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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
Microbial Evolution through the Lens of Metagenomics and Archaeogenetics
No full textMicrobial evolution is fundamental to fields ranging from industrial bioprocesses to agriculture and medicine, governing everything from pathogen emergence and transmission to environmental ecosystems and biotechnological advancement. However, microbiology’s historical reliance on culture-based methods and primarily clinically focused studies has limited our ability to fully integrate ecological and evolutionary perspectives, leaving critical gaps in knowledge regarding the genomic structure, diversity, and evolutionary dynamics of microbial populations. Host-microbial associations and microbial community interactions in particular drive several key biological events across Earth’s history - from organelle origins to evolutionary arms race dynamics. Recent advances in sequencing technologies have revealed a startling expansive picture of the genomic diversity of symbiotic microbes – including the enigmatic Candidate Phyla Radiation (CPR) – a group of abundant yet largely uncultured, ultra-small bacteria that are found ubiquitously from deep-sea hydrothermal vents to the human microbiome. In this dissertation, I integrate metagenomic, pangenomic, and paleogenomic approaches to investigate microbial eco-evolutionary dynamics. Altogether, this work illuminates how genomic plasticity facilitates microbial adaptation and diversification, with broad implications for the ecological understanding of microbial relationships and insights into host-microbial co-evolution.
In my first chapter, I utilize a novel statistical framework that combines longitudinal metagenomic sampling with clonal sequencing to track the strain-level population dynamics of industrial yeast (Saccharomyces cerevisiae) lineages across two Brazilian bioethanol refineries over two industrial seasons. The results show diverging evolutionary trajectories: one plant’s yeast community is characterized by the stable dominance of a domesticated starter lineage, whereas another plant experiences invasion by foreign but closely related strains. These findings highlight how ecological forces, such as competition and invasion, influence microbial communities within industrial processes in relation to industrial operational stability.
In my second chapter, I develop a scalable, integrative computational pipeline that combines metagenomic assembly and pangenomics to characterize the genome structure of over two thousand Parcubacteria (OD1) genomes in their environmental context, including novel genomes recently discovered from deep-sea anemones. Utilizing this approach, I demonstrate that Parcubacteria – despite having extremely reduced core genomes with limited metabolic capabilities – retain a flexible and modular accessory genome across clades, structured by phylogeny rather than habitat specificity. With a core genome that encodes primarily informational systems, DNA recombining and repair mechanisms, environmental sensing, and a conserved type IV pili, the Parcubacteria core genome reflects a host-dependent interaction-focused lifestyle. In contrast, the accessory genome exhibits remarkable modularity, with lineage-specific gene clusters encoding diverse specialized functions in secondary metabolism, stress responses, and signal transduction systems, with complete turnover between clades. Strikingly, co-occurrence analyses also show extensive genomic plasticity driven by insertion sequence (IS) elements – especially the IS21 family, and reveal structured mobility of antibiotic resistance genes (ARGs) and accessory gene clusters, highlighting ongoing gene transfer and mobility without disrupting core genomic integrity. Altogether, the results showcase a unique evolutionary strategy for small genomes where genome reduction is coupled with modular genomic innovation. Altogether, these findings redefine genome reduction paradigms by illustrating how Parcubacteria leverage dynamic accessory content and interaction alongside its genomic minimalism for flexible specialization and ecological persistence.
My third chapter employs a combination of archaeogenetics and Bayesian tip-calibrated phylogenetics to reconstruct the evolutionary history and habitat transitions of the prominent CPR lineage Saccharimonadia (TM7), a globally distributed bacterial group that is also commonly found in human microbiomes. Leveraging ancient DNA derived from archaeological samples from ancient human populations and Neanderthals spanning a range of 100,000 years, as well as oral microbiome samples from underrepresented traditional farming and hunter-gatherer communities, I curated a dataset of 4,317 genomes, establishing one of the most comprehensive temporal datasets available for a CPR bacterial group. I identified at least seven independent habitat transitions from environmental reservoirs into mammalian hosts, with distinct lineage diversifications driven by host colonization and subsequent specialization in oral or gut biofilms. Bayesian evolutionary analyses were used to calculate substitution rates, with TMRCA (Time to the Most Recent Common Ancestor) dating diversification events into the Pleistocene epoch. Notably, my analyses also uncovered several previously unrecognized human-associated lineages that persist within ancient and non-industrialized human populations, indicating underrepresentation linked to human lifestyle or subsistence differences. Altogether, these findings underscore the significance of ancient DNA approaches in providing high-resolution evolutionary modeling for tracking long-term microbial evolutionary trajectories, and revealed how evolutionary events shape host-specific diversity patterns observed in modern Saccharimonadia populations.Biology, Organismic and Evolutionar
Pragmatic Embodied Spoken Instruction Following in Human-Robot Collaboration with Theory of Mind
No full textSpoken language instructions are ubiquitous in agent collaboration. However, in real-world human-robot collaboration, following human spoken instructions can be challenging due to various speaker and environmental factors, such as background noise or mispronunciation. When faced with noisy auditory inputs, humans can leverage the collaborative context in the embodied environment to interpret noisy spoken instructions and take pragmatic assistive actions. In this paper, we present a cognitively inspired neurosymbolic model, Spoken Instruction Following through Theory of Mind (SIFToM), which leverages a Vision-Language Model with model-based mental inference to enable robots to pragmatically follow human instructions under diverse speech conditions. We test SIFToM in both simulated environments (VirtualHome) and real-world human-robot collaborative settings with human evaluations. Results show that SIFToM can significantly improve the performance of a lightweight base VLM (Gemini 2.5 Flash), outperforming state-of-the-art VLMs (Gemini 2.5 Pro) and approaching human-level accuracy on challenging spoken instruction following tasks.Computer ScienceAccepted Manuscrip
Cellular and functional heterogeneity of interhemispheric connections in the anterior olfactory nucleus
No full textThe olfactory system in most mammals begins with two unique air flows separated by a nasal septum. Olfactory signals are then relayed to the brain in two separate olfactory bulbs, from which the brain produces a unitary perception of the olfactory environment. The mechanisms by which the brain combines these separate inputs to obtain perceptual unity remain unknown. The anterior olfactory nucleus (AON) is the earliest olfactory cortical area to project contralaterally, making it an excellent candidate for the combination of bilateral olfactory information. The AON is also implicated in social behavior and olfactory memory. However, the specific neuron types involved in the interhemispheric AON connection are unknown, as are the functional consequences of contralateral input to the AON. Identifying the underlying circuitry within the AON is critical to understanding its role in the olfactory cortex and olfactory-dependent behaviors.
Interhemispheric projections between the AON pars principalis in mice are heterogeneous, with projection density varying widely between subregions. I have demonstrated that interhemispheric projections appear to be from a subtype of excitatory neurons expressing vesicular glutamate transporter-1 (VGLUT1-positive) and form synapses with both excitatory and inhibitory cells in the contralateral AON. These contralaterally projecting neurons exhibit distinct patterns of projections to downstream olfactory and non-olfactory cortical areas when compared to all VGLUT1-positive neurons in the AON. Additionally, I propose genetic markers for the identification of contralaterally projecting neurons based on spatial transcriptomic data and single-nucleus RNA sequencing. These findings suggest that contralaterally-projecting neurons form a distinct network capable of inducing specific and complex patterns of activity throughout the brain.
I investigated the functional properties of contralateral AON projections both in vitro, through slice electrophysiology, and in vivo, through behavioral manipulation. Stimulation of contralaterally-projecting fibers results in monosynaptic excitation followed by polysynaptic inhibition. The response probability for the connection was 0.45, with 21/47 recorded cells displaying EPSCs. The same responses were also seen in VGAT-positive neurons in the AON, corroborating the anatomical findings of synapses onto both excitatory and inhibitory neurons. In a pilot behavioral study, I also suggest that contralateral projections are necessary for the transfer of learned odorant associations by mice with unilateral naris occlusion in a go-nogo task. Mice whose anterior commissures were severed were both slower to learn the initial task and showed inefficient transfer of learning to a new odor set.
Overall, this work characterizes the circuitry underlying interhemispheric communication in the AON, investigates the resulting activity from its activation, and provides insights into the role of interhemispheric projections in olfactory behavior. This work will contribute not just to our understanding of the AON but also to the processing and computation done by the olfactory cortex. Insights from the cellular and functional diversity within the AON will guide future research on the role of the AON in olfactory-related disorders.Neuroscienc
Assessment of Efficacy of Human and Organizational Performance Methodology at a Large Biopharma Company
No full textThis study examines how the implementation of Human and Organizational Performance (HOP) principles contributes to an organization’s evolution into a learning organization. HOP, a philosophy centered on system-based thinking, risk management, and collaborative learning, provides a framework that shifts organizations away from blaming culture and toward continuous improvement. To evaluate the relationship between HOP adoption and learning‑organization behaviors, multi‑year trends in deviations, root‑cause classifications, corrective and preventive actions (CAPAs), and Human Performance Assessment (HPA) maturity were analyzed.
The results demonstrate a strong alignment between HOP implementation milestones and improved operational and learning outcomes. Deviation initiation rates declined steadily over several years, while root‑cause analysis shifted from Human Factors to Method‑based causes, indicating increased system‑based thinking. The rise in system‑focused CAPAs, particularly Change Controls, further reflects a move toward strengthening work design and organizational reliability. Periods of reduced HOP oversight—most notably following the dissolution of the HOP team in mid‑2024—corresponded with declines in training maturity, leadership engagement, and system‑level corrective actions, reinforcing the importance of sustained governance.
Overall, the findings support the hypothesis that implementing HOP principles enhances learning‑organization capabilities by improving psychological safety, problem solving, and error reduction. Re‑establishing strong HOP governance and leadership accountability offers a clear path to stabilizing performance, reducing deviation frequency, and embedding durable organizational learning.Extension Studie
Leveraging Big Data Modeling and Machine Learning for Improved Disease Prevention
No full textModifiable risk factors of chronic disease can be effectively addressed by maintaining a healthy lifestyle, which is a key component of the primary prevention of chronic disease—that is, preventing disease before it occurs. In recent years, ultra-processed foods (UPF) have been dominating the food supply of high-income countries, with consumption rapidly increasing in middle-income countries. A growing body of literature suggests that UPF exert adverse effects on health. However, data remain limited regarding their associations with mortality outcomes in large prospective cohorts with extensive follow-up and repeated dietary assessments. Beyond diet, physical inactivity represents another major contributor to the global burden of chronic disease. The health benefits of physical activity have been well established, but the longitudinal patterns of physical activity associated with long-term health outcomes remain insufficiently understood. Few studies have investigated whether physical activity requires consistent adherence to the recommended level, or whether sporadic high-volume activity interspersed with inactivity can confer sustained health benefits. Such information is critical to refine guidelines.
Secondary prevention, another aspect of prevention strategies, focuses on early detection and prompt treatment of disease among asymptomatic individuals at elevated risk. High-quality evidence demonstrates that colonoscopy screening, which enables the detection and removal of precursor lesions (colon polyps), effectively lowers colorectal cancer (CRC) incidence. However, there is insufficient evidence on the incremental effectiveness of surveillance colonoscopy after polyp removal, and the benefit may vary in magnitude between the high- and low-risk groups. Moreover, no effective strategies have been developed to prevent CRC occurring within recommended surveillance intervals after polypectomy (i.e., interval cancer), arising primarily from missed or incompletely resected lesions with suboptimal index colonoscopy quality. Therefore, there is an urgent need to advance risk stratification for tailored post-polypectomy surveillance strategies.
In Chapter 1, utilizing high-quality data obtained through valid repeated dietary assessments from two large US prospective cohorts including the Health Professionals Follow-up Study (HPFS) (1986–2018) and the Nurses’ Health Study (NHS) (1984–2018), we examined the associations of total UPF and nine UPF subgroups with risk of all-cause and cause-specific mortality including cancer, cardiovascular, respiratory, and neurodegenerative causes. Among 39 501 men and 74 563 women followed up for a median of 31 and 34 years, respectively, we observed that higher UPF consumption was associated with higher risk of all-cause mortality and higher risk of mortality from other causes than cancer or cardiovascular disease. No associations were found for cancer or cardiovascular mortality. The positive associations were mainly driven by meat/poultry/seafood-based ready-to-eat products, sugar- and artificially sweetened beverages, dairy-based desserts, and ultra-processed breakfast foods. In the joint analysis of assessing the individual and combined impact of food processing components and dietary quality, dietary quality was observed to exert a more predominant influence on mortality than UPF consumption. The findings provide support for limiting certain types of UPF consumption for long-term health.
In Chapter 2, utilizing the physical activity data obtained through repeated assessments for 32 years in three large US prospective cohorts (HPFS, NHS, NHS II), we examined long-term physical activity patterns during adulthood in relation to risk of major chronic diseases including type 2 diabetes, major cardiovascular disease, and total cancer. Among 45 426 men and 186 062 women, we observed that greater consistency (measured by the percentage of follow-up years meeting the recommended physical activity level) was associated with lower disease risk within each tertile of the cumulative average volume, and vice versa. Maintaining a volume of 8–10 MET-hours/week on average throughout the follow-up was related to a greater risk reduction than sporadic high-volume activity mixed with inactivity. Compared with individuals who were consistently inactive from ages 40 to 60, those maintaining a volume around the recommended level had a 12% lower risk after age 60, while highly active individuals throughout the period had a 28% lower risk. Overall, the findings emphasize the importance of maintaining physical activity over the long term for sustained health benefits.
In Chapter 3, we drew electronic health records (EHR) data from the Mass General Brigham (MGB) Colonoscopy Cohort that recruited all colonoscopies performed in patients aged 18 and older between October 2007 and August 2023 at Brigham and Women's Hospital, Brigham and Women's Faulkner Hospital, and Massachusetts General Hospital. After exclusions, 79 120 patients who underwent polypectomy at the index colonoscopy were included in the analysis, 155 of whom developed incident post-polypectomy CRC over a median follow-up of seven years. Utilizing routinely available EHR data spanning demographics, clinical history, colonoscopy quality indicators, and polyp findings from the index colonoscopy, we built machine-learning survival models to predict risk of post-polypectomy CRC. Each model was fine-tuned through five-fold cross-validation. The developed models—Lasso Cox regression, random survival forest, and gradient boosted model—demonstrated good performance, with test Uno’s C-statistics of 0.74 (0.67, 0.79), 0.69 (0.62, 0.76), and 0.72 (0.65, 0.78), respectively. Key predictors identified consistently across models included age, maximum adenoma size, maximum sessile serrated polyp size, polyp detection rate, and bowel preparation quality of index colonoscopy. This study demonstrates the feasibility of developing a clinically applicable, EHR-based risk prediction model for post-polypectomy CRC.Population Health Science
Structural and Functional Studies of Transcription Through Chromatin
No full textTranscription elongation by RNA polymerase II (Pol II) through chromatin presents a formidable challenge, as nucleosomes impede Pol II progression. Despite the nucleosomal barrier, eukaryotic cells routinely achieve high-fidelity gene expression while preserving chromatin structure, ensuring both transcriptional fidelity and epigenetic continuity. This dissertation investigates the molecular mechanisms by which Pol II overcomes the nucleosomal barrier and maintains nucleosome integrity during elongation. Through cryo-electron microscopy and in vitro biochemical approaches, I characterize structural intermediates that reveal how Pol II and associated elongation factors coordinate histone displacement, retention, and reassembly. I describe a nucleosome retention transcription elongation complex in the absence of FACT and a distinct hexasome intermediate stabilized by multiple acidic blocks in the N-terminal domain of SPT6 during FACT-assisted transcription. Together, these structures visualize chaperone-dependent and -independent models of nucleosome retention. Complementary in vitro assays further demonstrate how transcription-generated nucleosomal states modulate the enzymatic activity of transcription-associated chromatin modifiers RNF20/40-UBE2A ubiquitin ligase and MLL1 complex. Together, these findings establish a structural and biochemical framework for how the elongation machinery preserves chromatin architecture while directly coupling nucleosome traversal to the installation of transcription-associated histone modifications.Biological and Biomedical Science
Metabolic flux sensing of sugars in Saccharomyces cerevisiae
No full textA canonical view of nutrient sensing is that cells sense the concentration of nutrients. However, it is sometimes beneficial to regulate cellular processes based on the metabolic flux through a pathway, instead of the concentration of a nutrient. The mechanisms to achieve metabolic flux sensing remain largely unclear. The observation of flux-dependent regulation is also limited.
This dissertation work explores the phenomena and mechanisms of metabolic flux sensing of sugars in budding yeast Saccharomyces cerevisiae. Galactose and glucose are two types of sugar used by cells as carbon sources for growth. Cells sense the sugars for proper regulation of their metabolism. In the case of galactose, cells sense galactose for deciding the induction of the galactose-utilization (GAL) pathway. In the case of glucose, cells sense glucose for repressing genes involved in utilizing other carbon sources.
To study the metabolic sensing processes, first, a series of tools are developed to enable the necessary genetic perturbation and control of metabolism in living cells. A high-throughput imaging method is developed to monitor the perturbations and measure signaling readout of the pathway. Then, we study the signaling role of galactokinase Gal1 in the GAL pathway, and report that the enzyme can couple its catalytic activity to signaling, resulting in a signaling output proportional to the metabolic flux. Next, in the glucose repression pathway, I find that glucose repression depends on metabolic flux of glucose. However, I rule out the signaling role of hexokinase Hxk2, and find that Mig1 controls glucose repression via a non-canonical mechanism. Some candidate metabolites potentially for determining glucose repression are identified through differential perturbations of glycolytic metabolites and model predictions. Last, I describe a growth curve measurement device I developed, which enables easy and accurate measurement of growth curves.Systems Biolog
Spatial Organization of Cytoplasm Studied with Xenopus Egg Extract
No full textSpatial organization is essential for biological function at all scales. Within the cytoplasm, various processes require dynamic distribution of intracellular components and establishment of spatial compartments. During mitosis, cytoplasmic organelles as well as chromatin are partitioned into daughter cells; for protein quality control, aggregated proteins are sequestered into specific aggresome structures. In my thesis, I used Xenopus laevis egg extract as a model system to study spatial organization of cytoplasm in these processes.
Cell division during early embryogenesis requires spatial organization of the cytoplasm on length scales of up to a millimeter in species with large eggs. Questions that remain unclear include how intracellular forces are generated at such enormous spatial scales, and how the abundant cytoplasmic components are partitioned prior to cytokinesis. Microtubules are thought of as the main cytoskeletal network that spans the cytoplasm to organize mitosis and cytokinesis, while research on actin filaments and myosin II (together known as “actomyosin”) has mostly been focused on their function at the actin-rich cortex. Whether bulk actomyosin within the cytoplasm plays any role in cell division remains poorly understood. Here we developed a cell-free system with all cytoskeletal networks that recapitulated early embryonic cleavages of the frog Xenopus laevis, and used this system to study the role of bulk actomyosin. Cell-free divisions exhibited multifaceted defects when cytoplasmic F-actin was perturbed. Bulk actomyosin played a major role in partitioning cytoplasm after mitosis. It mechanically strengthened cytoplasm and microtubule asters, at the same time developed spatial heterogeneity in both material properties and stress distribution by setting up the actin depletion zone at future cleavage plane. Microtubule asters behaved as actin-reinforced composite gels that integrated centrosomes, nuclei, and organelles during their partition after mitosis. Actomyosin contraction provided driving force for the astral composite to move away from future cleavage plane. A fluid dynamics model with contractile stress recapitulated cytoplasmic flows away from the midplane. These findings uncover a role of bulk actomyosin in global partitioning of cytoplasm in large embryonic cells and lead to a novel framework for understanding cytoplasm as a composite gel whose dynamics are governed by principles of active fluid mechanics.
Beyond cell division, the second part of my thesis studied how protein aggregates are selectively transported to the aggresome to maintain protein homeostasis. Using the more conventional CSF egg extract, we reconstituted MTOC-directed aggregate transport in Xenopus egg extract. High-resolution single-particle tracking revealed that dynein-mediated aggregate transport was highly episodic, with average velocity positively correlating with aggregate size. We propose that size selectivity in this process enables efficient intracellular transport of protein aggregates.Biology, Molecular and Cellula
Elucidating the mechanistic role of NDRG1 in DNA repair, replication, and chemoresistance through characterization of novel protein-protein interactions
No full textFaithful DNA replication is critical for maintaining genomic stability but is constantly challenged by endogenous and exogenous replication stress, a hallmark of cancer. While many chemotherapies used to treat cancer induce replication stress, cancer cells frequently develop resistance, underscoring the need to understand mechanisms by which tumor cells overcome this stress and enhance their DNA repair efficiency. We have identified a novel ECM-induced resistance pathway involving N-myc downstream regulated gene 1 (NDRG1) that results in NDRG1-dependent protection from chemotherapy-induced replication stress in pancreatic cancer cells.
To uncover the molecular basis of NDRG1-mediated DNA repair, we utilized a BioID proximity labeling screen and identified Transglutaminase 2 (TGM2) and Meiotic Recombination 11 (MRE11) as two novel NDRG1 binding partners. We characterized the physical protein-protein interactions and functional interactions of these complexes using biochemical, co-immunoprecipitation, and DNA fiber assays.
We found that the NDRG1-TGM2 interaction is enriched upon hydroxyurea and gemcitabine-induced replication stress and is regulated by ECM-induced signaling, and serum- and glucocorticoid-induced kinase 1 (SGK1)-mediated NDRG1 phosphorylation. Importantly, we discovered that TGM2 modulates DNA replication fork homeostasis, and this function was dependent on both the nuclear localization and transamidase catalytic activity of TGM2. Furthermore, we identified a putative NDRG1-TGM2 binding site and demonstrated that this physical interaction contributes to efficient DNA replication fork progression and stalled fork recovery. This work establishes TGM2, an enzyme traditionally regarded to function in the cytoplasm and extracellular space, as a novel regulator of nuclear DNA replication.
The NDRG1-MRE11 interaction was found to be enriched during late S/early G2 phases and upon treatment with fork stalling agents. The lack of binding between purified MRE11 and NDRG1 suggests the interaction is indirect, implying the existence of a regulatory scaffold or post translational modification necessary to mediate the interaction. Functionally, we demonstrated that NDRG1 and MRE11 cooperate to promote the degradation of nascent DNA at stalled forks.
Taken together, our work identified novel mechanistic functions of NDRG1 in DNA replication and repair, through its interactions with TGM2 and MRE11, and provided fundamental new insights into the functions and interplay between these proteins. Furthermore, our work positions NDRG1 as a promising therapeutic target to suppress PDAC chemoresistance.Biological and Biomedical Science