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Functional and Structural Study of Alphavirus Receptors
Get PDFAlphaviruses are single-stranded, positive sense RNA viruses that can cause epidemic polyarthritis or encephalitis in humans and animals. Encephalitic alphaviruses include eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV), and Venezuelan equine encephalitis virus (VEEV). While EEEV and VEEV currently cause regionally contained outbreaks, their emergence into epidemics could be devastating. WEEV historically caused explosive epidemics of viral encephalitis in North America, but has since rapidly declined with the last case documented in the 1990s, a poorly understood process termed “submergence”. Alphaviruses enter host cells through attachment to specific protein receptors on the cell surface, a critical step targeted by antibodies and entry-blocking therapeutics. Here, we combine functional assays with in vitro, in vivo models and cryogenic electron microscopy (cryo-EM) to characterize the interaction of EEEV with its previously identified receptor, and of WEEV with newly identified receptors in this study. Our results provide insight into the ability of EEEV and WEEV to invade the central nervous system, and the molecular basis for the submergence of WEEV as a human and veterinary pathogen in North America, with implications for outbreak preparedness and the development of antiviral therapeutics.Virolog
Base Editing–Enabled Technologies and Multiplex Genome Editing
Get PDFBase editing is a precision genome editing technology that enables targeted single-nucleotide changes without requiring double-strand DNA breaks. This dissertation presents several distinct advances in multiplex base editing and base editing–enabled technologies in mammalian systems. First, we demonstrate large-scale editing of transposable elements, which can be targeted with a single guide RNA due to their repetitive nature. Using catalytically inactive Cas9 base editors, which minimize editing-associated cytotoxicity, we achieve several thousand edits per cell. Second, we develop Genomic Sequence Encryption (GSE), a cryptographic framework that uses multiplex base editing and pooled guide RNAs to encode information across more than one hundred distinct genomic loci. We implement GSE in mammalian cell lines and stem cells, establishing a robust method for introducing a high number of edits in both bulk populations and individual stem cells. We devise an enrichment strategy that enables the isolation of stem cells carrying more than two dozen distinct precision edits across a single diploid genome with minimal screening. This represents a significant advancement in the scale of simultaneous precision editing achievable in primary or stem cells, and, in the context of GSE, paves the way for encrypted genomic signatures in living animals. Lastly, we develop reprogrammable ADAR sensors, a programmable RNA-sensing platform that links endogenous transcript detection to protein translation through A-to-I RNA editing. Together, these contributions expand the scope of base editing by enabling large-scale genome modification, secure biological information encoding, and transcript-responsive regulation in mammalian cells.Engineering and Applied Sciences - Engineering Science
The Living Fossil Record: Crafting Time and Place through Natural Historical Narratives of Persistence and Extinction
No full textThe middle of the nineteenth century was in many ways the advent of the modern era for natural history as in broader North American culture. Each chapter in this dissertation centers an object of natural historical interest that represented a temporal anomaly or transition point for naturalists caught between eager anticipation of the advances of settler colonial modernity and sadness or unease at the destruction of nature that was narrativized as pre-historic. This ambivalent fascination with species, human groups, and environmental spaces that were made to represent a rapidly disappearing past was a driving force of the cultural reception of natural history during this era. Newfoundland and Labrador as North Atlantic colonial hinterlands served as a focal point for these hopes and anxieties. The effort to cast sea serpents, the Labrador Peninsula, and the great auk and Beothuk as contemporary relicts of a pre-modern age at the Atlantic margins of settler colonial reach was part of a larger effort at scientific storytelling that sought to justify the transformation of the natural world that colonialism had wrought.
This project asks: what does it mean that naturalists in the nineteenth century sought to cast certain contemporary organisms, landscapes, and people as relicts of a prior era? What meaning did the “living fossil,” the “prehistoric landscape” and the “extinct” hold for a public grappling with recent serious shifts in their understanding of the age of the earth and the nature of species within deep time? The answers to this question are varied and complex but ultimately reveal that these temporal narratives were created by natural historians to explain and justify their own place in the contemporary era. The designation of relict or living fossil was a byproduct of the construction of natural historical modernity that was occurring simultaneously. This natural modernity was not defined by any quality of its own, but rather in opposition to those species, landscapes, and people narrativized as premodern.
The process of narrativizing modernity has always been a careful balancing act, concerned with projecting confidence and yet fraught with anxiety. Concern for the human place within deep time and what natural science might suggest about the ultimate fate of modern civilization (and, implicitly or sometimes explicitly, the white race) was a current that ran through natural historical discussion of modernity during the latter part of the nineteenth century. This tension has been on display throughout this dissertation as natural historians attempted to explain and demarcate the passage of time using animal species, human groups, and landscapes as temporal landmarks to orient themselves.History of Scienc
Parallel Members – Parallelism, Translation, and Sacred Poetry, 1741- 1929
No full textParallel Members. Parallelism, Translation and Sacred Poetry, 1741-1929 is a comparative study of English and German translations and poetics of the Bible from the late 18th- to the early 20th-century. With chapters on Robert Lowth, Johann Gottfried Herder, Gerard Manley Hopkins and, finally, on Franz Rosenzweig and Martin Buber, its goal is to trace the pervasive influence of biblical parallelism on modern European poetics. In his 1741 Oxford lectures On the Sacred Poetry of the Hebrews, the English man of letters, Robert Lowth identified parallelismus membrorum as a chief structural principle of the language of the Old Testament: 'a certain equality, resemblance, or parallelism between the members of each period'. While ecclesiastic, rabbinic as well as academic sources commented on biblical parallelism more than once before Lowth’s work, it is thanks to their abundant reception that Lowth's lectures have often been viewed as the ‘invention’ of parallelism. Recent scholarly work on the influence of Lowth's concept has drawn on the resources of biblical criticism and the history of exegesis, on historiography as well as on rhetorical criticism, none has, however, investigated the implications of Lowth's parallelismus membrorum for modern European poetics and poetry. Neither biblical criticism, nor historiography, my dissertation reads specifically translations and poetics of the Bible to argue that parallelism has allowed for a radical reconceptualisation of poetic language in European modernity. Closely following the figures of parallelism at work in some of the readers of Lowth, who are themselves also translators of the Bible, my readings draw out the consequences of the skirmishes between parallelism, figuration and versification. I demonstrate that ever since its ‘invention’ in the middle of the 18th-century, the parallelism of Biblical poetry has served, again and again, as a way of reading and writing poetic language. The goal of my inquiry is to initiate a conversation on parallelism that will set novel, if necessarily parallel, ways for writing the literary history of modernity as well as for translation studies and Biblical poetics.Comparative Literatur
Acts of God and Government: Evidence for Charitable Crowd-Out from Natural Disasters and Government Spending
No full textIs the supply of charitable giving fixed? I explore this question in the context of natural disasters and President Biden’s announcement of student loan forgiveness, using data from the crowdfunding platform GoFundMe. I find that Biden's announcement induces short-run crowd-out of both fundraising for and donations to tuition-related causes. I also measure the charitable response to severe natural disasters, estimating a short-term donation substitution rate of 54\% away from non-disaster fundraisers, and that this effect is driven largely by a decrease in fundraising for non-disaster causes in the immediate aftermath.Applied Mathematic
Enteric Neurons utilize mechanoreceptor Piezo1 to sense force and regulate intestinal motility and inflammation
Get PDFThe enteric nervous system (ENS) controls many gastrointestinal (GI) functions including
motility which occurs via peristalsis— the rhythmic wave-like contractions that transit food boluses through the intestines, creating a plethora of mechanical stimuli. However, whether the enteric neurons that control this process can sense these self-generated mechanical stimuli is unknown. During digestive dysfunction in inflammatory bowel disease (IBD) there are major alterations in motility and pressure in the intestines which are concurrent with inflammation. As enteric neurons control motility which creates abundant mechanical stimuli, and since mechanical stimuli as well as enteric neurons can modulate inflammation, I wanted to investigate the role of mechanosensation in enteric neurons. I hypothesized that enteric neuronal sensation of mechanical force is required for regulating tissue homeostasis and inflammation. Herein, I establish that the mechanosensor Piezo1 is functionally expressed in cholinergic enteric neurons. Piezo1-deficiency reduces neuronal activity and slows peristalsis. Further, I uncover that Piezo1-dependent enteric cholinergic responses prevent aberrant inflammation during colitis. Finally, I discover that enteric neurons release canonical cholinergic neurotransmitter acetylcholine in response to mechanical stimuli which can mediate both motility and immune response. This work is the first to determine how the ENS senses and responds to mechanical force.Neuroscienc
Art Against the Anti-Communist Imperative: Chto Delat, Yevgeniy Fiks, and Elena Chemerska at the Limits of Social Practice Art
Get PDFThis dissertation follows the ways in which Russian performance art collective Chto Delat,
Russian-American conceptual artist and Yevgeniy Fiks, and North Macedonian multimedia artist
Elena Chemerska allude to the Soviet and Yugoslav past, and Communist internationalism more
broadly, in their work. Using Chto Delat’s Rosa House of Culture, Fiks’ Pleshkas of the
Revolution and Chemerska’s Fatherland as anchor points, this dissertation examines the ways in
which these critique the effects of capitalist transition in the Russian Federation and Yugoslavia
by imitating or invoking official, state socialist cultural infrastructures and art production. In
doing so, these artistic practices defy stubborn Cold War, anti-Communist attitudes that persist in
the context of contemporary art criticism and exhibitions, even as their work invites questions as
to the origins and efficacy of art activism and “social practice art,” two common, late-20th and
early-21st century models of artistic engagement in progressive politics.History of Art and Architectur
Computational Methods for Organizational Health Literacy: Risks, Opportunities, and Future Directions
Get PDFIntroduction
Health literacy emerged as a field of research and practice in the late 20th century, initially emphasizing individual capacity to obtain, process, and understand health information. Over time, the field expanded to focus on organizations’ capacity to provide clear, accessible health information, i.e. organizational health literacy. This shift in focus led to the development of tools to support organizational health literacy, such as the CDC Clear Communication Index. By helping organizations reduce the burden their communication materials place on target audiences, tools like the CDC Clear Communication Index can play a vital role in addressing today’s pressing public health issues of mistrust and misinformation. However, there are significant gaps in knowledge about how these tools have been used so far and how they might interact with computational methods better suited for high-volume communication online than traditional manual scoring practices.
This dissertation focused on the CDC Clear Communication Index, describing its use in research and experimenting with computational methods to apply it at scale. We chose the CDC Clear Communication Index due to its potential for impact at scale online. It is composed of 20 binary items, resulting in a percentage score. It is structured to suit a wide variety of media formats, message topics, and message lengths. It encompasses a holistic set of evidence-based communication guidelines, covering core message components, behavioral recommendations, use of numbers, and discussions of risk.
This dissertation focuses on two key types of computational methods often referred to as “artificial intelligence” (AI) applications. The first is supervised machine learning, in which a particular training algorithm is used to identify patterns in labeled data useful for predicting labels on new data. The second is generative AI, leveraging large language models to generate content based on text inputs.
Methods
This dissertation includes three separate studies examining the potential of the CDC Clear Communication Index through distinct methods.
Chapter 1 uses a scoping review methodology to describe the use of the Index as an assessment tool in descriptive research. Primary data analysis focused on study design. Secondary data analysis focused on reporting of results and methods.
Chapter 2 introduces the 4-Factor Framework to Assess the Suitability of AI in Health Communication. We demonstrate its utility through a hypothetical use case: a US federal health agency assessing the suitability of open-source academic machine learning models to rate public health social media posts according to guidelines from the CDC Clear Communication Index. We trained 8 bag-of-words models and fine-tuned 8 BERT models to predict expert raters’ labels of social media posts, based on a training dataset of US state health agencies’ pandemic social media posts. We used qualitative process document review and quantitative analysis of the training data to assess models’ explainability. We used qualitative process document review and qualitative analysis of model outputs to assess flexibility. We used a mix of quantitative metrics to describe models’ performance in accurately predicting the labels that trained human raters assigned to social media posts. We used concise comparative summaries to identify words that differentiated social media posts that received the most incorrect model predictions from those that models performed perfectly on.
Chapter 3 examines the performance of ChatGPT in applying binary items from the CDC Clear Communication Index to social media posts. We compare the results of prompt engineering between front-end user and back-end developer perspectives. To do so, we used 12 different prompting styles, varying in framing and length, to apply binary Index items to a test dataset of 27 social media posts. Using F1 and MCC as performance metrics, we compared each prompting style’s performance in accurately predicting labels from expert raters. We used these metrics to identify the optimal prompting style for each item and the overall best performing style across all items, from each stakeholder perspective. We then compared the performance of different model versions of ChatGPT on the same tasks using a validation dataset of 260 social media posts, using the optimal prompt styles we identified during prompt engineering from the back-end developer perspective.
Results
Our scoping review in Chapter 1 identified a wide breadth of research contexts in which the CDC Clear Communication Index has been applied. However, we also uncovered major gaps in study design and reporting. Despite largely employing purposive samples, studies using the CDC Clear Communication Index focused on quantitative assessments, making interpretation of results difficult. Despite this quantitative focus, studies often lacked key details in reporting, such as mean and median Index scores. We also found a prominent focus on materials in text formats, from government, academic, and nonprofit authors. These results point to the potential of the Index, demonstrating its reach thus far, as well as the need for researchers to expand its impact through more varied study design and more robust reporting.
Our analysis in Chapter 2 revealed significant tradeoffs between different facets of suitability that highlight the role institutional priorities play in implementation, especially in light of the potential for unfair model performance across social contexts. We found a tradeoff between model explainability and fairness. Further, while fine-tuned BERT models outperformed bag-of-words models, both demonstrated potential bias with social media posts containing references to time-sensitive local knowledge. In our hypothetical use case, we would recommend limited implementation of such models, suppprted through continuous evaluation. This study also demonstrates the transparency and documentation necessary for assessing AI suitability in health communication, with implications for implementation policies that should restrict the use of proprietary, closed-source tools.
Our analysis in Chapter 3 revealed several long-term complications that would stem from the use of off-the-shelf large language models as health communication tools. We found that back-end developers and front-end users would reach different conclusions about how to best prompt ChatGPT-3.5 to accurately assess posts using items from the CDC Clear Communication Index. This highlights the need for participatory evaluation methods to shape generative AI implementation and policy. In our analysis of performance across model versions, we found inconsistent performance, highlighting the need for continual evaluation of generative AI tools. Our results highlight the need for investment in health communication infrastructure, even in the face of generative AI tools like ChatGPT.
Conclusion
Though these studies focused on just one organizational health literacy tool, these conclusions are likely transferable to other aspects of health communication. Multiple assessment tools draw on the same kinds of evidence-based practices as the CDC Clear Communication Index, which are not defined in terms of readily quantifiable variables. Further, application of AI in content generation, text summary, and simulated conversations would all require evaluation to ensure acceptable performance across various contexts over time.Population Health Science
Photonic Interfaces for Neutral Atom Quantum Computers
Get PDFAs quantum computers advance toward larger, more powerful systems, scaling beyond a single quantum processing unit (QPU) will require the development of fast, high-fidelity interconnections between QPUs. One of the most promising strategies for achieving this is coupling qubits to optical cavities. Strong atom-cavity interactions enable the generation of atom-photon entanglement at rates orders of magnitude faster than alternative approaches, offering a critical advantage for scalable architectures. This thesis investigates the use of nanophotonic and microscale cavities to achieve exceptional atom-photon coupling while maintaining compatibility with state-of-the-art neutral atom QPUs.
The experiments presented in this thesis demonstrate coherent transport between a free-space atom array and an optical cavity, coherent Rydberg excitations and interactions in the presence of the cavity interface, fast high-fidelity readout and cavity-mediated operations, and novel fabrication techniques for improved microcavities that further enhance system performance. Together, these advances outline a pathway toward utility-scale quantum computing.Physic
STEM Characterization of Atomic and Ferroelectric Microstructure in Barium Titanate Thin Films
No full textThin film barium titanate is a promising material platform for photonic devices that allow for on-chip laser physics. These devices take advantage of the electro-optic effect, where the speed of light through a material varies with an applied electric field, and thus these devices must be fabricated on a material that has a high electro-optic coefficient. Barium titanate is one such strongly electro-optic material; however high-quality thin film barium titanate is challenging to fabricate due to its low Curie temperature that makes it prone to cracking. Thin film barium titanate can be grown from the bottom up with molecular beam epitaxy (MBE) and detailed characterization of MBE-grown thin films is needed to optimize growth. Additionally, the high degree of control that MBE affords means that films can be grown intentionally off-composition in order to inform the kinds of defects that may arise in films grown by other methods with less precise stoichiometry control.
In this dissertation, I present scanning transmission electron microscopy (STEM) characterization of MBE-grown thin film barium titanate. STEM is used because it is an atomic-scale imaging technique that enables picometer-scale polar domain mapping as well as highly localized defect characterization. Using STEM, I demonstrate the high quality of films achievable with metal-organic hybrid MBE. I also investigate the effect of stoichiometry on atomic and ferroelectric structures in conventional-MBE grown thin film barium titanate. I identify an asymmetry in how the barium titanate lattice accommodates off-stoichiometry composition; excess titanium leads to disordered polar structures whereas excess barium forms a water-soluble surface layer on an otherwise well-ordered film.Engineering and Applied Sciences - Applied Physic