP1 null mice subjected to a colon cancer-inducing regimen leads to a paucity of neutrophils in the tumor, coinciding with an influx of CD8+ T cells not seen in wild-type. Staining for mismatch repair proteins were markedly reduced, suggesting that these seemingly more aggressive tumors had acquired an MSI-H phenotype, indicative of immunotherapy responsiveness. In a separate work, the Coffey lab found that diffuse cytosolic staining for DPEP1 in CRC correlated with a worse progression-free survival of CRC patients. I explored how DPEP1, a GPI-linked cell surface protein, could have a diffuse staining pattern, discovering a previously unrecognized alternatively spliced isoform, called DPEP1 Isoform B, which is not membrane bound, but instead has an intracellular, cytosolic staining pattern. Expression of this novel isoform transforms cells to be tumorigenic and results in large invasive tumors in nude mice. Comparison of CRC cells that express the canonical isoform, DPEP1 Isoform A, and DPEP1 Isoform B demonstrates that Isoform B impacts expression of genes related to cell proliferation and epithelial-to-mesenchymal transition. My work has provided insights into multiple functions for one protein, DPEP1, in CRC and opened many avenues for future investigation
Location, location, location: analysis of subcellular insulin secretion localization in pancreatic beta cells
No full textTo maintain normal blood glucose levels, pancreatic beta cells secrete insulin into the bloodstream at specialized regions at the cell periphery, often called secretion hot spots. While many secretory machinery components are located all over the cell membrane, directed secretion relies on distinct cortical patches of the scaffolding protein ELKS and the microtubule (MT)-anchoring protein LL5β. However, using TIRF microscopy of intact mouse islets to precisely localize secretion events within ELKS/LL5β patches, we now show that secretion is restricted to only 5% of ELKS/LL5β patch area. Moreover, the majority of secretion occurs at the margins of ELKS patches. This suggests that additional factor(s) must be responsible for hot spot definition. Because the MT cytoskeleton plays a regulatory role in the insulin secretion process via both delivery and removal of secretory granules from the secretion sites, we test whether local MT organization defines secretory activity at hot spots. We find that the majority of secretion events occur at regions devoid of MTs. Based on our findings, we present a model in which local MT disassembly and optimal ELKS content are strong predictors of directed insulin secretion
Enabling Large-scale Analysis of Neurodegeneration through Diffusion Imaging Harmonization
No full textDiffusion-weighted imaging (DWI) plays a critical role in characterizing brain network structure and connectivity, yet its broader application is limited by methodological variability and site-specific biases that compromise reproducibility and scalability. This dissertation addresses these challenges by proposing harmonization strategies and machine learning methods to enable robust, large-scale analysis of white matter connectivity, particularly in the context of aging and Alzheimer’s disease (AD). First, we evaluate the reproducibility and comparability of tractography pipelines, a cornerstone of DWI analysis. Second, we tackle the problem of cross-site variability by assessing and developing harmonization techniques for DWI-based connectivity and bundle analysis. We organized QuantConn, a community challenge focused on harmonizing tractography and bundle metrics across protocols. Third, we present a machine learning framework to disentangle and remove site effects from connectome features while preserving biological variability. Leveraging a conditional variational autoencoder, we harmonize nine network connectivity measures across 38 unique DWI acquisition protocols from 6,956 individuals, including those with mild cognitive impairment and AD. Collectively, this work establishes a comprehensive pipeline for tractography characterization, data harmonization, and site bias removal in network connectivity analysis
Disrupting Anthropocentrism through Human and More-Than-Human Engagement in Afro-Descendant Women's Fiction
No full textBeginning with the seminal text, Their Eyes Were Watching God, and culminating with Jesmyn Ward’s 2011 novel, Salvage The Bones, this dissertation explores Afro-Descendant Women’s fiction from the largely avoided intersection of Black Studies and Animal Studies. From ants in Toni Morrison’s Tar Baby to frogs and “Mon Inutil” (useless mountain), in Edwidge Danticat’s Claire of the Sea Light, to the quiet presence of Oysters in Jesmyn Ward’s novel Salvage The Bones, this project engages the more-than-human to interrogate and deconstruct the heirarchical, anthropocentric relations between beings. The limits and capacities of literature and language must be examined to challenge and revise the damaging narratives of human supremacy rooted in the global history of colonialism and the consequences of plantation slavery. This project urges the reader to question pervasive dominant cultural “truths” and to acknowledge their incomprehensiveness, alongside the colonially-derived and socially constructed divisions between human and more-than-human life to aid in thinking through the implications of anthropogenic changing climate, and the accompanying violences of environmental exploitation and degradation. Ultimately, this project asks the reader to think and exist differently in relation to the human and more-than-human in service of a gentler future
Enhancing Volunteer Connectedness within a Chapter Based Mentor Program
No full textLeadership and Learning in Organizations capstone projectCollege Mentors for Kids (CMFK), a mentoring program uniting university students with local elementary students, was established in 1996 and has grown to serve over 30 chapters in the Midwest and East Coast. CMFK desired to understand how they could better foster a sense of connectedness between mentors at the university level to address concerns with mentor retention. A mixed-methods approach was taken using a survey, interviews, focus groups, and document analysis. Overall, five primary findings highlighted key insights about College Mentors for Kids. Mentors prioritize contributing to the mission over connecting with other mentors, while all stakeholders value the mission and focus on enhancing the little buddies' experience. Mentors also seek more training and individualized support. University partners desire better communication from the national team and greater involvement on campus. Finally, the fundraising requirement was seen as a barrier to peer mentor connections
Fabrication and Application of Thermoresponsively Patterned Microvasculature
No full textHydrogels are a potent platform for developing medical technologies: their biocompatibility, viscoelastic structure and high-water content make them ideal for applications ranging from artificial tissue scaffolds to medicated wound dressings. Critically, they act as a medium in which water-soluble molecules, including nutrients, growth factors and cellular waste products, may move via diffusion or advection. These mass transport properties can be directly affected, without significantly compromising the mechanical or chemical properties of the polymer network itself, by creating micrometer scale cavities throughout the hydrogel. Modern methods of fabricating such features are limited by any combination of feature size, lumen geometry, scalability, interconnectivity or 3D complexity. Such limitations restrict the potential for hydrogel-based technologies, especially with regards to patterning microvasculature in engineered tissues. Using microfibers made with a nontoxic, thermoresponsive polymer, I patterned complex, tortuous, microscale channel networks in hydrogels that enable fluidic access to the full gel volume.
Central to my research has been the application of 3D microchannel networks as exchange vessels, a necessary advancement on the path to artificial tissues that are not limited by diffusive transport. I patterned hydrogels using sacrificial, thermoresponsive templates to form channel networks whose size and architecture approached those of natural capillaries. Within these microchannels, I cultured endothelial monolayers that remained viable for over three weeks and exhibited functional barrier properties. Endothelialized microchannels were also cultured within hydrogels containing suspended fibroblasts, which remained viable at 14 days post-seeding, thereby demonstrating their potential for integration into more complicated artificial tissue systems.
The highly anisotropic geometry of the microchannels is also advantageous for designing drug delivery vehicles, as it creates fluidic connections throughout the gel volume which can tune its transport properties while sacrificing very little solid material. By patterning interpenetrating polymer hydrogels with full-thickness microchannel networks, I created devices with accelerated drug-release times without sacrificing payload. Initial data suggests that patterned interpenetrating hydrogels loaded with therapeutics can be used to effectively treat partial-to-full thickness burn wounds.
This work represents early steps in overcoming the mass transport barriers preventing the development of thick artificial tissues and the advancement of hydrogels as regenerative technologies