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Mania in Skamania
No full textMania in Skamania follows Colt Easton, a vagabond and bibliophile, whose survival skills pull him into the hunt for a missing game warden. What begins as a search and rescue mission through the wilderness unfolds into an investigation that uncovers poachers, corrupt public officials, and a conspiracy to take public land. As the mystery expands beyond one man’s disappearance, Colt is caught between his instinct for solitude and a growing obligation to pursue justice.Extension Studie
THREE ESSAYS ON HEALTH SYSTEM BARRIERS TO WOMEN’S ACCESS TO HIGH‑QUALITY HEALTH CARE IN SUB‑SAHARAN AFRICA
No full textDespite remarkable progress in reducing maternal and newborn mortality over the past 20 years, 800 women and 6,500 newborns still die every day globally during delivery or in the days and weeks afterward. These deaths are preventable with high-quality care provided throughout the lifecycle from preconception to childhood. Yet, women-newborn dyads often fall through the cracks of a weak continuum of care, especially after birth. Various factors contribute to these challenges, ranging from individual-level determinants to health-system constraints, such as limited health financing and low quality of care. In particular, postnatal period has received less focus than other periods, and its quality of care remains under-measured. More evidence is needed to identify the key factors that prevent women from accessing life-saving care during this critical time.
The following three chapters investigate how different components of health system influence variations in postnatal care quality and access to reproductive health services. By employing both quantitative and qualitative methodologies, I provide a comprehensive understanding of the health system barriers that impede women’s access to high-quality care. Following the introduction, Chapter 2 uses data from direct delivery observations in public facilities in Dire Dawa Administration, Ethiopia to examine health system competency on risk detection and management for newborns. Results find that both at-risk and healthy newborns receive similarly low quality immediate postnatal care, with non-clinical factors like mother’s education contributing to variation in care quality. Chapter 3 further investigates barriers to care quality for women and newborns after discharge from delivery facilities in Kakamega, Kenya. Employing an explanatory sequential mixed method, the study shows that the content of care received before discharge influences mothers’ decisions to seek routine postnatal care. Key drivers include trust in the provider’s supervision, counseling on the importance of postnatal care, and the formal scheduling for the next postnatal visits. Chapter 4 used Demographic Health Surveys to investigate the impact of disruptions in development assistance for health in social marketing programs, a key health financing scheme in low resource settings, on women’s reproductive health behaviors in Zambia. Analysis adopting difference-in-difference method supplemented by a synthetic control approach shows that funding discontinuation do not affect overall modern contraceptive use or pregnancy rate but do lead to decline in using condoms and oral contraceptives.
Together, this dissertation demonstrates that health systems underperform by providing low levels of routine care quality throughout the postnatal period and by reflecting weakness in health financing that hinder the consistent medical supplies. Findings can be used to design future interventions to improve service quality during the postnatal period and to develop strategies that enhance financing resilience in low-resource health systems.Population Health Science
Investigating the Mechanisms of Cholesterol 25-Hydroxylase in Promoting Pulmonary Fibrosis
No full textPulmonary fibrosis is a chronic and fatal disease characterized by progressive lung scarring. In many cases, its etiology is not fully understood, and treatment options are limited due to the complexity of profibrotic signaling pathways and the interplay between multiple cell types involved in the pathogenesis. Emerging studies have linked disruptions in lipid metabolism to pulmonary fibrosis, though the underlying mechanisms remain poorly defined, and some studies have reported contradictory findings. Our lab recently identified that cholesterol 25-hydroxlase (CH25H), an enzyme that converts cholesterol to 25-hydroxycholesterol (25-HC), promotes lung fibrosis elicited by diverse exposures including the common aeroallergen Alternaria Alternata and the chemotherapeutic agent bleomycin. To further understand the cellular and molecular mechanism(s) by which this occurs, we assessed the function of 25-HC in murine lung in vivo and in human fibroblasts in vitro. We found that 25-HC upregulates type 1 collagen expression in murine lungs and in human lung fibroblasts, suggesting that it promotes the activation of fibroblasts to myofibroblasts, a pathological cell state that readily remodels and stiffens the extracellular matrix. We showed that 25-HC-induced collagen upregulation in human lung fibroblasts is dependent on RORa activation, and also likely involves LXR and av integrin/FAK activation. Furthermore, CH25H is upregulated in lung fibrobalsts by several pro-fibrotic factors including TGF-β1, bleomycin, and the type 2 inflammatory cytokines IL-4 and IL- 13. Collectively, our findings suggest that CH25H drives pulmonary fibrosis through promoting lung fibroblast activation via the 25-HC/RORa axis. This potentially suggests a novel mechanism through which dysregulated cholesterol metabolism exacerbates pulmonary fibrosis and may offer new therapeutic targets for the disease.Graduate Educatio
Structural and biophysical investigations of [4Fe-4S] cluster coordinating proteins in malaria and herbicide biosynthesis
No full textRadical S-adenosylmethionine (RS) enzymes are the largest known enzyme superfamily, consisting of millions of reported sequences. RS enzymes use a [4Fe-4S] cluster to reductively cleave a S-adenosylmethionine (AdoMet) molecule to form a 5′-deoxyadenosine radical (5′-dAdo•). By using the 5′-dAdo•, RS enzymes catalyze a diverse portfolio of chemically difficult reactions. Cobalamin (Cbl)-dependent RS enzymes comprise a subfamily within the RS superfamily which employ both Cbl and 5′-dAdo• to catalyze reactions. Recently, two enzymes were identified as essential for the production of the herbicidal compound Albucidin: the RS enzyme AlsA and the Cbl-dependent RS enzyme AlsB. In this dissertation, we present our progress toward an X-ray crystallographic structure of AlsA and a cryogenic-electron microscopy (Cryo-EM) reconstruction of AlsB. The X-ray diffraction of AlsA crystals is low resolution, mosaic, and twinned, resulting in a 3.7 Å resolution electron density map with a disordered active site. Using Cryo-EM, a 7.12 Å resolution map of AlsB was generated. At 83.5 kDa in size, AlsB is small for Cryo-EM. The Cryo-EM map of AlsB closely resembles a closed conformation of the enzyme, a conformation that remains unobserved in the similar Cbl-dependent RS enzyme OxsB. Additionally, we describe an optimized procedure for the chemical reconstitution of AlsA suitable for structural studies. To assess the thermal stability of AlsA, a NanoDSF-based thermal shift assay was developed, demonstrating the presence of two protein populations. The two populations, hypothesized to be reconstituted and unreconstituted AlsA, react differently to the presence of dithiothreitol, a commonly used reductant for RS enzymes. Our findings suggest thermal shift assays can visualize heterogeneity in protein samples that otherwise could not be observed. Also, NanoDSF provides us with a high throughput method for determining suitable buffer conditions for structural studies for RS enzymes and other oxygen sensitive proteins. Finally, we report the second X-ray crystal structure of the essential lipocalin HAL from the malaria-causing parasite Plasmodium falciparum. Our crystal structure solved in the C2 space group shows a crystal lattice formed by repeated dodecamer rings. We identify chloride anion sites between two monomers, suggesting a role for chloride in the oligomerization of PfHAL. Altogether, this work provides a foundation for the structural investigation of Albucidin Biosynthesis and provides new information toward understand of the role of PfHAL in malaria.Biophysic
Elucidating mechanisms of cellular metabolic dysfunction and lipotoxicity
No full textThe accumulation of lipids is a hallmark of metabolic disease due to disruption of normal functions of cells and tissues, a condition referred to as lipotoxicity. For example, in lipodystrophy, excess lipids build up ectopically in non-adipose tissue, and in obesity, fat deposits in adipocytes are overwhelmed by lipid accumulation. Saturated fatty acids (SFA), such as palmitate, are particularly toxic lipids in skeletal muscle, heart, liver, and pancreatic β-cells and can contribute to obesity-associated diseases.
Although canonical adaptive metabolic processes like lipid storage or desaturation are known cellular responses to saturated fat exposure, the link between SFA metabolism and organellar biology remains an area of active inquiry. We performed a genome-wide CRISPR knockout screen in human epithelial cells to identify modulators of SFA toxicity. We combined unbiased screening methods to identify changes to the cellular lipidome and cellular pathways that were dependent on SFA exposure. This analysis identified Fas-associated factor family member 2 (FAF2) as a mediator of the stress response to SFA exposure.
We further reveal that organellar compartmentalization of metabolism, specifically peroxisomal proteins involved in ether lipid synthesis, are important regulators of lipotoxicity. We found that in addition to lipid regulatory effects, FAF2 is a critical bifunctional coregulator of peroxisomal and fatty acid biology. We further demonstrated the requirement of the ubiquitin-regulatory X (UBX) and UAS thioredoxin-like domains of FAF2 for peroxisomal protein abundance and SFA-induced cellular stress. Our work highlights the role of FAF2 in regulating peroxisomal abundance and function, and the peroxisome as a key organelle in the cellular response to SFAs.Biological Sciences in Public Healt
Transnational Japanese New Religious Movements: Sekai Meshia Kyō in Angola
No full textThis dissertation examines the transnational expansion and transformation of Sekai Meshia Kyō, a Japanese new religious movement founded in 1935 by Okada Mokichi (1882–1955). The group’s expansion from Japan to Brazil, and later from Brazil to Angola and other African countries, reveals how religions traverse and navigate political and cultural boundaries. Based on historical analysis and ethnographic fieldwork in Angola, Brazil, and Japan (2016–2025), I demonstrate that Angola—far from being a peripheral outpost—has become a central hub of Sekai Meshia Kyō, breathing new life into an aging religion from Japan while serving as the consecrated site for the “Sacred Grounds of Africa.” This dissertation also examines the 2017 schism between Sekai Meshia Kyō (SMK) and Sekai Kyūsei Kyō (SKK), arguing that SMK’s post-schism evolution is characterized by the centralization of religious authority under the Kyōshu (spiritual leader) and notable shifts toward Christianity and veganism. By analyzing how SMK’s leadership and adherents reinterpret and enact faith across borders, this study demonstrates how new religious movements adapt to global and local contexts, shaped not only by historical circumstances but also by their transnational networks and evolving faith practices.Religion, Committee on the Study o
Patterning the Vertebrate Retina - Molecular Mechanisms Underlying the Development of Retinal High Acuity Area
No full textThe vertebrate retina is not a uniform sheet of neurons but is patterned into distinct domains, with the central region being uniquely specialized. The ability to see in fine detail relies on this small region specialized for high-acuity vision. Known as the high-acuity area (HAA), this domain is defined by several striking features: a high density of retinal ganglion cells, which serve as the output neurons of the retina; an enrichment of cone photoreceptors, which mediate daylight and color vision; and a complete absence of rod photoreceptors, which instead support dim-light vision. This architecture allows signals from a small number of cones to be transmitted directly to individual ganglion cells, reducing convergence and enabling exceptional spatial resolution. Together, these specializations endow the HAA with its critical role in enabling sharp central vision.
The human HAA, known as the fovea, is distinguished by its characteristic pit-shaped morphology and by being a rod-free, cone-dense region that supports high-resolution tasks such as reading and facial recognition. However, very little is known about the molecular and developmental mechanisms that give rise to this specialized region. This gap in knowledge is compounded by the fact that commonly used mammalian models, such as mouse and rat, do not possess an HAA at all, thus, limiting their use for developmental and disease studies. Interestingly, certain birds possess an HAA that shares many structural and functional features of the primate fovea. Unlike in humans, the chick retina offers ready access to embryonic tissue and is highly amenable to experimental perturbation, making it a powerful system for probing the developmental logic of high-acuity specialization. In this dissertation, we use the chick retina to investigate how the HAA is generated, to define the molecular patterning events that localize and specify this specialized territory, and to understand how these principles extend across species.
First, we characterized the morphological development and cellular composition of the chick HAA, defining when specialized photoreceptor and ganglion cell patterns emerge and how they differ from peripheral retina. Using single molecule fluorescent in situ hybridization (smFISH) in combination with classical histological methods, we identified Fgf8 as a robust molecular marker of the HAA that persists throughout embryonic development. We showed that the ganglion cell layer (GCL) was consistently thickest at the HAA beginning during the period of neurogenesis. This pattern indicates that elevated production of retinal ganglion cells, rather than selective survival or death, accounts for their enrichment in this region. In contrast, rods photoreceptors were entirely absent from the HAA, and analysis of apoptotic markers showed no evidence of rod elimination, suggesting instead that rods fail to be generated there. Together, these findings show that distinct developmental processes (differential neurogenesis, delayed cone accumulation, and restricted rod genesis) combine to build the specialized architecture of the HAA.
We next asked how positional information is encoded to localize the HAA within the naso-central retina. To do so, we developed an integrated framework combining multiplexed gene expression imaging with single-cell transcriptomics, enabling quantitative 2D reconstruction of molecular expression domains. This approach revealed sharp boundaries in signaling pathways, identified novel HAA-enriched candidates, and provided a reproducible spatial atlas of the developing chick retina. By anchoring spatial reconstructions to experimental landmarks such as the Fgf8 expression domain, we demonstrated how expression domains of retinoic acid-Fgf8 signaling pathway components correlate with classical dorso-ventral and naso-temporal patterning axes to establish a unique retinal territory.
Finally, we extended this framework across vertebrate species. By comparing chick, human, and mouse single-cell datasets, we identified conserved axis-based programs as well as species-specific spatial patterns. Both chick and human retinas contained distinct domains consistent with an HAA, whereas mouse retinas resolved primarily into broad DV and NT axes, consistent with their lack of an HAA. Additional comparisons across birds, and reptiles highlighted both conserved and divergent molecular strategies underlying the evolution of high-acuity vision.
Together, our work provides an integrated cellular and molecular framework for HAA development. We investigated how gene expression boundaries, and distinct developmental programs potentially converged to create a specialized retinal territory and further used comparative approaches to understand these findings in an evolutionary context. More broadly, our integration of multiplexed imaging with single-cell transcriptomics offers a generalizable strategy for reconstructing spatial patterning logic in developing tissues. This study not only advances our understanding of human foveal development but also offers new tools to study the origins of tissue specialization across systems and species.Biology, Molecular and Cellula
Leveraging PhagoID to Define How Cytokines Reprogram the Phagosomal Proteome
No full textThe ability of phagocytosing diverse cargoes and maintaining tissue homeostasis under different immune contexts and challenges is what lends tissue resident macrophages their identity as immune sentinels. Previous studies that were aimed towards isolating and studying the macrophage phagosome suffered from certain limitations due to the highly dynamic and interactive nature of this organelle, making its proteomic analysis an especially arduous task. In a recent study, we reported the development of a novel tool called PhagoID which uses a proximity labeling-based strategy for resolving phagosomal lumen proteins with high specificity and efficiency, facilitating their identification using mass spectrometry and downstream proteomic analyses. Here, we validate the use of epigallocatechin gallate (EGCG) as a ROS scavenger capable of minimizing extracellular labeling in the case of PhagoID. Next, we adapted PhagoID to quantify the phagosome lumen proteome of fetal-derived alveolar-like macrophages (FLAMs) under the effect of type I interferon signaling.
The phagocytic activity of alveolar macrophages (AMs) is important both at baseline for routine cleaning of cellular debris, as well as to initiate a strong inflammatory responses to respiratory pathogens. We profiled the phagosomal proteome of FLAMs as a model for primary AMs and found proteins involved in the class I MHC pathway to be the only ER subset enriched in the phagosome on IFN-β activated FLAMs. Additionally, we identified the presence of proteins belonging to 3 families of interferon induced GTPases (IIGPs), including multiple GBPs and all IRGM proteins which have been well recognized for their role in cell autonomous immunity against bacterial infections like Mycobacterium tuberculosis and Chlamydia trachomatis. We also detected the enrichment of the enzyme aconitate decarboxylase (ACOD1/IRG1) involved in the production of the anti-microbial metabolite, itaconate. Going ahead, we propose the design of an itaconate biosensor targeted to the endosomal and lysosomal compartments to understand which host factors govern itaconate trafficking to phagosomes. Thus, using PhagoID enabled us to gain important insights into how IFN-β, a cytokine known for its highly context-dependent role in case of bacterial infections, can alter the phagosome proteome of AMs.Medical Scienc
Cell types of interoception and their response to acute injury
No full textInteroception is the ability of an organism to sense and regulate its internal states. Just as external sensory organs transduce environmental cues of various modalities, specialized cells are responsible for monitoring internal conditions within the body. However, unlike our exteroceptive abilities, the sensory mechanisms and circuits that underlie interoception are not well characterized and remain less understood.
Cells that comprise the sensory tissues important for interoception are highly specialized and express unique proteins that confer their ability to perform their specific function. Single-cell RNA (scRNA) sequencing provides a snapshot of the transcriptome of individual cells and provides a comprehensive and unbiased approach to interrogating molecular diversity that enables transduction and transmission of internal status. To gain a better understanding of the molecular diversity that permits interoception, I have worked on multiple projects atlasing interoceptive sites. The first site assayed mixed primary and higher-order sensory neurons of the Area Postrema, an anatomically privileged brain region that is responsible for conveying the sense of visceral malaise. The second site includes enteroendocrine cells (EECs) - primary sensory cells of the gut responsible for communicating nutrient status in the digestive tract. Collaborative work on these projects highlights the advantage single-cell transcriptomics offers to the facilitation of scientific discovery.
One major body-to-brain connection that has benefited from cell-type analysis in recent years is the vagus nerve. In the mouse, the vagus nerve is fused with the glossopharyngeal nerve. Afferents of these cranial nerves (CN IX and X) serve a wide array of physiological functions, helping establish tonic control of breathing, nutrient intake, blood pressure maintenance, and more. The cell bodies of CN IX and X reside in the nodose, petrosal, and jugular ganglia (NPJg)
and are diverse in their transcriptomic landscapes. However, mapping the transcriptionally defined identity of a neuron to its physiological role has proven difficult. My thesis work combines the anatomy and physiology of interoception with single-cell transcriptomics, focusing on adding more biological context to NPJg scRNA data. Using single-nucleus RNA sequencing, we provide the first detailed molecular characterization of the response to acute axotomy in the NPJg. We observe that a common transcriptional program is activated in response to injury. We further investigate vagal subtypes based on transcriptomic profiles and their branch contributions, offering new insights into the relationship between molecular identity and the complex branching anatomy of the vagus and glossopharyngeal nerves.Biological and Biomedical Science
Power and Enterprise
No full textThis thesis examines the interplay between State Power and Multinational Enterprise behavior at the intersection of International Relations and International Business. Adopting a Realist framework emphasizing anarchy, security, and power competition, integrated with Dunning’s OLI paradigm (ownership, location, and internalization advantages), it addresses the question: How do the observed actions of multinational enterprises challenge or reinforce prevailing theories in International Relations and International Business, and under what conditions does an integrated Realist–OLI mechanism best explain outcomes? Using a qualitative multiple case study design, the analysis draws on historical and contemporary examples—the Dutch East India Company, United Fruit Company, Huawei, and Emirates Airlines—to explore coproduced outcomes through theoretical triangulation, chronological narratives, and cross-case synthesis.
Findings reveal patterns of convergence, such as state-corporate symbiosis and control of strategic chokepoints, enabling mutual gains in power and profit, alongside divergences like asymmetric time horizons and moral hazards that expose tensions in agency and logic. These dynamics highlight Multinational Enterprises as pivotal actors in geopolitical arenas, blurring state-firm boundaries and fostering institutional innovations like charters and compliance architectures.
This thesis contributes to interdisciplinary scholarship by refining a hybrid framework while reflecting on the evolution of sovereignty in a fragmenting world order.Extension Studie