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EFFECTS OF PHARMACOLOGIC CELLULAR STRESSORS ON THE PRESENTATION OF A NON-CLASSICAL PEPTIDE-MHC COMPLEX
No full textThe adaptive immune response relies on precise antigen processing and presentation to CD8+ cytotoxic T cells and NK cells through major histocompatibility complex class I (MHC-I) molecules. At the heart of the antigen processing pathway are the human endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2. These enzymes are classically known for their crucial role in trimming peptides to optimal lengths for peptide:MHC-I (pMHC-I) complex presentation. Recently, ERAP1 and ERAP2 have been associated with broader physiological processes, including the unfolded protein response (UPR) and autophagy, alluding to a potential connection between cellular stress responses and immunosurveillance. With this study, we sought to determine if there were connections between ER stress and autophagy and Qa-1b restricted FL9 (QFL) epitope presentation, a murine non-classical pMHC-I complex known to be presented on the surface of antigen presenting cells (APCs) deficient in murine aminopeptidase ERAAP function. Using pharmacological modulators of autophagy and ER stress—bafilomycin A1, KU-0063794, thapsigargin, and tunicamycin—we evaluated their effects on QFL presentation, autophagic flux, and ER stress signaling markers in murine APC lines. Our results revealed bafilomycin A1 treatment reliably increased autophagy marker LC3-II expression, indicative of decreased autophagic flux, other pharmacological reagents did not significantly alter autophagy markers due to potential antibody affinity limitations. Thapsigargin treatment induced robust T cell hybridoma complicating interpretations of antigen-dependent immune responses. Fluorescence microscopy suggested differing ER morphology corresponding with specific pharmacological treatment, with KU-0063794 notably inducing ER puncta formation, suggesting an altered autophagic state. Significant technical limitations constrained overarching conclusions with respect to pharmacological ER stress-induced QFL presentation. Despite this, the findings of our study emphasize the complexity of interplay between ER aminopeptidases, ER stress, autophagy, and antigen presentation. Future studies employing more sensitive QFL detection, enhanced co-localization imaging techniques, and additional cellular models are vital to conclusively define these interactions
The role of NMyc downregulated gene 1 in testosterone paradox
No full textAndrogen deprivation therapy (ADT) has been the mainstay of treatment for metastatic prostate
cancer since the recognition by Dr. Charles Huggins in 1941 of its remarkable palliative benefits. In
lesser-known work, Huggins proposed that therapeutic response in hormonally-responsive cancers
could also be achieved through treatment with high doses of hormones, a strategy he called
“hormonal interference.” This paradoxical growth inhibition by supraphysiological testosterone (Supra
T), has been demonstrated in vitro and in vivo preclinical studies. Based on these preclinical
observations, a clinical trial was initiated at Hopkins that entailed administration of high dose of
testosterone termed “bipolar androgen therapy” (BAT). BAT is effective in 30% of prostate cancer.
Understanding molecular features that constitutes a high responder will help delineate pathways that
can be modulated to synergize with BAT, and lead to developing of biomarkers that would predict
response to BAT. Towards this goal, we explored the role of myc and its downstream regulated gene
NDRG1 in response to SupraT. Our data suggests that while c-myc and N-myc do not influence the
effect of SupraT on growth of prostate cancer they can affect the immune response triggered by
SupraT. This effect is acute in cells that lack the NDRG1. NDRG1 is able to influence SupraT immune
response by affecting both the canonical and non-canonical NFKB signaling. This is clinically relevant
as overexpression of c-myc or N-myc or downregulation of NDRG1 may serve as markers of BAT
resistance
THE CONVERGING COMMERCIAL LANDSCAPES OF TOBACCO AND CANNABIS: RETAIL, PERCEPTUAL, AND SPATIAL INSIGHTS
Full text linkBackground:
The intersection of tobacco and cannabis retail environments poses public health challenges, particularly as co-use of these substances is linked to increased health risks. This dissertation investigates how the retail availability of cannabinoid products intersects with the tobacco landscape, their combined impact on consumer perceptions through co-packaging exposure, and the spatial distribution of both retailer types.
Methods:
Aim 1 utilized in-person audits of licensed tobacco retailers (n=1,402) across New York City, Philadelphia, and San Francisco in 2023 to assess cannabinoid availability and store-level correlates. Aim 2 employed a randomized online experiment with adult participants (n=602) in 2024 to evaluate the effects of cannabis and tobacco packaging co-exposure on perceptions of tobacco products. Aim 3 analyzed spatial patterns of licensed tobacco retailers (n=6,525) and licensed cannabis dispensaries (n=63) in New York City using point pattern and regression analyses.
Results:
In Aim 1, 9.8% of tobacco retailers sold products labeled as containing tetrahydrocannabinol (THC) or the principal psychoactive constituent of cannabis, with the highest availability in smoke/vape shops (66.7%). Retailers with e-cigarettes or cigars available were significantly more likely to sell cannabinoids, while those with cigarette availability were less likely to do so. Aim 2 revealed that cannabis packaging reduced positive perceptions of cigarettes (e.g., quality, appeal) but increased interest in cigars and lowered perceptions of their harm. Aim 3 found clustering of tobacco retailers around cannabis dispensaries, with commercial zoning strongly correlating with high-density areas for both retailers.
Discussion:
These findings show patterns of convergence between tobacco and cannabis retail landscapes, suggesting this intersection may occur through various avenues including within individual retailers that carry both product types and through spatial proximity of distinct retailers. Findings further indicate that structural factors, such as zoning policies, may inadvertently influence patterns of tobacco and cannabis co-availability. This is worrisome as co-availability patterns can shape consumer perceptions of tobacco, complicating efforts to reduce use. Findings call for integrated regulatory approaches that account for the multiple pathways through which these markets intersect, including shared retail spaces, neighborhood-level co-exposure dynamics, and emerging patterns of product availability that contribute to dual exposure risks
EXPLORATORY ANALYSIS OF COLLECTED BAT AND TREE DATA FROM DATE PALM SAP HARVESTING IN BANGLADESH FROM DECEMBER 2023 TO MARCH 2024
Full text linkIn Bangladesh, the primary route of human exposure to zoonotic Nipah virus is through the consumption of date palm sap that has been contaminated with saliva, urine, or feces from Pteropus bats. Since the first outbreak in 2001, there have been almost annual human infections, with more outbreaks occurring in colder winters. Identifying a relationship between sap sweetness and quantity may provide insight into the factors driving the rise in Nipah cases during colder months. Additionally, understanding the timing of Pteropus visitations is critical, as increased visitation rates create more opportunities for date palm sap contamination and, consequently, a higher risk of spillover events. In this study, we aimed to better understand what factors, including weather and the ecology of bats and date palm trees, affect the frequency of sap contamination by bats. Between December 2023 to May 2024, infrared cameras were set up on 20 date palm trees for eight nights of observation in Bangladesh. For both Pteropus and non-Pteropus bats, there were more visitations in colder months, December (np = 155, nnp = 954) and January (np = 521, nnp = 1289). Overall, non-Pteropus bats visited more frequently than Pteropus bats. Measurements of date palm sap yield and sweetness showed that more, but less sweet sap was produced at lower temperatures. A slight negative trend (p = 0.664) was observed between sap quantity and sweetness, while a slight positive trend was found between sap quantity and total bat visitations for both Pteropus (p < 0.001) and non-Pteropus (p < 0.001) species. Among non-Pteropus bats, there was a slight positive trend between visitations and sap sweetness, but no such trend was observed for Pteropus bats. Based on our study findings, colder weather produced more (p-value = 0.003) but less sweet (p = 0.35) sap. Additionally, the increase in bat visitations to date palm trees seem to be more driven by colder temperature rather than sap quantity or sweetness
ASSOCIATIONS BETWEEN HIV CELLULAR RESERVOIRS AND CENTRAL NERVOUS SYSTEM OUTCOMES
No full textDespite sustained viral suppression with antiretroviral therapy (ART), many people with HIV (PWH) continue to experience chronic inflammation and central nervous system (CNS) complications. One explanation may be the persistence of HIV reservoirs, especially in CD4 T cells and monocytes. In this study, we assessed cognition (objective and subjective), blood-brain barrier permeability (BBB, brain imaging), immune profiles (cellular and soluble) and reservoir burden (HIV DNA) in a cohort of 102 virally suppressed PWH. The Intact Proviral DNA Assay (IPDA) was used to quantify intact, defective, and total HIV genomes in monocytes and CD4 T cells isolated from blood. Principal components analysis and hierarchical clustering algorithms were used to identify four distinct clusters of PWH based on their reservoir burden: Cluster 1 (high burden in both cell types), Cluster 2 (low burden in both), Cluster 3 (monocyte-dominant), and Cluster 4 (CD4-dominant). We observed that CD4 and monocyte phenotypes were driven by monocyte reservoir burden and that PWH with higher reservoir burden in both cell types had increased soluble markers of neuroinflammation (serum amyloid A, SAA) and BBB disruption. Interestingly, we did not find differences in cognitive performance across groups, which may reflect the relatively preserved cognitive profile of our sample. This study highlights the heterogeneity of HIV reservoir profiles and supports the idea that monocytes serve as a meaningful and functionally relevant HIV reservoir that actively contributes to ongoing immune changes in PWH
The expanded role of the conserved snpc-1 and snpc-3 genes in C. elegans small RNA transcription
No full textPIWI-interacting RNAs (piRNAs) are a class of small RNAs that have a conserved function in protecting the germline genome from the deleterious effects of mobile DNA elements. In repressing these elements, piRNAs preserve the integrity of the genome and ensure its faithful transmission to the next generation. While the transposon silencing function of piRNAs is well understood, the transcriptional regulation and sexual dimorphic expression of piRNAs remain largely unknown.
The conserved snRNA activating protein complex (SNAPc) is a well-established transcription factor complex that drives small nuclear RNA (snRNA) transcription. In flies and mice, the SNAPc holocomplex consists of SNPC-1, SNPC-3, and SNPC-4 subunits, which are each encoded by a single gene. In contrast, the C. elegans snpc-1 and snpc-3 genes have been amplified through gene duplications to comprise several paralogs, each with distinct roles.
We previously showed that the SNPC-1 family protein SNPC-1.3 is a male piRNA transcription factor expressed in the male germline. Here, we provide biochemical and genetic evidence to show that the SNPC-1 paralog SNPC-1.2 constitutes a novel female piRNA transcription factor and SNPC-1.4 may have a unique spatiotemporal role in mid-late pachytene piRNA transcription while SNPC-1.1 preserved the ancestral role of SNAPc in snRNA transcription. Additionally, genetic knockout and RNAi-based knockdown assays reveal that the snpc-3 family genes snpc-3.1 and snpc-3.2 comprise functionally redundant core piRNA transcription factors required for the transcription of both male and female piRNAs, while snpc-3.4 is uniquely involved in snRNA transcription.
Collectively, the snpc-1 and snpc-3 gene families encode specificity factors for possibly four distinct protein complexes that discriminate between the transcription of snRNAs and both sex-specific and temporally regulated piRNAs in the C. elegans genome. Our work provides insights into the sexually dimorphic and spatiotemporal piRNA-mediated regulation of germline genes to maintain proper germline development and suggests that piRNA biogenesis emerged from the duplication and diversification of ancient snRNA transcriptional machinery
Amour Noir: France, Love, and the Making of the Modern Black American Woman, 1884-1925
Full text linkBetween the 1880s and 1920s, France and the French language became a critical part of the training, leisure, and intellectual lives of educated Black women in the U.S. The love of France served many purposes. Some used French literature and history alongside Greek and Latin to prove their academic abilities, thus challenging Jim Crow’s racial hierarchies and pseudoscience painting them as unintelligent and uncivilized. Others claimed a familial connection to France and used associations with the French language to protect themselves from Jim Crow segregation. Using the ideals of French interracial republicanism, some made renewed claims to full citizenship and national belonging. France also served as a site of pleasure and personal development, through the consumption of material goods and experiences, often concentrated in Paris. Navigating the playground of transatlantic elites, educated Black women affirmed their status as representatives of “the race” and their belonging to a leadership class. Back home, connections to France were used as a form of social and cultural capital that allowed these representatives to speak to audiences from a place of authority and climb the ladder of professional success—from classical music to visual arts and more. World War One offered another chapter in the relationship between France and Black America. African American women served in the war camps of France and participated in the political aftermath of the war both as advocates of Peace and as champions of Pan African solidarity. In the 1920s, the “New Negro” movement embraced connections to the francophone world once more.
This project shows that the love of France and all things French was a central ideology among educated African American women at the turn of the twentieth century, which deeply shaped their understanding of racial, national and gendered identities. From an intellectual and linguistic exercise to a cultural marker, a source of joy, and a weapon of political organizing, France and its language loomed large in the world of Black female representatives of the turn of the twentieth century and informed the making of a modern Black American woman
The Ethics Engine: Operationalizing Reflective Practice in Interdisciplinary AI in Education Teams
Full text linkIncorporating AI into educational technology products requires interdisciplinary collaboration and moral resilience to meet the needs of educators and students. Teams of ed tech professionals, including data scientists, AI engineers, learning scientists, user researchers, and instructional designers, must navigate challenges such as interdisciplinary communication, negotiating decision-making power balances, and navigating their understanding of one another’s roles. These challenges impact their ability to integrate perspectives and maintain moral resilience. Inadequate integration of interdisciplinary perspectives across the team during design and development reduces the ability to address fairness, accountability, transparency, and ethics in AI-integrated product. Complex Adaptive Systems Theory analyzes how upstream team dynamics influence moral resilience and decision-making, leading to unintended consequences. An explanatory sequential study explores product team members' experiences, collecting quantitative data on disciplinary perspectives, attitudes toward AI, shared mental models, moral resilience, sociotechnical imaginaries, agile methodologies, and reflective design practice. This study suggests future support areas. Additionally, design thinking and reflective practices stand to benefit interdisciplinary ed tech teams, improving decision-making and overall design quality. A conversation-based assessment minimum viable product combining these approaches supports ongoing engagement in reflective practice and design thinking in the creation of learner- and educator-centered ed tech
THE ADOLESCENT MENTAL HEALTH CRISIS: RURAL TEACHERS’ EXPERIENCES WITH STUDENT MENTAL HEALTH
Full text linkIn recent years, adolescent mental health has been declining, which has become evident in schools. However, the impact of this student mental health crisis on teachers is not well-studied, particularly in rural schools. This convergent parallel mixed-methods study examined teachers' experiences in a rural Midwest high school with their students’ mental health and how those experiences have impacted them. Through interviews and surveys, teachers (n=13) shared their experiences with student mental health, perceived barriers to supporting their students’ mental health, self-efficacy for supporting student mental health, and how that self-efficacy is related to their work-related stress. Both data strands showed a high prevalence of anxiety, ADHD-related symptoms, depression, and family stress within the school. Additionally, teachers acknowledged three primary barriers to their efforts to support student mental health: lack of adequate training on student mental health, factors related to rurality, and uncooperative parents. Teachers also showed a middle-of-the-road self-efficacy for supporting student mental health, with high confidence only in their ability to identify struggling students. However, they did not feel the skills they lacked were an issue, as they felt that a teacher’s role in students’ mental health should be limited. Finally, a high positive correlation was seen between teacher self-efficacy for supporting student mental health and two factors of stress: burnout and secondary traumatic stress. Using these insights, policies and practices can be shaped to create more support for students and teachers to combat this mental health crisis while reducing the stressful impact of these efforts on teachers
ESSAYS IN LABOR ECONOMICS
Full text linkThese essays focus on research questions in labor economics, aiming to evaluate and design policies that improve the well-being of individuals affected by adverse economic shocks and those raised in disadvantaged environments.
Chapter 1 evaluates the long-term effects of unemployment insurance (UI) on post-displacement outcomes. I find that a 13-week extension in maximum UI duration reduces long-term earnings losses by 10–15% over a 10-year period. This reduction is primarily driven by an increase in hours worked, with minimal impact on wage rates. Evidence from the data and a search model suggests that the increase in labor supply is driven by improvements in non-pecuniary job attributes, which result from shifts in reservation utility.
Chapter 2 investigates the impact of maternal job displacement on children's educational attainment in single-mother households. After accounting for pre-displacement partnership dynamics, partner income, and the duration of single motherhood, I find that the effects on children’s educational outcomes are generally small and, in some cases, even positive depending on the child’s age at the time of displacement. These patterns are largely explained by differential household income dynamics following displacement.
Chapter 3 examines how genetic propensity for same-sex sexual behavior is associated with sexual orientation and socioeconomic outcomes from adolescence to adulthood, and how it interacts with the adolescent environment, measured by parental religiosity. We find that greater genetic propensity is associated with a higher likelihood of same-sex sexual behavior and risky behaviors, as well as worse mental health, educational attainment, and labor market outcomes. In contrast, higher parental religiosity is associated with a lower likelihood of same-sex sexual behavior and risky behaviors, and with better mental health, education, and labor market outcomes. Examining gene–environment interactions, we find that genetic propensity for same-sex sexual behavior interacts strongly with parental religiosity in predicting some of these outcomes