BCG vaccination induces TCR-dependent effector functions among Vδ1/3 T cells that are associated with protection against tuberculosis

Thesis (Ph.D.)--University of Washington, 2025Intravenous vaccination with Mycobacterium bovis strain bacillus Calmette-Guérin (IV-BCG) protects macaques against Mycobacterium tuberculosis (Mtb) challenge and intradermal BCG protects human infants from disseminated tuberculosis. γδ T cells expressing a Vδ1+ or Vδ3+ T cell receptor (TCR) are enriched at mucosal surfaces and recognize mycobacterial antigens, but their role in protection against Mtb is largely unknown. We used multimodal single-cell RNA sequencing, mass cytometry, and flow cytometry to profile γδ T cells from human infants and macaques after protective BCG vaccination. A subset of Vδ1/3 T cells in BCG-vaccinated human infants shows evidence of clonal expansion and differentiation into pro-inflammatory and cytotoxic effector cells that respond to Mtb. In macaques, IV-BCG induced pro-inflammatory and cytotoxic responses to Mtb among Vδ1/3 T cells that were enriched in the airway compared to the blood. Notably, these responses were dependent on signaling through the TCR, and clonal expansion was most prominent among cytotoxic Vδ1/3 T cells. Finally, the total frequency of Vδ1/3 T cells in the lung and frequency of cytokine-expressing Vδ1/3 T cells in the airway were associated with protection against Mtb challenge. Thus, Vδ1/3 T cells are activated by BCG in a TCR-dependent manner and accumulate in the lung, where they upregulate cytotoxic and pro-inflammatory functions that may contribute to protective immunity against Mtb

Representation of Minoritized People with Cystic Fibrosis in CF Therapeutics Development Network Clinical Studies

Thesis (Master's)--University of Washington, 2025Black and Hispanic people with CF (PwCF) experience a greater burden of worse health outcomes related to pulmonary disease compared to White, non-Hispanic PwCF. Prior evidence suggests that these communities are underrepresented in clinical research in CF. We used clinical study data from four recent modulator studies (CHEC-SC, PROMISE, PROSPECT, and GOAL) as well as CF Foundation Patient Registry data on persons seen at the same centers while these studies were enrolling. We selected potential registry controls who had not enrolled into studies but were otherwise eligible based on inclusion and exclusion criteria. We assessed rates of study enrollment separately for Black race and Hispanic ethnicity versus non-Hispanic White PwCF as a reference. We used propensity weighted Poisson regression models to account for potential confounders in the relationship between race and study participation. This study analyzed the enrollment characteristics of 3,594 persons in modulator studies and compared them with 14,888 eligible individuals based on CFF Patient Registry data. Enrollees were younger (median age 19 years) and more likely to have at least three baseline visits and live within 30 miles of the study site. Multivariable analysis revealed racial/ethnic disparities in enrollment. Black individuals were significantly less likely than non-Hispanic White individuals to enroll in CHEC-SC and PROMISE, with a 17% and 32% lower likelihood, respectively. Hispanic individuals had lower enrollment in PROMISE but higher enrollment in PROSPECT. The differences in enrollment rates were stronger at sites with fewer minority participants. These results suggest that Black and Hispanic PwCF are significantly less likely to be included in CF clinical research than White PwCF. Future research will include analysis of multiple CF clinical studies to evaluate if this relationship is upheld in studies with varying inclusion/ exclusion criteria and clinical sites

Differential Drag-Based Orbital Maneuvers using Origami-Inspired Drag Area Modulation

Thesis (Master's)--University of Washington, 2025In recent years, a surge in demand for small satellites has generated interest in propulsion-less orbital control methods—differential drag, specifically—as a way to minimize propellant usage and cost. While successful in a number of missions, present implementations typically limit this technique to an On-Off mode, which can limit maneuver flexibility and interfere with other mission requirements. This research introduces a continuous drag control system employing origami-inspired foldable structures. Such foldable panels allow for continuous modulation of the spacecraft's projected area, thus enhancing maneuver accuracy without sacrificing solar power or any other pointing related requirements. Rendezvous maneuvers between two identical satellites are designed using linear equations, with battery State-of-Charge considerations. Results indicate that continuous control leads to a significant improvement over discrete On-Off control in terms of energy consumption for control inputs, while delivering equivalent performance. Additionally, incorporating additional degrees of freedom in origami design was proposed and evaluated, which significantly improved the power levels throughout the mission. A bar-and-hinge model is utilized to simulate dynamic unfolding behavior of the origami panels, and a proportional-integral-derivative control scheme is utilized for hinge actuation to achieve desired angles. Overall, this integrated approach not only optimizes differential drag control but is an efficient design for future small satellite missions with propellant-free orbital maneuvers

Utilizing stream temperature in regional barrier removal planning does not substantially improve cool-water habitat restoration

Thesis (Master's)--University of Washington, 2025Mathematical optimization strategies which maximum quantity of restored habitat are a common approach to prioritize small fish passage barriers for removal. Despite the importance of cool summer stream habitat for adult migrating salmon, such approaches have not been evaluated for their efficacy at restoring thermally suitable habitat. In this study, I analyze how well a habitat-maximizing optimization strategy performs at increasing cool-water habitat access, based on mean August stream temperatures, for barrier removals in western Washington. I additionally evaluate whether recent historical stream temperatures can serve as an effective proxy for future stream temperatures in cool-water-focused restoration. I find for this region, there is little relationship between temperature and habitat value, and the habitat-maximizing strategy achieves 70% or better of possible cool-water habitat gains for most relevant summer stream temperatures, making it moderately effective at cool-water restoration. Furthermore, when considering climate change, current stream temperature models indicate spatially homogeneous stream warming, making current temperatures an effective proxy for future temperatures. This study will help inform the utility of incorporating stream temperature information into fish passage planning strategy on regional scales

Penguins in the Coal Mine: Unraveling Sentinel Species Responses to Human-Caused Stressors

Thesis (Ph.D.)--University of Washington, 2025Given the urgent need to understand the rapid changes in marine systems, seabirds can serve as effective sentinel species, offering valuable insights into marine conditions and food webs across a range of spatiotemporal scales. I explore the use of seabirds—specifically Magellanic penguins (Spheniscus magellanicus) at the large, but declining breeding colony of Punta Tombo, Argentina—as sentinel species in multiple contexts. First, I examined the effects of extreme heat on Magellanic penguin adults and chicks. Due to climate change, extreme weather events are becoming more frequent and severe, leading to an increase in direct, adverse thermoregulatory impacts on wildlife. I document the magnitude of an unprecedented, single-day, heat-related mortality event of Magellanic penguin adults and chicks. Mortality rates of adults were unevenly distributed across the colony, suggesting that the presence of microclimates or easier beach access were important factors to penguin survival. Next, I examined how intrinsic traits, specifically sex and body size, affect the foraging success of adult Magellanic penguins, before examining how extrinsic factors, like commercial fishing impact their foraging success. Many seabird species are sexually size dimorphic, with males and females often displaying different foraging behaviors. Sex-specific differences in foraging are often attributed to sexual size dimorphism, yet few have quantified the foraging success of males and females and/or of large and small conspecifics. We found males brought back 38% more food than females and males were more efficient foragers than females, bringing back 69% more food per day. Size did not influence foraging success or foraging efficiency suggesting sex-specific foraging behaviors or roles during breeding are driving differences in foraging success and efficiency. Understanding competition between fisheries and seabirds is critical for developing ecosystem-based management strategies that balance fisheries harvest and conservation goals. I assessed the effect of commercial fishing hours on the foraging success and foraging efficiency of chick-provisioning Magellanic penguins. We found that (1) as the average number of fishing hours increased within the penguins' foraging area, adult foraging efficiency decreased, and (2) both adult sex and the timing of fishing effort relative to chick age influenced this effect. When adults were feeding small chicks, an increase in the number of fishing hours within the foraging range was associated with reduced foraging efficiency, especially for males. When adults were raising large chicks, however, foraging metrics had no relationship to fishing hours, likely because adults can leave larger chicks for longer and are thus less spatially and temporally constrained in their foraging efforts. These results indicate fishing may not be affecting the amount of food breeding adults acquire on a foraging trip, but the rate at which they acquire it

Exploring Regulators of Anti-Tumor Immunity: Chorionic Gonadotropin Beta & Major Vault Protein

Thesis (Ph.D.)--University of Washington, 2025Checkpoint immunotherapy has become a pillar of cancer treatment over the past decade. Immune checkpoint inhibitors (ICIs) have been highly efficacious for many patients, but ultimately many patients do not achieve durable responses and response rates remain variable across cancers and indications. These remain significant challenges in the field, as the patterns of response and resistance and the factors that influence them remain incompletely understood. Here I describe two proteins associated with tumor-immune interactions and response to ICIs. I identify that chorionic gonadotropin beta 7 (CGB7) is expressed widely across cancers and is associated with hallmarks of immune evasion and decreased survival probability in advanced urothelial carcinoma patients undergoing treatment with ICIs. Random survival forest modeling reveals that CGB7 is predictive of decreased survival probability in the context of ICI treatment. This supports the clinical value of CGB7 as a biomarker of immune evasion and resistance to checkpoint immunotherapy. I also describe associations between Major Vault Protein (MVP) and increased response to ICIs in melanoma. In an immunocompetent model, MVP expression in both the host and in the tumor increases survival probability in vivo. Tumoral expression of MVP influences survival in an immune-dependent manner. Single cell RNA-sequencing of tumors from an immunocompetent model reveals that tumor MVP expression is associated with increased abundance of effector CD8+ T cells expressing hallmarks of exhaustion, suggesting a potential mechanism for MVP in protecting effector CD8+ T cells against dysfunction. Taken together, this work identifies both CGB7 and MVP as valuable biomarkers and/or therapeutic targets associated with blunted or augmented anti-tumor immunity in cancer, respectively

The Impact of Warming Temperatures on Snowpack Structure

Thesis (Master's)--University of Washington, 2025Warming winters will lead to a greater fraction of rain falling in traditionally snowy areas. Here we investigate the impact of these changes on snowpack stratigraphy, focusing specifically on the presence and duration of melt-freeze crusts. In this work, we use a hydrologic model with high vertical resolution (Structure for Unifying Multiple Modeling Alternatives, SUMMA) to test the sensitivity of melt-freeze crusts to warming. Model runs with up to 100 layers were initialized with observed precipitation and temperature for 2°C and 4°C uniform warming sensitivity tests. We found warming temperatures increased the frequency of crusts at colder sites, while warmer sites had fewer crusts. Melt-freeze crusts increase the complexity of avalanche forecasting and mitigation for highway, recreational forecasting, and ski area operations. These changes to the snowpack will also impact ecosystem function, with greater snow density altering large mammal movements and predator-prey interactions

Interpretation of Visible Labs: The Benefits and Drawbacks

Thesis (Master's)--University of Washington, 2025Natural history museums (NHMs) face a conundrum: they appeal broadly to audiences yet struggle to compete with other informal science venues such as science centers, aquariums, zoos, and botanical gardens (Steiner & Crowley, 2013). NHMs are unique in that they hold collections, and many are also sites of active research. More recently, some of these NHMs have begun to showcase their research to the public via visible lab spaces. These attributes can position NHMs as distinctive sites for public engagement. Despite their potential, relatively few studies have examined the unique role of visible labs in informal learning venues such as NHMS. This study investigated the interpretative strategies used within visible labs and examined how these strategies aligned with educational frameworks. A case study approach including interviews with museum professionals engaged in interpretive planning and interpretation for visible labs and supplemented with document analysis was employed. Findings show that the unique features of visible labs include the process of science as a learning outcome, the demystification of scientists and science, and personalization and connection between the public and scientists. However, to leverage these benefits, scientists in visible labs need more support and validation. These findings demonstrate that visible labs are a unique resource for NHMs, adding to their value and separating them from other informal science venues

Lymphatic chain gradients regulate the magnitude and heterogeneity of T cell responses to vaccination

Thesis (Ph.D.)--University of Washington, 2025Upon activation, T cells proliferate and differentiate into diverse populations, including highly differentiated effector and memory precursor subsets. Initial diversification is influenced by signals sensed during T cell priming within lymphoid tissues. However, the rules governing how cellular heterogeneity is spatially encoded in vivo remain unclear. Here, we show that immunization establishes concentration gradients of antigens and inflammation across interconnected chains of draining lymph nodes (IC-LNs). While T cells are activated at all sites, individual IC-LNs elicit divergent responses: proximal IC-LNs favor the generation of effector cells, whereas distal IC-LNs promote formation of central memory precursor cells. Although both proximal and distal sites contribute to anamnestic responses, T cells from proximal IC-LNs preferentially provide early effector responses at inflamed tissues. Conversely, T cells from distal IC-LNs demonstrate an enhanced capacity to generate long-lasting responses to chronic antigens in cancer settings, including after checkpoint blockade therapy. Therefore, formation of spatial gradients across lymphatic chains following vaccination regulates the magnitude, heterogeneity, and longevity of T cell responses

Developing non-invasive neuroimaging biomarkers for Alzheimer's disease using machine learning

Thesis (Master's)--University of Washington, 2025With the FDA’s recent approval of the anti-amyloid antibodies lecanemab and aducanumab, the prospect of disease-modifying therapies for Alzheimer’s disease has become a clinical reality. However, these treatments are only effective in the early stages of the disease which is why there is a need for accurate AD early detection methods. PET imaging has the ability to detect key biomarkers associated with AD up to 20 years before symptoms occur. However, PET is largely unavailable in many countries and even in the U.S. is limited and costly. Here, we present a deep learning framework for synthesizing Aβ, Tau, and FDG-PET from MR images, which can reduce reliance on standard PET imaging by reconstructing the same pathology from learned representations in the MR inputs. We find that our UNet is able to synthesize structurally similar and clinically relevant Aβ, Tau, and FDG-PET images, potentially introducing MRI as a more accessible biomarker detection modality. Early AD is also characterized by network-wide functional connectivity changes, which have been observed in the DMN and other regions including the salience and dorsal attention regions. Currently, functional connectivity evaluation methods do not incorporate spatial information into their analysis nor do they evaluate connectivity dynamically, which neglects important interactions that occur in the brain. In the second portion of this thesis, a previously developed Graph Diffusion Autoregressive (GDAR) Model is applied to fMRI data to analyze dynamic functional changes in physiologically distinct brain networks. We found notable differences in connectivity among AD versus control subjects, informing future analysis to develop features that can separate AD from control subjects with the ultimate goal of developing AD early detection functional biomarkers