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Proximity t o Nuclear Power Plants and Cancer Risk: A Multi-Scale Epidemiological Investigation in the United States"
No full textPurpose
This dissertation provides a comprehensive, first-level investigation of the associations between residential proximity to nuclear power plants and cancer outcomes in the United States. While nuclear energy is promoted as a low-carbon alternative to fossil fuels, longstanding concerns remain regarding potential health risks from chronic low-dose radiation exposures. Prior studies have been hampered by limited geographic scope, crude exposure definitions, and inconsistent analytic frameworks. This work addresses these gaps through three interlinked studies that systematically evaluate cancer mortality and incidence across multiple spatial scales, outcomes, and designs.
Methods
We developed a consistent spatial exposure metric based on inverse-distance proximity to operational nuclear power plants, updated annually to account for plant operations. Using national cancer mortality data (2000–2018) and Massachusetts cancer registry data (2000–2018),
Dissertation Advisor: Petros Koutrakis Yazan Alwadi
we applied generalized estimating equation Poisson regression models for longitudinal analyses and cross-sectional Poisson regression for site-specific incidence. Models incorporated demographic, socioeconomic, environmental, and healthcare access covariates, and accounted for spatial clustering. Attributable fractions (AFs) and counts were estimated to characterize the cancer burden.
Results
Proximity to nuclear power plants was consistently associated with increased cancer risk, with relative risks strongest among older adults. National analyses estimated over 115,000 cancer deaths attributable to nuclear plant proximity during 2000–2018, including 54,349 female deaths (AF: 1.5%, 95% CI: 0.7–2.3%) and 61,237 male deaths (AF: 1.6%, 95% CI: 0.7–2.5%). Cancer site-specific analyses indicated 33,915 attributable female deaths and 25,586 male deaths from breast, colon, and lung cancers, with lung cancer accounting for the largest share. In Massachusetts, proximity was associated with 10,815 attributable cancer cases among females (AF: 4.1%, 95% CI: 2.4–5.7%) and 9,803 among males (AF: 3.5%, 95% CI: 1.8–5.2%), with elevated risks across multiple cancers, including lung, prostate, breast, colorectal, bladder, melanoma, leukemia, thyroid, uterine, kidney, and pancreatic cancers. Risk declined with increasing distance, with the highest relative risks observed within 30 km of facilities.
Conclusion
This dissertation represents the most comprehensive evaluation to date of cancer outcomes in relation to nuclear power plant proximity in the United States. By systematically resolving key technical challenges that limited prior studies, it establishes a foundation for more refined investigations. The consistent proximity-based associations observed here underscore the importance of future research incorporating dosimetry, exposure-specific pathways, individual-level effect estimates, and cohort designs. As nuclear energy re-emerges in climate and energy policy debates, these findings highlight the need to integrate rigorous epidemiologic evidence into broader assessments of its long-term public health implications.Population Health Science
Between Power and Protection: Maternal Imagery in the Religious Art of South Asia, 1st–7th Century CE
No full textThis dissertation examines the “mother-child” image ubiquitous in South Asian religions in the first millennium CE to understand how and why the concept of “motherhood”—embodying complex structures of physical and emotional experiences—inflected the religious landscape of South Asia. These images of motherhood take the form of Hārītī in Buddhism, Saptamātṛkā (Seven Mothers) in Brahmanical tradition, and Ambikā in Jainism and are dispersed in rock-cut shrines, temples, and museum collections. Past scholarship has characterized these goddesses within the strict confines of sectarian categories, often overlooking their shared iconographic representation, myths, and functions. My study challenges this categorization and sheds light on the complex interplay and interconnectedness among the various religious traditions of South Asia. I consider the mother-child image as a crucial iconographic type through the lens of gender, trans-regionalism, and trans-sectarianism. Utilizing a longue durée approach, I read art-historical evidence—such as sculptures, inscriptions, and built environments—alongside religious and literary textual sources to offer insights into how diverse communities recognized and experienced shared religious imagery over time. Central to this investigation is the articulation of motherhood in this early period through the visual arts. I frame the evolving nature of the mother-child imagery against the backdrop of the political, social, and religious transformations taking place between the first and the seventh centuries CE and emphasize the contributions of patrons, artists, and devotees in shaping the role of maternity within the religions active in South Asia. Lastly, I identify overarching patterns within the artistic traditions spanning an extended period through the study of visual data to uncover the intricate contours of fragmented histories rarely found in written records. My research contributes to recovering the feminine presence within the histories of South Asia and developing innovative approaches to understanding pre-modern South Asia.History of Art and Architectur
From Spatial Spread to Sexual Networks: Leveraging Infectious Disease Epidemiology Tools to Monitor and Respond to Strep Throat and Gonorrhea
No full textAt a moment of intense divisions and distrust, it remains critical to highlight the ways scientific tools contribute positively to society and improve public health. This work shows how three distinct methods within infectious disease epidemiology applied to answer different questions produce results that can inform public health guidance and translate to improvements in the health of individuals. First, we show that spatiotemporal analysis of strep throat visits data in the U.S. identifies geographical and seasonal trends and points to key demographic groups that may drive transmission. Next, we show how mathematical modeling can inform public health guidance on the rollout of new antibiotics to treat gonorrhea in the face of rising antimicrobial resistance. Finally, we show that combining mathematical modeling with pathogen genomic analyses can inform gonorrhea surveillance strategies to yield insights on sexual network structures. These findings together emphasize the important role infectious disease epidemiology plays in preventing people from suffering from illness, and in continuing to interrogate the natural world.Population Health Science
Intrinsic and Extrinsic Regulation of Autoreactive B cell Responses in Systemic Lupus Erythematosus
No full textSystemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the sustained production of autoantibodies with a range of specificities that contribute to immune complex deposition and systemic inflammation. Autoantibody production signifies the breakdown of tolerance by autoreactive B cells. The positive selection of autoreactive B cell clones is succeeded by the differentiation of autoantibody-secreting cells (ASCs) through the extrafollicular (EF) and germinal center (GC) pathways. In this dissertation, we explore the complex mechanisms underlying B cell breaks of tolerance and autoantibody production using various SLE mouse models designed to interrogate distinct B cell differentiation pathways.
In Chapter 2, we utilize a TLR7-driven B cell adoptive transfer lupus model to characterize the kinetics and regulators of extrafollicular pathogenic B cell differentiation. We additionally address the molecular mechanisms of complement receptor 2 (CR2/CD21) downregulation and CD21lo B cell accrual in SLE. Finally, we delineate the rapid, extrafollicular evolution of the follicular B cell repertoire in an autoreactive environment and outline the selective expansion of autoreactive clones.
In Chapter 3, we investigate the complex roles of the integrin and complement receptor CD11c in regulating B cell tolerance. Through adoptive transfer and mixed bone marrow chimera approaches, we provide evidence for tissue-specific CD11c modulation of central and peripheral B cell tolerance, potentially supporting location-directed functions. In parallel, we demonstrate early evidence that exogenous C3 sensitization restricts the autoreactive B cell repertoire, implying a possible role for C3 ligand-receptor interactions in regulating autoreactivity.
In Chapter 4, we demonstrate that the germline human IGHV1-69 allelic leucine (L54) and phenylalanine (F54) variants exhibit distinct functional autoreactivity in vivo. Using the 564Igi-based adoptive transfer lupus model, we show that L54-expressing murine B cells have a selective advantage in 564Igi recipients over the F54-expressing B cells, indicating that an intrinsically autoreactive germline B cell pool can be triggered to expand and differentiate in an autoimmune environment.
Collectively, this work highlights multifaceted dysregulation of B cell development and responses in SLE and refines the mechanistic understanding of B cell tolerance.Virolog
Applications and Host Responses to Adeno-Associated Virus (AAV) as a Gene Therapy Vector in the Eye
No full textAdeno-associated virus (AAV) vectors are state-of-the-art delivery vectors to treat genetic diseases. In 2017, the first AAV gene therapy was approved by the Food and Drug Administration. Called Luxturna, this AAV gene therapy helps restore vision in patients suffering from an inherited form of blindness called Leber’s Congenital Amaurosis Type 2 (LCA2). Beyond LCA2, there are many blinding diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), for which it may be possible to slow vision loss via gene agnostic therapies leveraging AAV delivery vectors.
Dry AMD is the most frequent cause of visual impairment in individuals over age 50 in developed countries. It is characterized by subretinal deposits of oxidized proteins and lipids and results in progressive loss of high acuity vision. One major risk factor is smoking, which causes oxidative stress in many tissues, including the eye. We previously showed that an adeno-associated viral vector expressing human NRF2 (AAV8/Best1-Nrf2), a transcription factor that regulates responses to oxidative damage, slowed degeneration in mouse models of another blinding disorder, RP, which also includes oxidative stress. Here, our AAV8/Best1-Nrf2 vector was tested in a model of oxidative stress wherein sodium iodate was injected systemically, as this is often used to model dry AMD. Sodium iodate causes acute oxidative damage to supporting cells of the retina, the retinal pigment epithelial cells, and ultimately leads to photoreceptor death. Subretinal injection of AAV8/Best1-Nrf2 led to protection of the retinal pigment epithelium and photoreceptors, as well as preservation of visual function, in rat and mouse sodium iodate models. AAV8/Best1-Nrf2 may serve as an effective gene-agnostic therapy for diseases with oxidative stress, including dry AMD.
As AAVs have also been reported to elicit ocular toxicity in the clinic, we additionally sought to elucidate mechanisms of toxicity upon subretinal injection of toxic or nontoxic AAVs in wild type and immune KO mice. Several transgenes, self and non-self, were tested for toxicity, with no clear correlation for this variable. Bulk RPE RNA-sequencing revealed upregulation of translational processes, cell stress, cytokine release, antiviral responses, and leukocyte infiltration pathways. Possible toxicity-inducing pathways were explored for causality by injecting toxic AAVs into mice deficient for intrinsic, innate, or adaptive immune pathways. Knocking out the interferon receptor, IFNAR1, partially alleviated toxicity. RNA-sequencing revealed >200 interferon stimulated genes upregulated in toxic vs. non-toxic AAV-injected RPE samples. In situ hybridization of interferon pathway transcripts (IFNB1, IFNAR1) revealed that the RPE and retina can produce and potentially respond to interferon. These data suggest that transgene-induced cell stress responses and host interferon responses contribute to toxicity following subretinal injection of AAVs encoding particular transgenes. This work elucidates mechanisms of toxicity following ocular AAV administration.Virolog
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
Generation of genotypes and phenotypes from sequencing data
No full textDNA sequencing of hundreds of thousands of human samples has become a component of research biobanks over the last several years. Unlike previous efforts using genotyping arrays and whole exome sequencing, whole genome sequencing imposes no prior expectation on captured genetic information. Whole genome sequencing thus allows for the characterization of novel human polymorphisms such as large structural variation and for the identification of incidentally captured DNA sequences that are non-human in origin. When performed at scale, human structural variation can be associated with phenotypes and the presence of non-human sequences can be considered phenotypes to then be associated with human genotypes. These concepts have been employed in separate lines of work spanning retrotransposons, human DNA viruses, and the oral microbiome.
Retrotransposons comprise about 45% of the human genome, but their contributions to human trait variation and evolution are only beginning to be explored. Here, we find that a sequence of SVA retrotransposon insertions in an early intron of the ASIP (agouti signaling protein) gene has probably shaped human pigmentation several times. In the UK Biobank (n = 169,641), a recent 3.3-kb SVA insertion polymorphism associated strongly with lighter skin pigmentation (0.22 [0.21–0.23] s.d.; P = 2.8 × 10−351) and increased skin cancer risk (odds ratio = 1.23 [1.18–1.27]; P = 1.3 × 10−28), appearing to underlie one of the strongest common genetic influences on these phenotypes within European populations. ASIP expression in skin displayed the same association pattern, with the SVA insertion allele exhibiting 2.2-fold (1.9–2.6) increased expression. This effect had an unusual apparent mechanism: an earlier, nonpolymorphic, human-specific SVA retrotransposon 3.9 kb upstream appeared to have caused ASIP hypofunction by nonproductive splicing, which the new (polymorphic) SVA insertion largely eliminated. Extended haplotype homozygosity indicated that the insertion allele has risen to allele frequencies up to 11% in European populations over the past several thousand years. These results indicate that a sequence of retrotransposon insertions contributed to a species-wide increase, then a local decrease, of human pigmentation.
It is largely unknown which human genetic variants shape a person’s oral microbiome and potentially promote its dysbiosis. We characterized the oral microbiomes of 12,519 people by analyzing whole-genome sequencing reads from previously sequenced saliva-derived DNA. Human genetic variation at 11 loci (10 novel) associated with differences in oral microbiome composition. Nearly all of these associations implicated candidate genes with readily interpretable functions, several related to carbohydrate availability. The strongest association (p=3.0x10-188) involved the common FUT2 W154X loss-of-function variant, which associated with the abundances of 32 bacterial species. Human host genetics also appeared to powerfully shape within-species genetic variation in oral bacteria. Variation at the 11 human loci associated with variation in gene dosages in 68 regions of bacterial genomes. Several such associations implicated interactions of bacterial proteins with histo-blood group antigens presented on host mucosal cell surfaces and salivary proteins. Common, multi-allelic copy-number variation of AMY1, which encodes salivary amylase, associated with oral microbiome composition (p=1.5x10-53) and with dentures use in UK Biobank (p=5.9x10-35, n=418k), suggesting that amylase abundance impacts oral health by influencing the oral microbiome. Two other microbiome composition-associated loci, FUT2 and PITX1, also significantly associated with dentures risk, collectively nominating numerous microbial taxa that might contribute to tooth decay.
Many viruses have adapted to persist in infected humans for life. Variable host control of their abundance (or load) can lead to clearance or disease. Here, we analyzed the viral load of 31 DNA viruses in human blood and saliva using whole-genome sequencing data from UK Biobank (n=490,401), SPARK (n=12,519), and All of Us (n=414,817). Viral load varied markedly with age, time of day, and season, and was higher in men than women for most viruses. Human genetic variation at dozens of genomic loci associated with load of seven viruses: Epstein-Barr virus (EBV, 45 loci), human herpesvirus 7 (HHV-7, 24 loci), HHV-6B, Merkel cell polyomavirus, and three anelloviruses. Variation at the human leukocyte antigen (HLA) complex generated the strongest associations (p = 1.1×10-8 to 9.1×10-851). Effects of HLA alleles exhibited specificity to different viruses and varied by age and body site, and HLA-B*08:01 also exhibited a host-virus genetic interaction with EBV subtype (p = 2.3×10-44). Other human genetic effects involved genes encoding proteins that process peptides for antigen presentation, such as ERAP1 (HHV-7, p = 2.7×10-78) and ERAP2 (EBV, p = 4.6×10-111). Mendelian randomization analyses indicated that although EBV infection strongly increases risk of multiple sclerosis (MS), EBV DNA load is unlikely to further modulate risk of MS (p = 0.52). In contrast, EBV viral load exhibited a strong causal effect on increased risk of Hodgkin lymphoma (OR = 19.81 [3.04–129] per s.d. increase in EBV load, p = 1.8×10-3). This suggests that higher chronic EBV viral load increases lymphoma risk, whereas associations of EBV infection with autoimmune conditions reflect host immune responses to particular viral epitopes.Biomedical Informatic
Expanding Spatial Genomics to Resolve the Epigenome
No full textThe genome is not only encoded in linear sequence but also organized into complex 3D structures that regulate cellular identity, genome stability, and disease. While many tools exist to profile either chromatin states or nuclear architecture, current methods struggle to jointly measure genome sequence and spatial organization at high resolution. In this thesis, I present methodological advances that bridge this gap by extending spatial genomics technologies to connect DNA sequence, epigenetic state, and nuclear organization. First, we improve upon in situ genome sequencing by incorporating expansion microscopy, creating Expansion in situ Genome Sequencing (ExIGS), which enables nanoscale imaging of nuclear proteins and sequencing of chromatin fragments within expanded nuclei. We validate this approach in fibroblasts and then apply it to Hutchinson-Gilford progeria syndrome (HGPS) cells, revealing how lamin abnormalities in HGPS generate local hotspots of disrupted euchromatin organization and transcriptional repression. Second, I describe advances to ExIGS as well as other complementary methods that I contributed to during my PhD. Together, these tools expand the resolution and functional contexts in which genome structure can be interrogated. Beyond their technical contributions, these methods reveal how nuclear abnormalities and epigenetic mechanisms reshape genome organization across development, aging, and disease. Collectively, this work establishes new experimental frameworks for connecting sequence and structure, advancing our ability to study the genome in its full spatial context.Systems Biolog
Kant’s Free Play and Aesthetic Judgment in Architecture: A New Interpretation as Visual Calculating
No full textFollowing Kant’s view of drawing or shape as the “proper object” of aesthetic judgments in architecture, I present an interpretation of a central concept in his theory of aesthetic judgment, viz., the free play of imagination and understanding, as visual calculating in shape grammars. Calculating with identity rules formalizes Kant’s reflective judgments in free play, which he explains as imagination sustaining a “lively engagement” with form. This interpretation departs from determining judgments, which underlie twentieth-century mathematical and computational approaches to aesthetics. With this interpretation in place, I address a central issue concerning computation and aesthetic intelligence, engaging Kant’s concept of “adherent beauty”: How are we to employ computation as a practical method for value judgment while preserving free play’s reflective property that refreshes aesthetic experience, especially when creative work must meet defined functions and end-goals?Computer ScienceHistory of Art and ArchitecturePhilosophyArt, Film, and Visual StudiesAccepted Manuscrip
Postcards or Porches, Close Friends or County Fairs: A New Theory of Political Participation Under Social Risk
Get PDFSocial risk is inherent to political participation. Activists have difficult political conversations with the people they love. They knock on strangers’ doors to persuade them to take political action. They protest in the streets, express their opinions on social media, and testify in public forums. All of these activities require self-revelation. Where the activist and their audience disagree, social alienation is possible, particularly in the contemporary American context where issue moralization and affective polarization are at their peak.
Existing scholarship has focused exclusively on understanding how social risk helps locate people along a participatory continuum. According to this model, those who face high social risks participate “less” and those who face fewer social risks participate “more”. This model is unnecessarily reductive and, in some cases, misleading. In this mixed methods dissertation, I propose a novel theory of political participation under social risk called the theory of selective participation. My theory asserts that as perceived social risk increases, people narrow the scope of audiences and activities they are willing to engage with. When people have consistent access to participatory opportunities within that narrowed scope, they can and do maintain high levels of participation. When they run out of opportunities within that narrowed scope, they participate less, consistent with previous scholarship. In this dissertation I also show that different types of social risk concerns create qualitatively different forms of political participation, producing the variety of participatory patterns we observe in the political world. Finally, I explain how people can become more or less selective in their participation over time through a dynamic response process that reacts to both their personal experiences and shifting social contexts.Governmen