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    Structure and dynamics studies of proteins using solid-state NMR

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    Solid-state NMR serves as a powerful method for investigating atomic-level details of insoluble biomolecules, enabling the determination of protein 3D structures and probing molecular motions across a broad range of timescales. In this thesis, I present structural studies on a novel heterotypic and functional amyloid, dynamics studies, and chemical shift anisotropy studies of a microcrystalline protein, ubiquitin. In Chapter 1, I provide a summary of the main interactions in solid-state NMR and discuss relevant pulse sequences employed in this thesis. Chapter 2 briefly explores the characteristic properties of amyloids, highlighting well-studied examples of disease-related and functional amyloids. Special treatments employed in amyloid structure determination using solid-state NMR are also summarized. Chapter 3 presents structural studies on a heterotypic functional amyloid, mcmvM45-hsRIPK3, where M45 is a protein encoded by murine cytomegalovirus (MCMV) and RIPK3 is from humans. Both M45 and RIPK3 belong to a family of RHIM-containing proteins, which are involved in innate immunity and immune response through necroptosis. SSNMR data on various isotopically labeled samples enable the chemical shift assignment for both M45 and RIPK3, providing intra- and inter-molecular contacts. By combining these constraints, we calculate the structure of the hetero-amyloid M45-RIPK3, reporting two structures distinct from RIPK1-RIPK3. In Chapter 4, I measure backbone 15N-13CO order parameters of microcrystalline ubiquitin using DCP-REDOR. Two isotopically labeled samples, 1-13C-glucose and 1,3-13C-glycerol, D₂O labeled, are studied and compared, identifying mobile residues and assessing the effect of isotropic labeling on the measurements of backbone 15N-13Co order parameters. Experimental order parameters are compared with a 1μs MD simulation for insights. Chapter 5 focuses on the chemical shift anisotropy (CSA) of uniformly labeled microcrystalline ubiquitin using a novel pulse sequence allowing the measurement of large CSAs under practical conditions. We explore CSA parameter trends, correlations between isotropic shifts, and hydrogen bond geometries. Comparison with solution-NMR results demonstrates high consistencies with asymmetry parameters (η), providing insights into the motion modes of microcrystalline proteins alongside order parameter measurements. Chapter 6 provides a comprehensive summary of the conclusions drawn from the preceding chapters, while also outlining future directions for each project

    Toward a holistic and data-driven framework to evaluate livestock-derived protein systems

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    The environmental toll of protein production systems, such as greenhouse gas (GHG) emissions and land use associated with the production of livestock-derived foods, poses a substantial challenge for global agricultural sustainability. At the same time, livestock possess significant cultural and economic value for billions, while providing essential macro- and micronutrients. Such tensions fuel a debate on how to optimize livestock production systems, with implications for global nutrition, the environment, and society. Here, we introduce the Protein for Nutrition, Environment, and Society (ProNES) framework to address challenges related to the holistic evaluation of livestock-derived protein systems. ProNES uses publicly available data to comprehensively assess livestock-derived commodities in terms of their nutritional, social, economic, and environmental aspects. The exercise underscores areas where data gaps must be filled for more precise assessments, such as the contributions of livestock production systems to livelihoods across a range of geographic, economic, and sociocultural contexts

    Hominin population bottleneck coincided with migration from Africa during the Early Pleistocene ice age transition

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    Two recently published analyses make cases for severe bottlenecking of human populations occurring in the late Early Pleistocene, one case at about 0.9 Mya based on a genomic analysis of modern human populations and the low number of hominin sites of this age in Africa and the other at about 1.1 Mya based on an age inventory of sites of hominin presence in Eurasia. Both models point to climate change as the bottleneck trigger, albeit manifested at very different times, and have implications for human migrations as a mechanism to elude extinction at bottlenecking. Here, we assess the climatic and chronologic components of these models and suggest that the several hundred-thousand-year difference is largely an artifact of biases in the chronostratigraphic record of Eurasian hominin sites. We suggest that the best available data are consistent with the Galerian hypothesis expanded from Europe to Eurasia as a major migration pulse of fauna including hominins in the late Early Pleistocene as a consequence of the opening of land routes from Africa facilitated by a large sea level drop associated with the first major ice age of the Pleistocene and concurrent with widespread aridity across Africa that occurred during marine isotope stage 22 at ~0.9 Mya. This timing agrees with the independently dated bottleneck from genomic analysis of modern human populations and allows speculations about the relative roles of climate forcing on the survival of hominins

    Evaluating the Promise of Biological Aging as a Leading Indicator of Population Health

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    Several substantive observations formed the basis for this research. First, the observation of stagnating life expectancy in the United States over the first two decades of the 21st century, representing a dubious form of American exceptionalism. Second, evidence suggesting that novel measures of biological aging might provide allow for early evaluation of population-level health trajectories, based on direct observation of health status in still-living people. Third, the opportunity to apply these measures for study of population-level phenomena, using methods routinely used in the fields of sociology, demography, and economics. This dissertation represents a proof-of-concept work to support the application of biological aging measures to population health surveillance. In Chapter 2, I conduct a systematic literature review of novel measures and approaches to the quantification of population aging published since 2000, and identify 3 major classes of novel population aging measures. Biological-aging measures can be understood as a specific application of Sanderson and Scherbov’s α-ages approach, which indexes “true age” to the distribution of some aging-related characteristic in a reference sample. Relative to other novel measures and approaches, however, biological-aging algorithms hold particular promise in their ability to provide direct measures of pre-clinical, aging-related health risk across the entire adult age range of a population. In chapters 3 and 4, I apply published biological aging algorithms to blood-chemistry and organ-test data collected by the National Health and Nutrition Examination Surveys (NHANES) to test whether the U.S. population has grown biologically older over the past two decades, as some interpretations of life expectancy data would suggest, and to evaluate the extent to which selected social and environmental exposures might explain these trends. Formal age-period-cohort analysis revealed consistent period increases in biological aging from 1999-2018; while population aging slowed after the training cohort was measured in NHANES III (1988-1994), aging trajectories have reverted towards early-1990s levels since the turn of the century. Limited evidence of cohort effects was observed, with findings consistent regardless of age, race, and sex – although racial disparities in biological aging persisted over the entire study period. Kitagawa-Blinder-Oaxaca decomposition analysis of four candidate exposures (i.e., BMI, smoking status, blood lead, and urinary polycyclic aromatic hydrocarbon levels) suggested that changes in the distribution of behavioral and environmental risk factors accounted for a substantial proportion of observed period trends and/or racial disparities in biological aging over the first two decades of the 21st century. Broadly, these results suggest that measures of biological aging can provide earlier and more precise readouts of population health trajectories and their drivers, ultimately informing next-generation public health efforts to promote healthy aging and aging health equity

    Using heterogeneous, longitudinal EHR data for risk assessment and early detection of cardiovascular disease

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    Cardiovascular disease (CVD) affects millions of people and is a leading cause of death worldwide. CVD consists of a broad set of conditions including structural heart disease, coronary artery disease and stroke. Risk for each of these conditions accumulates over long periods of time depending on several risk factors. In order to reduce morbidity and mortality due to CVD, preventative treatments administered prior to first CVD event are critical. According to clinical guidelines, such treatments should be guided by an individual’s total risk within a window of time. A related objective is secondary prevention, or early detection, wherein the aim is to identify and mitigate the impact of a disease that has already taken effect. With the widespread adoption of electronic health records (EHRs), there is tremendous opportunity to build better methods for risk assessment and early detection. However, existing methods which use EHRs are limited in several ways: (1) they do not leverage the full longitudinal history of patients, (2) they use a limited feature set or specific data modalities, and (3) they are rarely validated in broader populations and across different institutions. In this dissertation, I address each of these limitations. In Aim 1, I explore the challenge of handling longitudinal, irregularly sampled clinical data, proposing discriminative and generative approaches to model this data. In Aim 2, I develop a multimodal approach for the early detection of structural heart disease. Finally, in Aim 3, I study how different feature inclusion choices affect the transportability of deep risk assessment models of coronary artery disease across institutions. Collectively, this dissertation contributes important insights towards building better approaches for risk assessment and early detection of CVD using EHR data and systematically assessing their transportability across institutions and populations

    Unraveling Canvas: from Bellini to Tintoretto

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    Over the course of the fifteenth and sixteenth centuries, canvas substituted panel or wall as the preferred support for painting in Venice, moving from the periphery to the core of artmaking. As it did so, canvas became key to the artistic processes and novel pictorial language developed by painters like Titian, Tintoretto and Veronese. Sixteenth-century critics associated canvas with painting in Venice, a connection that has persisted to become a veritable trope of Venetian art history. Despite this, we have hitherto lacked a convincing account of Venetian canvas supports and their impact. This dissertation, by examining the adoption, development, and significance of canvas in Venetian art over the period 1400 to 1600, attempts to provide one. Approaching canvas from multiple perspectives, this project offers a deeper understanding of what early modern canvas was at a material level, how it was made and supplied to painters, and its catalyzing role in early modern Venetian art. By tracing precisely how canvas operates within paintings, focusing on lodestar examples whilst drawing on extensive and intensive object-based research carried out on a large corpus, this thesis demonstrates how actively canvas participated in the elaboration of the pictorial poetics of mature Cinquecento art in Venice. It argues that we owe the existence of this distinctive artistic idiom in no small part to the twist of a yarn, the roughness of a thread, the thickness of a stitch. Canvas was critical to both the making and the meaning of these pictures. The wider aims of the project are twofold: on the one hand, to model a methodology that integrates approaches such as visual, textual, and sociocultural analysis with technical art history and conservation-informed comprehension of the materially altered nature of art objects; on the other, to contribute to an account of the history of an art form—the canvas picture—that still occupies a central role in the global art world today

    UVSSA regulates transcription-coupled genome maintenance

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    DNA damage is a constant threat to our genomes which drives genome instability and contributes to cancer progression. DNA damage interferes with important DNA transactions such as transcription and replication. DNA lesions are removed by repair pathways that ensure genome stability during transcription and replication. Here, we identify and characterize distinct roles for the ultra violet stimulated scaffold protein A (UVSSA) in the maintenance of genome stability during transcription in human cells. First, we unravel a novel function for UVSSA in transcription-coupled repair of DNA interstrand crosslinks (ICLs), genotoxic adducts that covalently bind opposing strands of the DNA and block transcription and replication. UVSSA knockout cells are sensitive to ICL inducing drugs, and UVSSA is specifically required for transcription-coupled repair of ICLs in a fluorescence-based reporter assay. Based on analysis of the UVSSA protein interactome in crosslinker treated cells we propose a model for transcription-coupled ICL repair (TC-ICR) that is initiated by stalling of transcribing RNA polymerase II (Pol II) at an ICL. Stalled Pol II is first bound by CSA and CSB, followed by UVSSA which recruits TFIIH to initiate downstream lesion removal steps. Second, we establish that UVSSA counteracts MYC dependent transcription stress to promote genome stability in cells aberrantly expressing the cMYC oncogene. UVSSA knockdown sensitizes cells to MYC expression, resulting in synthetic sickness and increased doubling time. UVSSA knockdown impacts Pol II dynamics in MYC activated cells. We conclude that UVSSA is required for regulation of Pol II during MYC induced transcription to prevent transcription stress. Together, these studies expand our understanding of UVSSA’s role in genome stability during transcription and elucidates the poorly understood transcription-coupled ICL repair pathway

    Legitimation Trials. The Limits of Liberal Government and the Federal Reserve's Quest for Embedded Autonomy

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    Economic sociologists have long produced rich accounts of the economy’s embeddedness in social relations and the hybridity of contemporary governance architectures. However, all too often, they contented themselves with merely disenchanting a liberal ontology that divides the social world into neatly differentiated spheres, such as the state and the economy or the public and the private. In this dissertation, I argue that this is not enough. If we want to understand actually existing economic government, we also need to attend to the consequences of its persistent violation of the precepts of liberal order. This dissertation does so by accounting for the simultaneity of the Federal Reserve’s rise to the commanding heights of the US economy and the repeated, multi-pronged controversies over it. I contend that together, the Fed’s ascendance and the controversies surrounding it are symptomatic of the contradictions inherent to a liberal mode of governing ‘the economy’ which, on the one hand, professes its investment in a clear boundary between the state and the economy but which, on the other hand, operationally rests on their entanglement. Its embeddedness in financial markets exposes the Fed to attacks that it is either colluding with finance or that it unduly smuggles in political considerations into an otherwise apolitical economy. In response, to secure its legitimacy as a neutral arbiter of market struggles, the Fed needs to invest in autonomization strategies to demonstrate that it is acting neither in the interests of capital nor on behalf of partisan politicians but in the public interest. Its autonomization strategies in turn feed back onto the modes of embeddedness and governing techniques the Fed deploys, often resulting in new controversies. Combining insights from economic sociology and the sociology of expertise, the perspective developed in this dissertation thus foregrounds the persistent tension between embeddedness and autonomy and the sequences of reiterated problem-solving it gives rise to.Based on extensive archival research and interviews with actors, I reconstruct three such sequences in the Fed’s more-than-a-century long quest for embedded autonomy in three independent but related empirical essays. The first focuses on the decade immediately following the Federal Reserve System’s founding in 1913. It traces how the confluence of democratic turmoil in the wake of World War I, its hybrid organizational structure, and an alliance with institutionalist economists led Fed policymakers to repurpose open market operations from a banking technique into a policy tool that reconciled different interests. This made it possible to take on a task no other central bank had attempted before: mitigating depressions. This major innovation briefly turned the Fed into “the chief stabilizer” before it failed to fulfill this role during the Great Depression. The essay thus adds a critical, oft-forgotten episode to the genealogy of the Fed’s ascendancy and the rise of central banks to the foremost macroeconomic managers of our time. The second essay most explicitly develops the theoretical argument underlying this dissertation and applies it to a practice that has been all but ignored in the scholarship on central banking and financial government: bank supervision. Emphasizing its distinctiveness from regulation, I reconstruct how the Fed folded supervision into its project of governing finance as a vital, yet vulnerable system over the course of the second half of the 20th century and into the 21st. I especially focus on the Fed’s autonomization strategies in the wake of the 2008 Great Financial Crisis and its internal struggles which resulted in a more standardized, quantitative, and transparent supervisory process centered around the technique of stress testing. However, the Fed’s efforts to reassert its autonomy and authority have in the meantime become attacked themselves. The essay traces these controversies, and subsequent reforms, to the present day, further demonstrating the recursive dynamic of the Fed’s quest for embedded autonomy. The third essay finally zooms in on a single event during the Great Financial Crisis: the first major public stress test run by the Fed and the Treasury between February and May 2009. By reconstructing its socio-technical assembling in detail and comparing it to the failures of stress tests run by European agencies between 2009 and 2011, I show that the stress test’s success rested on a reconfiguration of the state’s embeddedness in financial circuits, allowing the Treasury’s material and symbolic capital to back the exercise and the Fed to function as a conduit that iteratively gauged and shaped its audiences’ expectations as to what a credible test would look like. This made it possible to successfully frame the test as an autonomous exercise based on expertise. Probing the structural, socio-technical, and performative conditions of the Fed’s claims to legitimacy, the essay thus resolves the ‘mystery’ (Paul Krugman) how a simulation technique could become a watershed event in the greatest financial crisis in a lifetime

    Making a Country out of a Harbor: The Transnational Everyday Life of Migrant Port Workers in Singapore, 1913-1972

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    Circular mobility to settlement; casual laborer to national worker; citizen back to migrant. This dissertation examines the history of Singapore’s port and the everyday life of its migrant workers as the city moved from British imperial port integrated into the region of Malaya to inexplicable city-nation-state. Port workers’ everyday lives were structured by the flows of migration and capital around the Indian Ocean that underpinned the British empire, defined the relationship between port worker and labor contractor, and produced ethnicized urban and social life. As an imperial port, Singapore developed thick historical connections with other British colonial ports. Chinese and Indian capital knitted together Singapore, Hong Kong, and Bombay and made them the hubs of their respective regions reliant on a constant supply of migrant labor. Previously connected and functionally similar, Singapore, Hong Kong, and Bombay began to diverge in the 1950s as the post-war trends of decolonization, the Cold War, and containerization changed their importance as models of Asian urbanism. These trends reshaped working practices, composition of worker gangs, and the urban fabric of the Singapore port to co-opt the transnational lives of port workers into the new nation. Drawing on port authority reports, police reports, kinship association records, and oral history collections, this dissertation intervenes in the historiography of Singapore by showing how the economic miracle of Singapore was built on forgetting the port’s place in the Malay and Indian Ocean worlds and port workers’ visions and experiences of a Singapore that was deeply connected to its region and the liberation movements of the Global South

    High-throughput Characterization of Diagnosis Disparities Across Conditions and Observational Datasets

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    Health disparities are preventable differences in health status and outcomes that adversely affect certain populations, and are generally attributable to unjust social or environmental influences. Mitigating health disparities is crucial toward preventing unnecessary and avoidable human suffering, and as such there has been a significant increase in health disparities research and funding. However, existing health disparities publications are geographically-constrained to specific institutions or populations, and often rely on disease definitions that cannot be easily applied elsewhere. While more recent publications have begun identifying differences utilizing larger datasets, for most diseases, differences in prevalence, age of onset, and time to diagnosis differences remain unstudied and unknown. This dissertation leverages informatics solutions built atop observational health datasets to enable high-throughput, reproducible assessments of disparities across subgroups, conditions, and datasets. In the first aim, this dissertation examines the literature to identify how health disparities in disease diagnosis are measured, computed, and reported. It then proposes an iterative approach for generating fair phenotype definitions that are more inclusive of subgroups of interest by utilizing algorithmic fairness measurements translated to epidemiological measures. In the second aim, this dissertation conducts large-scale characterizations of disease diagnosis patterns across subgroups (gender and race), conditions, and datasets. In particular, this dissertation conducts a prevalence-based assessment of disease diagnosis by computing prevalence differences, risk ratios, and age of onset differences across diseases and datasets. The dissertation then conducts a scalable assessment of time to diagnosis differences across 122 disease phenotypes. Finally, in the third aim, this dissertation moves from quantifying differences to identifying disparities in diagnosis. To do so, the dissertation applies a framework for causal fairness to decompose observed time to diagnosis differences into direct, indirect, and spurious effects. In conclusion, this dissertation's primary contributions are providing a systematic, scalable approach for identifying health differences and then quantifying health disparities at-scale across large-scale observational health datasets. The dissertation (1) proposes an iterative approach for systematically assessing the fairness of phenotypes used in observational health research, (2) systematically characterizes differential patterns of disease diagnosis across diseases and observational datasets, and (3) causally decomposes differences into quantifiable effects that suggest the presence of potential health disparities

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