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Integrating environmental, clinical, and metadata streams for enhanced viral surveillance
No full textThe global burden of respiratory viral infection is high, due not only to the severe disease and outbreak potential of specific viruses or viral variants, but also to the great diversity of circulating viruses. Genomic surveillance of these viruses serves many purposes, including: identification of an unknown agent of disease, classification of new variants, interpretation of
disease spread during outbreaks, and data generation relevant for therapeutic or vaccine development. Traditionally, genomic surveillance has often been limited to sequencing clinical samples for only a specific pathogen of interest, i.e. single-pathogen approaches.
In this dissertation, I demonstrate the relevance of integrating other tools and approaches into surveillance systems, including: wastewater monitoring and surveillance, sequencing of rapid tests, and pan-pathogen sequencing approaches. In Chapter 2, I demonstrate the efficacy of a multifaceted university surveillance program implemented in response to the COVID-19 pandemic during the 2020-2021 academic year. In Chapter 3, I optimize sequencing from SARS- CoV-2 rapid tests and implement this methodology to analyze an isolated outbreak in a senior housing facility in 2022. In Chapter 4, I introduce a new metadata standard for wastewater genomic surveillance projects, developed in 2023 alongside an international cohort of scientists and public health officials. In Chapter 5, I present an unbiased metagenomic sequencing approach and leverage it to simultaneously surveil dozens of viruses circulating in Boston during the 2023-2024 respiratory season.
Collectively, these projects advance viral surveillance efforts through demonstrating where non-standard or underutilized tools can have high impact in our understanding of viral disease.Systems Biolog
More than the sum of its parts: the molecular mechanism of Oskar
No full textHow do microscopic molecules coordinate complex biological programmes? This thesis investigates the molecular mechanisms of the Drosophila melanogaster protein Oskar, which scaffolds the assembly and patterns the organisation of germline fate determinants in the developing oocyte. First, we tested long-standing hypotheses about Oskar’s domain-level molecular interactions in vivo using a suite of genetic perturbations, revealing that its domains act non-redundantly and cooperatively to assemble germ plasm components. This updated, nonmodular model of Oskar’s function aligns with its emergent role in nucleating germ granules, ribonucleoprotein particles enriched in germline determinants. Given the characterisation of germ granules as gel-like condensates, I developed a platform for high-resolution live imaging of these structural units and designed experiments that can be used in future work to test whether germ granule material properties correlate with functional outcomes. These experiments address critical questions about the functional relevance of biomolecular condensates in development. Finally, motivated by Oskar’s known role in neuronal granules in the larval peripheral nervous system, we investigated whether Oskar’s function extends beyond the germline to the Drosophila brain. Together, this thesis positions Oskar as a model for studying the biophysical and functional logic of granular organisation, offering insights into how local molecular interactions give rise to cell fate decisions across cellular and developmental contexts.Biology, Molecular and Cellula
When Faith Is No Longer the Gate: Lay Buddhist Navigation of Care in Contemporary Japan
No full textThis dissertation examines contemporary Japanese lay Buddhist engagement in social welfare through a case study of Kōdō Kyōdan, a Tendai-derived lay Buddhist organization founded in 1936. While a growing body of literature has explored Buddhism’s social contributions and its public role in Japan, gaps remain in understanding the relationship between lay Buddhism and established temple Buddhism, as well as the connections between Buddhist social engagement and civic participation. This study positions lay Buddhists as key nodes in the largely overlooked network of Buddhist and civic organizations by analyzing their evolving interactions with both religious and secular actors. Based on historical and ethnographic research within the theoretical framework of secularization, this dissertation argues that social welfare as a legally and publicly recognized secular sphere both enables and compels Kōdō Kyōdan members to navigate and reconstruct their Buddhist identities in efforts to rejuvenate their religious tradition and broader society. Structured into five main chapters, this study traces Kōdō Kyōdan’s doctrinal development, its postwar public image-building efforts, the dynamics of its eldercare and childcare programs with internal and external stakeholders in the nonprofit sector, and the current leadership’s strategies for sustaining the organization’s legacy and operations. By highlighting lay Buddhists’ negotiation of their distinctive roles in Buddhist and civic communities, this research contributes to broader discussions of religion’s public role in contemporary societies.Religion, Committee on the Study o
Exploring the Mechanisms of Multiple Sclerosis and The Role of Intestinal Microbiota Dysbiosis – A Comprehensive Scoping Literature Review of Pathogenic Mechanisms
Full text linkMultiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder that damages myelin in the central nervous system through autoimmune attacks leading to neurological disability in young adults. Research shows that changes in gut microbiota may influence the development of MS with limited clinical evidence. This scoping literature review analyzed the relationship between intestinal microbiota and its effects on MS progression and disease course and activity. Following PRISMA-ScR guidelines, multiple databases were searched. Sixteen studies with 1,052 MS patients and 690 healthy controls from 12 countries were analyzed. Most studies (81%) used crosssectional design; most participants (70%) were female with relapsing-remitting MS (70.5%). Analysis of microbial diversity produced no uniform results, but specific taxonomic changes were detected. SCFA-producing bacteria including Bacteroidota, Roseburia inulinivorans, and Bifidobacterium were present at lower levels in MS patients, but their presence was associated with improved clinical results. The species Clostridium and Collinsella aerofaciens linked to negative results and higher disability scores. Studies revealed SCFA levels dropped significantly in MS patients with major decreases in butyrate. This review shows MS patients have persistent gut microbiota imbalance involving decreased SCFA-producing bacteria instead of overall diversity changes, identifying gut microbiome changes as a major factor leading to MS progression. Future research needs to study MS-related microbiomes for diagnostic and therapeutic applications by studying their characteristics and modification methods.Extension Studie
The Synergy of Real-World Evidence, Transportability, and Decision-Analytic Modelling in the Evaluation of Disease Screening Programs
No full textDecision Science is an interdisciplinary field that focuses on generating and integrating evidence to understand, inform, and optimize decision-making. In this dissertation, I used decision-analytic modelling to evaluate the cost-effectiveness of an emerging class of tuberculosis (TB) infection diagnostics; I leveraged real-world data and observational study designs to improve our understanding of long-term mortality following TB diagnosis; and, I developed a novel framework that integrates causal inference with decision analysis to quantify bias in value of information analyses arising from transportability issues. Collectively, this dissertation demonstrates the synergy of real-world evidence, transportability methods, and decision-analytic modelling in guiding resource allocation of disease screening programs and advancing healthcare research.
In Chapter 1, I evaluated the cost-effectiveness of using host-response-based transcriptional signatures (HrTS) to screen for incipient tuberculosis (TB) among migrants arriving in the United States. HrTS have emerged as promising tools to identify individuals with elevated risks of developing TB disease. In this study, I created an individual-based discrete event simulation model to compare the projected health and economic impact of four post-arrival TB screening strategies. Strategies included no screening, screening using conventional interferon gamma release assays (IGRA-only), IGRA followed by HrTS (IGRA-HrTS), and HrTS-only, based on the WHO Optimal Target Product Profile for HrTS. Cost- effectiveness varied by TB incidence in migrants’ countries of origin, with no screening favored for very low-incidence settings. Overall, HrTS may be cost-effective in specific migrant subgroups, but results are sensitive to several assumptions, including progression risk trends post-entry.
In Chapter 2, I leveraged claims data, national TB and mortality registries, and electronic health record to quantify long-term mortality risks associated with pulmonary TB. Individuals with a history of TB have been shown to face elevated long-term mortality, but the impact of TB disease, as opposed to underlying risk factors, on mortality risks remains unclear. In this study, I estimated the long-term mortality risks among individuals with pulmonary TB compared to matched individuals without TB using a retrospective cohort design in Taiwan. Using coarsened exact matching with a risk set sampling approach, we constructed a cohort of 2,038 TB cases and 6,114 matched controls, followed for a median of 7.2 years. Using Cox regression models with time- varying coefficients, the 10-year survival probability among TB exposed individuals was estimated to be 17 percentage point lower than their unexposed counterparts, with one-third of this survival difference attributable to post-TB effects. The findings highlight the importance of early TB detection and prevention. They also indicate that not accounting for long-term TB mortality risks may underestimate the value of TB intervention programs in policy modeling studies, affecting resource allocation decisions.
In Chapter 3, I bridged causal inference and decision science methodologies to enhance the quality of evidence translation from clinical trial findings into real-world healthcare decisions. Decisions on whether to adopt new healthcare technologies often rely on evidence from randomized controlled trials (RCTs). However, trial and target populations often differ in important ways that can limit the generalizability and transportability of RCT results, raising questions about the need for additional evidence. Value of information (VOI) analysis can help guide research investment decisions by quantifying the value by reducing uncertainty before making policy decisions. However, conventional applications of VOI methods in health care research do not formally address biases that could arise from transportability issues. To address this gap, we proposed a novel framework that incorporates transportability methods from causal inference literature into VOI estimation to more accurately calculate the value of new research (expected value of sample information (EVSI)). We formally defined metrics to quantify components of systematic errors in EVSI calculations when transportability issues are neglected. Finally, we demonstrated this proposed approach through a simulation study and a case study using data from the National Lung Screening Trial. This novel approach has the potential to enhance the quality of evidence translation and the efficiency of clinical trial designs.
Health Polic
Advancing Chemical Transport Modeling for Air Quality, Satellite Retrievals, and the Clean Energy Transition
Full text linkTropospheric oxidant chemistry affects air quality by controlling the formation pathways of air pollutants. It also determines the atmospheric lifetime of key greenhouse gases (GHGs) such as carbon dioxide (CO2) and methane (CH4), as well as indirect GHGs like hydrogen (H2). GEOS-Chem is a state-of-the-science atmospheric chemistry model that represents our current understanding of tropospheric oxidant chemistry. The GEOS-Chem chemical transport model (CTM) is used to support the satellite retrievals of air pollutants like nitrogen dioxide (NO2) and to assess the warming potential of GHGs.
Recent advances in satellite observations of air pollutants (e.g., NO2) have emerged with the launch of three geostationary satellites: GEMS (2020), TEMPO (2023), and Sentinel-4 (2025). GEMS is the first geostationary satellite that provides hourly NO2 data over East Asia, rather than just one observation per day. As a result, improving our understanding of geostationary satellite retrievals and interpreting hourly data observed from it is an important task.
In this work, we first evaluate the ability of GEOS-Chem to accurately simulate the tropospheric oxidant chemistry over East Asia by comparing model output with an extensive suite of aircraft measurements from the KORUS-AQ campaign. Following this validation, we use GEOS-Chem vertical profiles to support geostationary satellite retrievals and investigate how diurnal variation in NO2 profiles affects hourly NO2 satellite retrievals (Chapter 1).
Next, we examine how the diurnal variation in column NO2 observed by geostationary satellite differs from that measured in surface NO2 measurements. We leverage GEOS-Chem’s ability to separate the effects of chemistry, transport, and emissions to interpret the observed NO2 variation (Chapter 2). Lastly, during the KORUS-AQ aircraft campaign, we identified a discrepancy between observed and modeled concentrations of methyl hydroperoxide (CH3OOH), which is unexpectedly elevated over the Seoul Metropolitan Area. GEOS-Chem fails to reproduce this behavior. We show that measurement interference from methanediol, a chemical species formed via in-cloud hydration of formaldehyde, may explain part of this discrepancy. We also explore the role of methanediol in oxidant chemistry and formic acid formation (Chapter 3).
While air quality is important to human health, transitioning to cleaner energy is also essential to mitigate climate change. The Intergovernmental Panel on Climate Change (IPCC) recommends achieving net-zero anthropogenic CO2 emissions by 2050 to keep global warming to 1.5 ◦C. One proposed solution is switching from fossil fuels to hydrogen. However, hydrogen emissions can affect atmospheric abundances of methane, ozone, and water vapor, making hydrogen an indirect GHG. The global warming potential (GWP) is a commonly used metric to evaluate the climate impact of GHGs. Previous studies using models have shown that soil sink is the largest uncertainty in estimating its GWP. However, current models have known biases in their simulations of OH concentration and reactivity, and how these biases affect the evaluation of hydrogen global warming potential has not been considered. We find that these biases lead to a 20% overestimate in the GWP of hydrogen (Chapter 4).Engineering and Applied Sciences - Engineering Science
Application of Lipid Nanoparticle (LNP) Design and Optimization Concepts to the Emerging Field of Protein-Based Virus-Like Particles (VLPs)
Full text linkLipid nanoparticles have emerged as the dominant delivery technology for genetic
medicines, reaching global use and attention with the success of mRNA-based COVID
vaccines. However, LNPs face notable challenges related to biodegradability,
extrahepatic targeting, and immunogenicity. VLPs, a newer class of protein-based
nanocarriers, present a compelling alternative with distinct advantages including inherent
biodegradability due to non-synthetic components, cellular targeting capability by
leveraging viral surface proteins, and reduced immunogenicity enabling repeat-dose
therapeutics.
This thesis systematically evaluates the applicability of LNP design and
optimization concepts to VLPs to help explore parallels and potential divergences to
investigate if VLPs should be considered the superior delivery technology. The concepts
explored include mechanisms of nanoparticle formulation, cargo encapsulation,
biodegradability, cellular uptake, endosomal escape, and immune system evasion. While
significant design parallels exist, the primary challenge limiting VLPs is their slower
manufacturing speed due to reliance on cellular expression systems. The conclusion of
this document proposes a future usage of VLPs as a modular technology to help increase
the speed of discovery and help bring VLPs into the mainstream.Extension Studie
Architecture Within Reason: Construction, Labor, and Rationalization in Weimar Germany
No full textWorld War I shattered millions of lives and left much of Europe in ruins. In postwar Germany, artists, architects, politicians, and industrialists cultivated utopian visions of the future that were motivated by hopeful optimism for renewal and redemption despite a degraded reality. Weimar never became what its greatest visionaries hoped, but the impulses for these imaginary pursuits were nonetheless real. Importantly, postwar architectural currents converged with the rise of rationalization in Weimar Germany. This dissertation contends with the “constructed meanings” of rationalization after World War I and examines how this concept came to encompass much more than a technical doctrine. Rather, rationalization is investigated as a complex cultural and technical terrain that saw the embrace of science, technology, and industry by architects, in parallel with reinvigorated beliefs in social transformation as the ultimate objective of art.
Rationalization was inflected by, and also hybridized with, other cultural and artistic concepts. The legacy of older artistic ideals, such as the Romantic Gesamtkunstwerk, remained pivotal even as rationalization ascended to epistemic dominance. In turn, the concept was directed toward numerous purposes of politics and social reform. While the Gesamtkunstwerk ultimately comprised a failed framework for artistic and social renewal—what Andreas Huyssen describes as “a false totality and … an equally false monumentality”—it nevertheless exerted a powerful influence in cultural discourse after the cataclysm of the Great War and profoundly shaped the subsequent rise of rationalization in architecture.
This study defines a culture of reason that was specific to architecture in Weimar Germany, plural in its manifestations, and unresolved in its ideological ambitions—a complex of thought and practice that embraced industrial techniques, state interventions, and scientific management just as fervently as it did idealist aspirations of utopian renewal and Romantic conceptions of spiritual and communal redemption. Considering historical developments as varied as colonial building, wartime resource management, state-led housing initiatives, and industrial psychotechnics demonstrates how rationalization was often taken as the means to ends not reducible to reason alone. Rather, Weimar rationalization enjoined science, technology, and construction to numerous purposes that were variously pragmatic, artistic, political, or militaristic. Historicizing rationalization as an elastic concept opens the door to a richer understanding of its multiple configurations as well as its participation in a multitude of historical domains. The dissertation pursues this project across five chapters that examine the negotiations of German Kultur and industrial Zivilisation in Weimar Germany.Architecture, Landscape Architecture and Urban Plannin
Investigating the Role of RAC1 in TIM-3-Dependent Suppression of Dendritic Cells and its Impact on Stem-Like T Cells
No full textT cell stemness is essential for sustaining long-term immune responses in chronic infections, cancer, and autoimmunity. Dendritic cells (DCs) are known to associate with stem-like T cells niches, but the mechanisms by which DCs regulate T cell stem-like populations remain unclear. This study investigates the role of TIM-3, an inhibitory receptor expressed on DCs, in modulating T cell stemness through its interaction with the small GTPase RAC1. Using bone marrow–derived dendritic cells (BMDCs), CRISPR-mediated gene editing, and multiple in vivo models—including MC38-OVA, B16-OVA tumors, and experimental autoimmune encephalomyelitis (EAE)—this work suggests that TIM-3 deletion in DCs enhances their activation and promotes the expansion of TCF1⁺PD1⁺ stem-like T cells in both the CD8⁺ and CD4⁺ compartments. Mechanistically, TIM-3 and RAC1 were shown to physically associate, and deletion of RAC1 in TIM-3–deficient DCs reversed the enhanced cytokine production, T cell proliferation, and tumor control observed in the TIM-3 knockout condition. Moreover, among several candidate TIM-3 interactors identified by mass spectrometry and CRISPR screening, only RAC1 showed a functional rescue effect, reinforcing its specific role downstream of TIM-3. These findings reveal a previously uncharacterized TIM-3–RAC1 signaling axis in DCs that regulates the induction of stem-like T cells and shapes adaptive immune responses. This work not only advances mechanistic understanding of DC–T cell crosstalk but also opens new avenues for targeting the TIM-3–RAC1 pathway to enhance T cell–based immunotherapies.Graduate Educatio
Investigation of the impact of αCD45 cellular backpacks on the mechanobiology of T cell activation and tumor cell cross-talk
No full textImmune checkpoint blockade-resistant solid tumors present a major therapeutic challenge. Although adoptive T cell therapies, such as CAR T cells, have shown remarkable success in treating hematological malignancies like leukemia, they have not yet achieved comparable efficacy in solid tumors. In the majority of patients with solid tumors, transferred T cells rapidly lose their functional phenotype following adoptive transfer, leaving them vulnerable to the immunosuppressive tumor microenvironment (TME) [#zhao2019TcelltherapyReview]. Considering the significant promise of adoptive T cell therapies, there is intense interest in developing strategies to enhance their persistence and function within solid tumors. Recent work under review for publishing in the Mitragotri lab has shown that equipping primed polyclonal murine CD8+ T cells with micropatches, namely "cellular backpacks (BPs)", can enhance their anti-tumor response against aggressive tumors by providing localized stimulation. These BPs are 6 μm polymeric poly(lactic-co-glycolic acid) (PLGA) microparticle disks functionalized with anti-CD45 antibodies[#Fukuta_Mitragotri_neutrophilBPBrain], which can attach to the cellular membrane of T cells. BPs show strong clinical promise as a companion therapy to extend the persistence of T cell therapies. Therefore, to fully realize their potential, it is essential to understand the diverse ways in which BPs influence T cell behavior, in order to improve the technology and optimize for its clinical application. Previous studies have investigated the biological effects of BPs on immune cells through receptor clustering[#Prakash_2023_BP_NKcells, #Prakash_2024_BP_Bcells] and biophysical interactions[#Ninad_2024_neutrophilBP], as well as their chemical effects for drug and cytokine release[#Kapate_2023_BPMacrophageforTBI, #Kapate_2023_BPMyeloidforMS, #Shields_2020_BPMacrophage]. However, the mechanical impact of BPs on the cytoskeleton and plasma membrane has not been thoroughly explored. Preliminary observations have shown that BPs induce morphological changes and cytoskeletal remodeling in immune cells while still permitting migration, suggesting a unique form of mechanical modulation. The consequences and depth of these effects, however, have remained largely uncharacterized. This thesis specifically has addressed this previously unexplored topic by investigating the impact of BPs on the mechanobiology of T cells. Although interest in T cell mechanosensation has grown in recent years, most studies have focused on the formation of the immunological synapse (IS) and the influence of substrate stiffness, leaving other mechanical aspects of T cell regulation underexamined. BPs provide a unique platform to investigate these questions, as they induce cytoskeletal and morphological changes while maintaining T cell motility and functionality.
This work has identified and characterized two well defined aspects of mechanobiology to shed light on how BPs influence T cell mechanobiology, contributing new insights with potential implications for optimizing BP-based immunotherapies. First, the project explored whether BPs could alter the mechanics of physical tumor cell cross-talk with T cells. A 2022 study revealed a new mechanism of immune evasion whereby cancer cells extend tunneling nanotubes (TNTs) structures to pump out the mitochondria of immune cells. This mechanism has been shown to promote premature exhaustion of T cells in the TME, contributing to their lack of efficacy[#saha2022nanotubes]. Exocyst complex proteins of the Sec family and the Rho and Ras GTPase family are known to be involved in actin remodeling during TNT formation and mitochondrial trafficking. The same protein complex is involved in cytoskeletal remodeling due to a mechanical stressor. Hence, this project hypothesized that modifying T cells with cellular BPs would alter this complex from allowing mitochondrial transfer and protect them from mitochondrial theft by cancer cells, thereby prolonging their persistence. We investigated whether BP attachment on T cells would hinder mitochondria transfer by co-culturing them with tumor cells. Although BP attachment to Jurkat T cells was achieved with high efficiency (~80%), it did not impair mitochondrial transfer, suggesting that BP-induced cytoskeletal remodeling may not be sufficient to disrupt TNT formation or that alternative mechanisms of transfer may exist. These results suggest that BPs do not interfere with beneficial intercellular mitochondrial exchange, which could allow T cells to remain metabolically supported in the tumor microenvironment.
The second focus investigated whether a biomechanical effect participates in the non-specific activation of T cells caused by BP attachment. Shear stress alone has been shown to activate T cells via the Piezo1 stretch-activated calcium (Ca2+) channel[#sarna2024_ShearStressTcells], and Ca2+ influx is a critical downstream event in T cell receptor (TCR)-mediated signaling. Thus, we hypothesized that the mechanical interaction of the T cell membrane with a BP could trigger Piezo1-mediated Ca2+ entry, thereby promoting an activated T cell phenotype. To test this hypothesis, a pharmacological inhibitor of Piezo1 was applied to T cells, and intracellular Ca2+ levels were monitored. As expected, BP attachment led to elevated intracellular Ca2+ levels, an early marker of activation. However, pharmacological inhibition of Piezo1 did not significantly reduce this Ca2+ influx. Interestingly, longer-term studies revealed that Piezo1 inhibition suppressed the upregulation of the activation marker CD25 and also reduced BP retention on the T cell surface, suggesting that Piezo1 contributes to sustained activation and cytoskeletal stabilization in the context of BP attachment. This indicates that Piezo1 may not initiate the Ca2+ influx but instead plays a role in maintaining T cell responsiveness to sustained mechanical stimuli.
In summary, this thesis identified BPs as a unique platform for modulating T cell mechanobiology, revealing both their compatibility with intercellular communication and a potential role for Piezo1 in sustaining mechanical activation of T cells by BPs. These insights lay the groundwork for refining BP-based immunotherapies and uncovering new strategies to support T cell function in solid tumors.Graduate Educatio