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Writing Communities into Being: The Art of Linked Verse
No full textLinked verse (lianju 聯句) is both a unique art form and a social practice, with over a millennium of recorded history in Premodern East Asia. It is produced by two or more poets taking turns supplying “links,” or segments of poetic lines, to expand and respond to the previous poet’s passage. I theorize linked verse as a nexus of social bonding and individual creation, examining how it plays a central role in forging communities in every sense of the word: from intimate friendships and social circles, to a textual microcosm of empire, to articulating romance in fictional representation, and as part of a shared poetic language in the premodern Sinosphere.
Chapter One traces the origins of linked verse in early medieval China from the fourth to sixth centuries. It is traditionally believed that two pieces attributed to emperors and ministers are the earliest examples of linked verse; this chapter proposes a more historically grounded lineage of linked verse that grew out of literary collections and anecdotes in standard histories. Chapter Two discusses three sets of linked verse composed during the Tang Dynasty (618–907). I contend that these works demonstrate how linked verse functions as a medium of inscribing space, how the cultural past of a site informs physical experience within such a medium, and how collective authorship is both a harmonious and disjointed endeavor. Chapter Three focuses on linked verse in works of fictional narrative composed between the fifteenth and eighteenth centuries. This chapter highlights the performative aspect of linked verse; it also draws attention to the fraught question of what it means to write in the voice of others. Chapter Four looks beyond China to examine linked verse composition in premodern Japan and Korea, where it was reinvented in ways that are both similar to and vastly different from its place of origin.
I believe this project will contribute both to Chinese poetics and to transnational East Asian studies, as well as address broader questions about human connection and artistic creativity. In an age when communication between cultures becomes ever more crucial, this study is a timely one.East Asian Languages and Civilization
Identifying the Molecular Triggers of Allergic Immunity: A Systematic Approach to Allergen and Adjuvant Discovery
No full textAllergic diseases reflect a misdirected immune response toward innocuous environmental or dietary components. While the major food allergens and their molecular identities are known, few systematic efforts have identified unique allergens or small-molecule adjuvants that influence allergic immunity. In this dissertation, I integrate protein language models and neuronal screens to identify protease allergens and small-molecule adjuvants that modulate allergic inflammation.
Immunodominant allergens from plants, animals, and fungi are enzymatically active serine or cysteine proteases that share a conserved catalytic triad in their active site. Despite their diverse origins, these enzymes appear to have convergently evolved similar proteolytic functions that initiate type-2 immune responses. As a result the enzymatic activity of protease allergens is required for their functional detection by the immune system. Given long-standing associations between microbiome dysbiosis and allergic diseases, we hypothesized that the commensal microbiome represents an untapped source of allergenic proteases. To identify candidates, we developed a protein language model-based framework to learn shared features of conserved catalytic domains in known allergenic proteases and applied it to human gut and oral microbiome gene catalogs, predicting thousands of putative serine and cysteine protease allergens. Two high-confidence candidates from Staphylococcus schleiferi and Tannerella forsythia were validated in vivo where they activated hallmark type-2 responses consisting of CD301b+ dendritic cell (DC) activation and Th2 cell differentiation, confirming our classifier can predict allergenicity through protease activity.
The identity of the adjuvants that shape allergic immunity are also unknown. We previously showed that sensory neurons directly respond to protease allergens, raising the possibility that neuronal responsiveness may reveal substances with allergenic potential. Thus, we screened a subset of plant derived small molecules using an in vitro primary neuronal plate-based assay. We found that while plant derived saponins (PDSs), a diverse group of immunomodulatory molecules, activated sensory neurons in vivo, they did not induce the release of the neuropeptides Substance P and/or calcitonin gene-related peptide (CGRP) in vitro. One subclass, the Ginsenosides, altered responses to the protease allergen papain in vivo through distinct effects on DC migration and T helper cell differentiation, while Polyphyllins, broadly activated DCs and promoted CD8⁺ T cell responses in vivo. Overall, this dissertation showcases two strategies for allergen and adjuvant discovery across biological systems.Immunolog
Building better models for human disease genetics
No full textInterpreting the functional consequences of genetic variants is a central challenge in human genomics. Despite the rapid acceleration of sequencing technologies, the majority of protein-coding variants remain uncharacterized and classified as variants of unknown significance (VUSs). Variant effect predictors (VEPs) aim to address this gap by scoring the potential impact of variants, but most current models are limited by biases in training data, lack of interpretability, and poor generalizability beyond known disease genes. These limitations are particularly problematic in clinical settings where accurate, genome-wide prediction of variant effect is essential.
To promote the development of clinically useful and generalizable VEPs, we worked to establish best-practice guidelines to address transparency, training data sourcing, and evaluation design. These guidelines identify common pitfalls such as circularity, overfitting to clinical labels, and limited benchmarking scope. Emphasis is placed on rigorous separation between training and evaluation data and open-source availability of models and scores. Building on these principles, we introduced a large-scale benchmarking resource, ProteinGym, to harmonize data from hundreds of deep mutational scanning (DMS) experiments and clinical variant annotations, enabling robust comparisons across predictors.
We developed a novel model, popEVE, to integrate evolutionary sequence data with human population variation in a probabilistic framework. By calibrating missense variant scores against gene-level constraint derived from population data, popEVE enables comparison of variant deleteriousness across the proteome without relying on clinical labels or allele frequency-based heuristics. Applied to rare disease cohorts, popEVE identifies over 100 novel candidate developmental disorder genes and successfully ranks causal variants without parental data. When extended to phenome-wide burden testing in population cohorts, our model uncovers hundreds of novel gene–phenotype associations and enables the construction of disease-specific polygenic risk scores from rare missense variants alone. These results demonstrate the utility of combining deep evolutionary context with human-specific constraint to build generalizable, clinically meaningful models of variant effect.Systems Biolog
Mechanisms of cytotoxic immune evasion by disseminated tumor cells in breast cancer metastasis
No full textMetastasis is the major cause of death for patients with solid cancer. Within these malignancies, Triple Negative Breast Cancer (TNBC) is one of the most aggressive and lethal diseases for women worldwide. Metastases arise from cancer cells that disseminate from the original tumors, survive systemic immune surveillance, and colonize new organs. Current therapies often fail to eradicate these Disseminated Tumor Cells (DTCs), leading to metastatic recurrence. Targeted clearance of DTCs, therefore, presents an opportunity to prevent metastasis. Immunotherapy holds immense promise as a strategy to sustain a systemic anti-tumor immune response against metastasizing cells. However, current immunotherapies yield low response rates and metastatic recurrence remains frequent. Increasing evidence suggests that this is because DTCs develop distinct tactics to evade immune responses that differ from those employed in a primary tumor. As such, leveraging the immune system to target DTCs requires precise understanding of how tumor cells overcome anti-tumor immunity upon dissemination. Studies in this context to date remain limited, largely due to the challenge of studying the interactions between surveillant immune cells and the rare surviving DTCs that resist their attack. Developing effective immunotherapies to eliminate DTCs requires a stronger understanding of immune evasion during the initial stage of metastatic seeding.
To address this question, we leveraged a visible antigen and cognate CD8+ T cells in a TNBC model of lung metastasis to profile resistant DTCs and identify their acquired mechanisms of immune escape. These studies uncovered a program of Glucocorticoid Receptor (GR) activation in disseminated tumor cells that evade immune response. We found that loss of GR in cancer cells reduced initial metastatic seeding by sensitizing DTCs to both CD8+ T cell and Natural Killer (NK) cell elimination, proving that GR activation drives metastasis by providing DTCs with broad resistance to cytotoxic lymphocytes. We engineered a niche labeling system to profile lymphocytes that interact with DTCs and discovered Fas-Fas Ligand (FasL) as a key cytotoxic pathway in DTCs for early metastatic survival. GR activation represses the death receptor Fas on tumor cells, which blocks FasL-mediated killing by cytotoxic lymphocytes. Pharmacologic inhibition of GR in combination with immunotherapy drastically reduced DTC metastatic survival and extended mouse lifespan.
Thus, we uncovered the GR-Fas axis as a metastasis-specific mechanism of immune evasion that operates specifically in DTCs and protects from pan-cytotoxic immunity. These findings illustrate the unique features of cancer-immune interactions during different stages of disease, and highlight the distinct adaptations developed by DTCs for immune resistance at this bottleneck stage of the metastatic cascade. Therapeutic strategies to prevent metastasis are lacking, and our findings suggest that there are opportunities to precisely eliminate DTCs separately from treatments aimed at primary tumors. This work proposes GR as one promising combinatorial target to attack DTCs and reduce metastatic recurrence.Biological and Biomedical Science
From transport to transcription- the nuclear pore complex as a conduit for metabolic longevity signaling
No full textThe Nuclear Pore Complex (NPC) is the sole gatekeeper between the nucleus and cytoplasm; therefore, its function is critical throughout life. One conserved biomarker of aging is the loss of nuclear membrane integrity, which can be seen in the increased leakiness and instability of the NPC. An unbiased genetic screen performed by our lab in Caenorhabditis elegans (C. elegans) found that NPC proteins (nucleoporins/Nups) are required for the pro-longevity biguanide drug, metformin, to inhibit the mTOR growth pathway. Connecting NPC function to this genetic pathway, treatment with biguanides also leads to restricted passive transport through the NPC in human cells– reverting it to a more youthful state. How the physiological modification of Nups affects longevity, and the upstream or downstream effect of the NPC on pro-longevity mechanisms, is a new and exciting area of research.
In our first study, we leverage a passive transport model in living cells to further clarify the mechanism of biguanide passive transport restriction of the NPC. We find not only biguanides, but multiple mitochondrial electron transport chain (ETC) inhibitors restrict passive nucleocytoplasmic transport. Expression of O-GlcNac transferase (OGT) is significantly decreased in biguanide treated cells, leading to a decrease in global O-GlcNAcylation levels, and importantly locally reducing O-GlcNAcylation of Nup98. Further, inhibition OGT is sufficient to restrict NPC passive transport and upregulation of O-GlcNAcylation alone reverses biguanide mediated effects on nuclear permeability. These findings reveal that O-GlcNAc serves as a mitochondrial–nuclear signal, and that altered mitochondrial energetics, driven by ETC inhibition, lead to rapid changes in nucleocytoplasmic transport in human cancer cells through post-translational modification of the NPC.
In our second study, we discover that CeNup153 is one of the select nucleoporins (Nups) required for biguanide mediated lifespan extension in C. elegans. CeNup153 has several roles within the nucleus, including passive transport, active transport, and chromatin organization. CeNup153 is also necessary for starvation and daf-2 mutant pro-longevity pathways, but how CeNup153 activity is altered, as well as the specific mechanisms by which CeNup153 is required to promote longevity, were not previously investigated. Here, we demonstrate that biguanide treatment increases CeNup153 expression during aging, and that CeNup153 overexpression alone is sufficient to extend lifespan. We identify CeNup153 dependent biguanide-activated or repressed genes- and find many are within pro-longevity pathways. Interestingly, one of the top differentially expressed genes (DEGs) elo-2 was previously found in our lab to be part of a biguanide longevity pathway involving ether lipogenesis. Linking these pathways, we find that CeNup153 mediated lifespan extension requires expression of these lipid biosynthesis genes. Furthermore, we show that CeNup153 binds directly to the promoter of lipid metabolism genes fard-1, elo-2, and lbp-8, supporting a model in which CeNup153 promotes longevity through epigenetic regulation of lipid metabolism.Biological and Biomedical Science
Control Approaches for Exosuits in Clinical Populations during Diverse Activities
No full textIndividuals with musculoskeletal or neurological diseases often experience mobility challenges, including reduced walking efficiency and limited automaticity. For example, gait patterns of individuals post-stroke are hemiparesis, characterized with slowness and asymmetry; more than half of individuals with Parkinson's Disease (PD) experience Freezing of Gait (FoG), characterized with brief, episodic reduction or absence of forward progression. Despite existing solutions such as rehabilitation and passive assistive devices, these impairments elevate injury risk and diminish quality of life for clinical populations.
Wearable electromechanical devices have been developed to restore mobility, compensate for impairments, and enhance rehabilitation outcomes for clinical populations. Specifically, joint-targeting devices have achieved notable success in clinical populations to reduce physical effort, increase practice volume, and retrain regular biomechanics. Nevertheless, controllers of joint-targeting devices have been tuned for continuous, steady walking, relying on gait phase estimation or gait event detection algorithms only reliable under supervised, controlled conditions. Pathological gait poses additional challenges in controllers with atypical and varying joint kinematics, short and intermittent walking bouts, and impaired endurance.
This thesis seeks to address the challenge in assisting pathological gait in real world settings by designing and evaluating control systems that are robust in diverse activities. First, we deployed a unilateral hip flexion exosuit for inpatient gait retraining in clinics. We expanded the use of exosuit to non-ambulatory patients and non-walking repetition practices during actual rehabilitation sessions by implementing assistance triggered by pysical therapisyt (PT). The exosuit eliminated the needs for manual limb support from PTs and increased participants' gait endurance or speed. We also executed a community Robotic Exosuit Augmented Locomotion program to support community walking practices with a semi-active ankle exosuit. Four participants in the chronic stage of stroke independently used the ankle exosuit for 4 weeks. Two participants significantly increased their unassisted paretic propulsion and daily steps following the program.
Second, we developed a turning-specific controller to provide assistance during transitional activities and reduce FoG for individuals with PD This is an advancement from a case study of a single individual performing straight-line walking to a full study of nine participants performing turning and freeze-provoking activity. We developed a controller for a bilateral hip flexion exosuit to accommodate asymmetry and reduced range of motion during turning. The turning controller successfully assisted various activities, including individual-specific hotspots, and led to a significant reduction in freeze severity and improvements in turn quality.
Third, we further innovated the controller for individuals with PD and established a control strategy combining adaptive oscillators and machine learning models to accommodate complex freeze-provoking trajectories at home. We introduced a phase-coupling term in adaptive oscillators to greatly improve the reliability and adaptability of gait phase estimation in transitional activities. As gait further deteriorated due to FoG, we switched to a kinetic-based gait phase realized by a machine learning (ML)-estimated weight distribution, along with ML-estimated FoG probability to determine FoG in real time. This control strategy was validated in complex at-home hotspots, demonstrating reliable assistance across various gait representations and a successful reduction in freeze severity and improvement in functional outcome.
Together, this thesis advances control systems for wearable assistive devices that consistently assist pathological gait patterns, validated in real-world deployment in clinics and communities for individuals post-stroke, and versatilely adapt to diverse activities and complex trajectories at home, demonstrating a life changing reduction in FoG for individuals with PD. We removed several key barriers and established a practical path to implement exosuits from laboratory to clinics and home.Engineering and Applied Sciences - Engineering Science
Geometry and Design in Palladio's Architecture
No full textAndrea Palladio (1508-80) is among the most loved and influential of the architects of the Italian Renaissance, famous for his elegantly proportioned buildings and for his treatise on architecture, the Quattro Libri dell’Architettura, first published in Venice in 1570. However, in terms of our understanding of exactly how Palladio achieved his‘elegantly proportioned’results, surprisingly little is known. Palladio does say that good proportions are very important, but he never explains his own methods, nor any more general theory of design. What Palladio does instead is to present us with a set of examples. The Quattro Libri as it stands is a collection of these examples, ancient and modern, some built and some not. Many attempts have been made to decode Palladio’s system, the most influential of which remains Wittkower’s treatment in his book Architectural Principles in the Age of Humanism (1949). Wittkower’s harmonic proportions hypothesis has fallen out of favour, but the more fundamental questions Wittkower poses have not gone away. Whether Palladio used a particular geometric or proportional system within his design process, and if so, what precisely that process or system was, remains a subject of intense interest and research.
This dissertation aims to significantly advance our understanding of the process that Palladio used to design his buildings. It does this by identifying the geometric basis of his design method. First it shows that the equilateral triangle, and its related forms, was integral to his design process, indeed it was ubiquitous. Recognising this allows us to move past the limitations of previous analyses which have viewed his designs using the framework of a two-dimensional Cartesian grid. Relationships which were previously overlooked become obvious, such as those based on the ratio of an equilateral triangle’s base to its height: 1: √3/2. Secondly, this dissertation demonstrates that an understanding of Palladio’s use of these specific proportions, and the numerical ratios used to approximate them, makes interpreting his designs straightforward. Once we are familiar with Palladio’s number systems, we can explain his marked dimensions and his unmarked dimensions. The methods shown allow us to decode Palladio’s designs in plan and in elevation, as a whole and in detail, with orders and without orders, as well as Palladio’s own designs for the five orders, results that were previously out of reach. This dissertation concludes that this method of working was not unique to Palladio. Rather the use of geometric templates, with forms based on the equilateral triangle, was common practice among pre-modern architects. Palladio appears to have developed his own geometric methods based on methods still in use that had survived within the craft techniques of medieval masonry, and which can be traced back, and which Palladio reconnected, to ancient Roman practice.
For purposes of comparison, this study also analyses several ancient Roman and medieval designs using these same methods. The examples and methods demonstrated will also be of interest to historians of these periods, to historians of science, and to those interested in the history of knowledge, in particular the craft, metrology, and mathematics used by ancient, medieval, and Renaissance master masons and carpenters. The methods and principles demonstrated may also be of interest to practicing architects, to professors of architectural practice and architectural theory, as well as to those more generally interested in design, and in the history of design. In addition to Palladio, references are made to the methods of Vitruvius, Villard de Honnecourt, Cesare Cesariano, Falconetto, Sebastiano Serlio, Antonio da Sangallo the Younger, Vignola, Vincenzo Scamozzi, and Ottavio Bertotti Scamozzi.
The dissertation is divided into two parts. The first half is centred on a geometry primer, followed by selected examples of how Palladio applied his geometry to architecture. The second half provides a comprehensive set of case studies. The primer is designed to introduce the reader, step-by-step, to the fundamental geometric concepts, number systems, and methods used by Palladio. So equipped, the reader will be able to understand, weigh, and evaluate the arguments, evidence, and examples which follow. The reader will also be equipped to examine additional buildings, from any pre-modern period, with respect to the possible presence and usage of such geometries and methods.
Chapter 1 introduces Palladio’s use of geometry and considers Palladio’s ancient, medieval, and contemporary sources for such methods. Chapter 2 contains the geometry primer. The primer introduces a look-up table (Appendix 3) to help the reader become familiar with the number systems which Palladio uses hand-in-hand with his geometry. Chapter 3 considers Palladio’s application of his geometric methods to architecture, including his use of short-cuts, and types (typologies), and his approach to design in elevation, in plan, and in three dimensions. Chapter 3 includes an explanation of Palladio’s method of budgeting for wall thicknesses, and the role of the orders within his geometric design system. Chapters 4 to 7 contain case studies. The case study chapters examine and explain Palladio’s use of these methods across four general classes of design problem. These are: (1) Palladio’s designs for the five orders, as published in his own Quattro Libri, (2) Palladio’s designs for Vitruvian ideal temple types, as designed by Palladio for the Barbaro Vitruvius, (3) Palladio’s designs for his own buildings, and (4) Palladio’s reconstructions of ancient Roman buildings.History of Art and Architectur
Beyond Narrative: The Rise of Historical Scholarship in Song Historiography
No full textThis dissertation explores the development of historiography in the Song dynasty, focusing especially on two distinctive undertakings: the evidential investigation of historical sources and “facts” as Song scholars understood them, and the pursuit of historical analysis, interpretation, and explanation in the form of historical commentary. I argue that whereas earlier historians had treated narrative as the core, if not the sole, task of historical writing, the emergence of new historiographical genres in the Song and the shifts in historical consciousness that accompanied them gave rise to a distinct domain of historical scholarship alongside narrative history. The dissertation seeks to delineate these changes, explain their emergence within broader political, intellectual, and historiographical contexts, trace their subsequent development, and assess their long-term significance for the evolution of Chinese historiography.
Chapters One and Two focus on historical evidential investigation. Chapter One examines Sima Guang 司馬光’s Zizhi tongjian kaoyi 資治通鑒考異—the first work to systematically lay out procedures for comparing, analyzing, and selecting among sources. Beyond reconstructing Sima Guang’s methods of evidential investigation, this chapter also seeks to contextualize the background in which this endeavor took shape and to explain why he was so determined to make it available to a broader public. Chapter Two turns to two Southern Song historians, Li Tao 李燾 and Li Xinchuan 李心傳, situating them within the aims and constraints of contemporary history compilation in the Song to understand and analyze how they inherited and transformed Sima Guang’s evidential investigation.
Chapters Three and Four then turn to historical commentary. Chapter Three first traces changing attitudes toward personalized commentary and interpretation of history and shows that this previously much-contested practice came to be widely accepted and actively practiced in the Song. It then proposes possible explanations for this shift and, finally, highlights the new forms of historical consciousness that emerged in historical commentary. The last chapter offers a detailed reading and analysis of the different interpretative tendencies and explanatory orientations found in these commentaries.East Asian Languages and Civilization
Elucidating Novel Immunomodulatory Mechanisms in the Metastatic Cascade
No full textEvery step of the metastatic cascade, from invasion to colonization, is modulated by the immune system. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy of the pancreas, and the mechanisms regulating its propensity to metastasize remain mostly elusive. We sought to investigate the contribution of the fibroinflammatory responses in the PDAC tumor microenvironment (TME) to metastasis. Type 2 (Th2) immune responses evolved for anti-parasite defense and cause allergic disease, but thus far have been minimally linked to cancer. We found that eosinophils, effector cells of a Th2 response, are abundant in pancreatic cancer in mice and humans. Genetic loss of eosinophils in mice does not affect primary tumor growth but increases rates of spontaneous metastasis. Treatment with the Th2 alarmin IL-33 or the allergen papain increases intratumoral eosinophil activation and decreases metastasis. Tumor-resident eosinophils in humans and mice produce IL-4, which prevent epithelial-to-mesenchymal transition, preserving tumor cells in an epithelial state and thus stopping their egress from the primary tumor. Systemic delivery of extended half-life IL-4 or a computationally designed IL-4 mimic ameliorates PDAC prognosis, by reducing primary tumor burden and preventing metastasis to liver and lung.
Besides metastasis in major organs, lymphatic colonization has been linked to worse prognosis in several cancers, as lymph nodes act as a reservoir of malignant cells, allowing their dissemination to distant organs. More recently, lymph node metastasis was found to promote systemic immunosuppression, further highlighting the need for a better understanding of the mechanisms supporting its formation. To this end, we investigated the transcriptional profiling of immune cells in pre-metastatic tumor-draining lymph nodes and observed a phenotypic change in the activation state of B cells. We developed a mouse model of trackable PDAC highly metastatic to the draining lymph node and investigated the contribution of B cells to the metastatic cascade. We observed that metastatic PDAC cells fail to successfully colonize lymph nodes when B cells are depleted either genetically, in μMT-/- mice, or following αCD20 therapy. Similar findings replicated in metastatic melanoma. We found that a role for B cells in supporting metastasis is through antigen presentation to CD4+ T cells, as absence of MHCII on B cells led to a reduction in lymph node metastasis. We analyzed CD4+ T cells in the tumor-draining lymph node of μMT-/- mice and observed a deficit in T regulatory cells, which correlated with stronger systemic anti-tumor responses.
Collectively, these findings elucidate novel immunomodulatory mechanisms in the suppression or support of the metastatic cascade.Immunolog