Within the complex landscape of the human genome, even a single mutation can trigger devastating neurological consequences. The reality is exemplified by a single missense mutation p.G192R in the RAB39B gene causing X-linked dominant Parkinson’s disease (PD) with reduced penetrance in females. Previously, loss of function mutations in the gene were associated with X-linked intellectual disability and autism spectrum disorder. RAB39B is a member of the human Rab GTPase family which plays a role in early autophagosome formation and is implicated in intracellular vesicular trafficking. This project investigates how defects in endolysosomal trafficking caused by the p.G192R mutation in RAB39B leads to pathogenic protein aggregates and subsequently, parkinsonism and neurodegeneration. To investigate this, we developed a RAB39 G192R Drosophila model which is characterized by neurodegeneration and protein aggregation using western blot, locomotor deficiency, and lifespans. Complementary to the Drosophila model, we developed a human neuronal model by generating induced pluripotent stem cells (iPSCs) from an affected male and similar age unaffected male from a kindred with X-linked PD due to the p.G192R mutation. Neurons differentiated from the iPSCs are analyzed for endolysosomal trafficking alterations by immunocytochemistry, and western blots for evaluating insoluble ubiquitinated protein aggregates and oligomerized forms of alpha-synuclein. Our preliminary results show increased ubiquitinated protein aggregation when a constitutively active RAB39 transgene was expressed in neuronal tissue. The G196R RAB39 adult flies appear morphologically normal, and the G192R mutation does not seem to affect dRAB39 protein expression in Drosophila. RAB39B G196R neurons also do not have altered expression of RAB39B, but have reduced cellular compartment size of p62-stained autophagolysosomes, and Plin2-stained lipid droplets. Understanding mechanisms underlying the pathogenesis of X-linked PD could reveal novel therapies to slow the rate of progression of neurodegeneration and development of PD.

Mutations in glucosidase, beta acid 1 (GBA) are the strongest genetic risk factor for Parkinson’s Disease (PD) and are associated with faster progression of cognitive and motor symptoms. We hypothesize that GBA mutations disrupt the endolysosomal pathway, altering extracellular vesicle (EV) biogenesis and impairing autophagy, leading to faster spread of Lewy pathology from cell to cell in the brain and consequently accelerated disease progression. To study this connection, we utilize a Drosophila model of GBA deficiency that exhibits increased protein aggregation and neurodegeneration. We found that expression of WT GBA in the muscle of GBA mutant flies reduces protein aggregation in the brain, and EVs isolated from these flies have normalized levels of EV-intrinsic proteins that were elevated in GBA mutant flies. These findings suggest that GBA deficiency mediates PD pathogenesis by accelerating the propagation of protein aggregation to distant tissues. To complement this fly model, we differentiate induced pluripotent stem cells (iPSCs) from a PD patient carrying a null GBA IVS2+1 mutation (GBA IVS PD), isogenic wildtype iPSCs generated by CRISPR repair of the IVS2+1 mutation (GBA WT PD), and iPSCs from an unrelated healthy age and sex match control into neurons. To further investigate how GBA influences EVs, I extract EVs from the GBA IVS PD, isogenic GBA WT PD, and sex-age-match control iPSC-neurons to determine if there is a difference in protein cargo in EVs from GBA deficient neurons. I hypothesize that higher levels of aggregated alpha-synuclein will be present in EVs from GBA deficient neurons. I utilize size exclusion chromatography to isolate EVs from neuronal conditioned media. I then conduct western blots to determine protein within EVs. Understanding how GBA mutations influence EV dysregulation and whether EVs act as a vehicle for spread of Lewy pathology could help us uncover new therapeutic targets to slow neurodegeneration.

In December 2022, the U.S. Department of Health and Human Services approved a State Innovation Waiver under section 1332 of the Affordable Care Act (ACA), allowing Washington State to provide health and dental insurance coverage to all its residents, regardless of immigration status, from 2024 to 2028. The goal of the Section 1332 waiver is to decrease the number of uninsured, minimize the cost burden of healthcare on individuals and the government, improve health outcomes, and address health disparities. Health insurance navigators, who help people select, enroll, and use health insurance coverage, are charged with implementing this policy change. Their contributions to improving access to health insurance for vulnerable communities are often undervalued, even ignored, but will be crucial to ensuring migrant, refugee, and undocumented individuals are able to enroll for health insurance. This project presents key insights gained from interviews with navigators working in public health departments, community-based organizations, non-profit hospitals, and health clinics across the state, as well as, policymakers and activists focused on expanding healthcare access for immigrant communities. Using semi-structured interviews with insurance navigators, I explored their responsibilities and tasks, the process of enrolling immigrant communities for health insurance, and training and resources that support navigators. Additionally, I analyzed official documents used for the section 1332 waiver application to examine the motivations and narratives used to justify this insurance access expansion. My research shows how navigators deal with punitive immigration policies, xenophobic political rhetoric, financial uncertainty, cybersecurity concerns, staffing inadequacies, and high demand. This project advances our understanding of the systemic constraints, decision-making processes, and discretionary power that shape access to and use of healthcare and will inform policies that aim to codify health equity for immigrant communities.

Nearly all forms of cardiac disease are characterized by cardiac fibrosis, which contributes to heart failure and arrhythmias due to the accumulation of collagen deposits. Collagen, a crucial extracellular matrix (ECM) protein, is secreted by cardiac fibroblasts—the primary cell type responsible for generating this stiff scar tissue known as fibrosis. Fibroblasts are highly plastic cells that can transition between quiescent and activated states. The Davis Lab has developed a minimally invasive intermittent injury model to cyclically stress cardiac fibroblasts in vivo, allowing for a deeper investigation into the role of cellular memory in regulating the fibrotic response. Notably, we can reduce fibrotic remodeling in this model by inhibiting p38 gene function in the activated population, thereby encouraging a shift back to a quiescent state. My work aims to determine whether the once-activated population is proliferating at the second injury stimulus as well, or if a new population of fibroblasts is proliferating with repeat injury. To address this, I am utilizing genetic lineage tracing and Click-iT EdU technology, which allows for precise biolabeling while also preserving cell morphology and integrity by integrating into the cell's DNA. I am also performing immunohistochemistry staining to detect other proteins of interest that will serve as proliferation markers as well. Based on prior findings in the Davis Lab, we hypothesize that once-activated fibroblasts will go on to activate again when exposed to repeated disease stimuli, but there will be no second wave of proliferation as there was no change in total fibroblast number. 

Medical debt is a significant burden with fourteen million Americans owing at least $1,000, and the U.S accumulating at least $220 billion (Rae & Rakshit, 2024). Researchers have developed the concept of financial literacy to help patients understand health insurance and apply this newly-acquired knowledge to actively manage their medical bills. Our research challenges the portrayal of medical debt as the patients’ fault for lack of financial literacy and reframes it as a structural problem that purposefully blocks people’s access to financial aid resources. We conducted seven semi-structured interviews with healthcare workers, representatives from non-profit organizations, and financial counselors who help with medical debt. In the interviews we asked about their work, challenges they may face, and recommendations for improving access to financial aid. We recorded these interviews on Zoom, transcribed, and coded them with qualitative analysis software, Dedoose. Our interviews showed that hospitals mandated to have financial aid policies do not help patients access these policies. The documents contain excessive jargon and lack uniformity across hospital systems. Because of this obscurity, many patients are unaware of financial aid opportunities, unable to understand their eligibility and end up with exorbitantly high medical bills. Furthermore, we discovered that healthcare providers are unable to navigate these policies, leaving patients without adequate support. Our results show that policies solely focusing on improving financial illiteracy among individual patients fail to address that hospitals and insurance companies block patients from resources that mitigate medical debt. We advocate for widespread user-friendly financial aid guides, health financial literacy curricula for healthcare staff, and the public dissemination of financial aid resources across clinical settings. Addressing financial illiteracy as a systemic instead of an individual problem helps create a more equitable and accessible health system that enables patients to prioritize their well-being over managing their medical debt.

The Jewish people span international and political borders in a widespread diaspora. Today, many Jewish people worldwide oppose Zionism and the existence of the nation of Israel due to religious, cultural, moral, and philosophical reasons. How was this opposition founded, and what can be learned from it? In essence, what is the early history of the anti-Zionist movement in the Jewish community? This literature review examines the shared histories of Eastern European and American Jews to explore this organized Anti-Zionist Judaism, through analyzing and comparing accounts and articles detailing the major groups, ideologies, and figures of the movement. I use this historical information to create an organized synthesis of events and locations that are especially significant to the development of the current anti-Zionist Jewish movement, revealing its roots in organized struggle. I focus on the years 1897-1948 and organizations at the forefront of this movement like the General Jewish Labor Bund in Lithuania, Poland and Russia and the American Council for Judaism. I further explore how this history has led to the current modern reality of anti-Zionism in Judaism. This literature review uncovers a rich history of the early Jewish anti-Zionist movement, supporting the conclusion that the current Jewish-led anti-Zionist movement is neither unfounded nor a sudden development. This finding suggests a precedent for further Jewish-led organized labor parties and anti-Zionist organizations to draw upon the history set by the earlier anti-Zionist groups to organize more effectively and affirm the legitimacy of their movement. Looking to the future, research conducted by any person, whether that be Zionists, anti-Zionists, or unaffiliated groups and individuals, can use these findings to better inform their understanding of accurate anti-Zionist history and improve the understanding of anti-Zionism today.

Approximately 320 million years ago, teleost fish experienced a whole-genome duplication event, which is theorized to have contributed to developmental and morphological innovations that enhanced the reproductive success of their modern descendants. However, the role of duplicated genes in the genesis of novel cell types remains unknown. Here we show that the African Turquoise Killifish (Nothobranchius furzeri) possesses a novel immune lineage specified prior to gastrulation—a far earlier stage than observed in other teleosts. Surprisingly, through single-cell RNA sequencing, we found that this lineage unexpectedly expresses nanos1b, a duplicated paralog of nanos1, a gene well known for its role in germline development across vertebrates. To verify this novel expression of nanos1b in immune cells before gastrulation, I performed RNA in situ hybridization to visualize the expression of nanos1b, eomes (a mesodermal marker), and lcp1 (a marker of mature immune cells). The results revealed co-expression of nanos1b with both eomes and lcp1, supporting the hypothesis that nanos1b expression links the myeloid lineage to the developing mesoderm. These investigations will help elucidate the pathway through which the killifish embryo fast-tracks the production of immune cells during early development.