Elucidating the role of Protein Kinase RNA-like ER Kinase (PERK)-mediated unfolded protein response in modulating smooth muscle cells during atherosclerosis

Atherosclerosis is the main underlying cause of cardiovascular disease (CVD) and is characterized by the buildup of inflammatory lipid-rich deposits containing smooth muscle cells (SMCs), fibroblasts, endothelial cells, and various infiltrating immune cells including macrophages and T-cells in the arterial vessel. The size and cellular composition of these lesions impact their stability, with less stable lesions imposing increased CVD pathological risk. Atherosclerotic lesion development begins within the first two decades of life, and while existing lipid-lowering therapies can significantly reduce atherosclerotic burden, additional strategies to bias developing lesions towards stability will further reduce residual CVD vulnerability. During lesion development, SMCs de-differentiate and modulate to form non-classical SMC-derived cell types (SDCs) in a process termed phenotype switching. Together, SMCs and SDCs form the majority of a lesion’s cellular content and can therefore influence lesion stability. However, little is known about SDC function, the factors driving their modulation, and their effect on CVD outcomes. A recent paper from Chattopadhyay et al. linked the modulation of a subset of SDCs to the Perk unfolded protein response (UPR). The UPR describes a three-pronged approach to reinstating endoplasmic reticulum (ER) homeostasis in response to ER stress. Perk, an ER stress sensor and activator of one prong of the UPR pathway, was reported to be necessary in the formation and expansion of a subset of SDCs in atherogenic mice. The UPR has been studied previously in the context of other diseases, and Perk inhibition was reported to influence infiltrating leukocyte proportions and function in developing lesions. However, it is not clear what role a Perk-dependent SDC population plays in atherosclerotic lesions and if this has any impact on lesion stability. Using single cell analysis (scRNA-seq) and SMC lineage-traced atherogenic mice, we assayed the effect of Perk on SMC modulation. As pharmacological Perk inhibition resulted in adverse events that confounded our efforts to characterize Perk’s role in lesion development, we created a SMC-specific, inducible Perk knockout (KO) mouse on our atherogenic SMC lineage-traced background. Across multiple timepoints of lesion development, we determined that SMC modulation was unchanged by SMC Perk depletion. Perk WT and Perk KO mice developed lesions of comparable sizes, compositions, and features predicting lesion stability. We integrated our data with scRNA-seq data from Chattopadhyay et al. and determined that the SDC population previously reported as being Perk-dependent was not entirely SMC derived nor detectable in other comparable studies. Furthermore, analysis of human carotid lesion samples failed to identify a correlation between UPR activity at the transcriptional level and CVD outcomes. Our findings suggest that the Perk UPR pathway in SMCs is not significantly coupled to its modulation, and that furthermore, UPR does not sufficiently correlate with lesion stability in human lesions to be an ideal therapeutic target for addressing residual CVD risk

Essays on Collaborative Innovation

This dissertation examines how technological and policy shifts transform collaboration ininnovation across three different contexts: healthcare, commercial space, and entrepreneurship. Using large-scale empirical data and advanced econometric methods, I demonstrate how individuals and organizations can leverage technology and strategic partnerships to accelerate innovation while navigating complex market dynamics. My first study analyzes the impact of adopting digitization technology on scientific collaboration among 313,257 researchers at 148 U.S. teaching hospitals. Exploiting the staggered implementation of Electronic Health Records (EHR) systems as a quasi-experimental shock, I find that digitization increases research collaboration by 6.1% and intellectual diversity of teams by 1.1%. The effect is 24% stronger than other traditional health information technology (IT) systems such as data management software, driven by improvements in data interpretability, and doubles when collaborators use the same EHR system because of increased data shareability. This study reveals how standardized IT infrastructure can unlock collaborative potential, with policy implications for the 3.8 trillion dollars U.S. healthcare industry and the innovation of medical Artificial Intelligence (AI) and machine learning (ML). The second study assesses the outcomes of NASA’s commercial space initiative by analyzing the scientific and economic impacts of experiments carried out onboard the International Space Station (ISS). Using NASA’s launch records, I constructed a novel dataset of space experiments conducted between 2001 and 2021. Analyzing the publications and patents resulting from these experiments, I find that ISS-based research generates 63% more paper and 82% more patent citations than their digital twins—comparable experiments conducted in Earth labs—controlling for confounding factors such as the reputation of the principal investigator and the publication outlet. However, this impact diverges sharply between public and private research, with commercial experiments showing limited knowledge spillovers. These findings contribute to our understanding of how innovative organizations such as NASA, academic institutions, and high-tech companies responds to sudden shifts in technological and policy environments. They also inform the design of public-private partnerships in emerging industries, particularly as the space economy is projected to approach $500 billion by 2030. My third study examines how high-tech entrepreneurs strategically position themselves for different exit outcomes. Two specific outcomes are considered—acquisition and Initial Public Offering (IPO), given that more than 90% of startup entrepreneurs exit through one of these channels. Applying ML methods on the U.S. federal SBIR program data, I developed an “orientation score” that isolates a firm’s positioning toward one outcome over the other while holding its underlying quality constant. My analyses reveal important variation in orientation associated with both the technological specialty of firms and the economic environment surrounding them. IT firms orient 40% more toward collaborative exits via acquisition, while biotech firms favor the more competitive path through IPO. Regional innovation ecosystems strongly predict these strategies, with local patenting activity increasing acquisition orientation by more than 30%. Collectively, these three studies advance our understanding of how organizations adapt to technological disruption and policy change to create value through collaboration. The findings have immediate applications for healthcare systems implementing digital transformation, government agencies designing innovation programs, and investors evaluating startup strategies. My work demonstrates that successful innovation increasingly depends not on isolated brilliance but on the strategic orchestration of collaborative networks, a capability that determines competitive advantage across scientific domains and industries. This dissertation contributes methodologically through the application of advanced econometric models, such as the staggered difference-in-differences estimators, to address treatment effect heterogeneity, the use of ML to resolve endogenous selection, and the construction of unique datasets linking innovation inputs to measurable outcomes. These approaches enable rigorous causal inference and prediction, allowing me to address important questions facing the production of scientific knowledge and the strategic dynamics within innovation ecosystems

Extending the availability of living allogeneic heart valves for transplantation

There remains an urgent clinical need to develop durable heart valve replacements which can act as life-long substitutes for the native heart valve, especially for pediatric patients wherein the current standard of care is multiple reoperations to repair or replace failed valve prostheses throughout a child’s lifetime. These reinterventions are often required within just months of the valve replacement’s original implantation. This is because there are currently no valve prostheses with the capacity for growth or self-repair. Both bioprosthetic valves (including cryopreserved human allografts, which represent the historic gold-standard for pediatric patients) and mechanical valves suffer from limited durability and are unable to support the somatic growth of a child. Living heart valve transplantation is a recently introduced surgical technique wherein valvular allografts are procured from a heart deemed unsuitable for orthotopic transplantation or from a living valve donor who is receiving a heart transplant for a non-valvular indication. In heart valve transplantation, these living valves are semi-emergently transplanted in the recipient, with the core advantage of functioning as a viable, growth-capable valve. The in vivo adaptive growth and durability of living heart valve transplants is currently being studied in single and multi-center clinical studies, with promising early outcomes. However, there remain key translational challenges to this technique’s implementation – namely, lack of donor availability as well as the time, resource, and logistic constraints involved in urgent transplantation. These challenges are exacerbated by the difficulties of donor-recipient size matching in pediatric patients. In this dissertation, we therefore work towards establishing a strategy for the storage and preservation of living allogeneic valves, with the hypothesis that integrating physiologic biochemical and mechanical cues will enable the preservation of valvular tissue physiology ex vivo. In Aim 1, we develop a custom preservation solution aimed at preserving valvular tissue viability. We thoroughly evaluate the preservation solution’s capacity to maintain valvular leaflet and pulmonary artery viability, metabolism, microarchitecture, and cell physiology for up to 7 weeks ex vivo. Our experimental model employed freshly sourced porcine valves that had been subject to the upper limit of static cold storage currently used in clinical practice. We found that our preservation solution could preserve valvular viability and metabolism for at least 7 weeks, with maintenance of key phenotypic markers of valvular interstitial cells. However, the leaflet microarchitecture began to degrade by 3 weeks ex vivo, with increasing collagen content. Building on these results, we sought to integrate physiologic mechanical cues to more effectively preserve valvular microarchitecture. In Aim 2, we designed, built, and tested a custom bioreactor for the storage of valvular allografts. With clinical translation as a primary goal, a key design specification of our bioreactor was to avoid the use of a pump. We created a low-cost, user-friendly, compact system which was composed of a closed loop, wherein the valve is maintained in a valvular housing chamber and fluid flow through the valve is dependent on axial rotation of the bioreactor. We validated that rotation could introduce native-like open/close cycles in porcine valves and obtained fine-tuned control over the hydrodynamic environment by manipulating the bioreactor’s rotation protocol. Finally, we demonstrated the capacity to maintain valvular viability in the bioreactor for up to 4 weeks. We found that valves exposed to mechanical stimulation demonstrated maladaptive remodeling, characterized by leaflet retraction and fibroblast proliferation. Therefore, we then performed a parameter-controlled study which identified a unique biochemical treatment which could prevent valvular fibrosis in response to mechanical stimulation ex vivo. In Aim 3, we evaluated the in vivo response to living valvular allografts in the preclinical and clinical settings. We established a porcine model for heart valve transplantation and then applied this model towards evaluating the impact of static cold storage on valvular allograft function. We found that fresh valve transplants demonstrated preserved function for 2 months of follow-up, versus a valve that had been subject to 4 weeks of static cold storage which showed severe insufficiency and diffuse calcification throughout the pulmonary artery on explant. We next investigated clinical outcomes following heart valve transplantation at Columbia, following two patients who received “domino” heart valve transplant at our center. Our outcomes demonstrated maintained valve function with adaptive valvular growth in both patients. We also report the first-ever evidence of immunosensitization following heart valve transplant, with both patients developing donor specific antibodies within 100 days post-transplant. Collectively, this dissertation functions as a foundation for normothermic storage and preservation of living allogeneic valves through integration of key homeostatic signals in the ex vivo environment. Moving forward, the strategy developed in Aims 1 and 2 will be evaluated in vivo, as per the preclinical model establish in Aim 3. In tandem, we are continuing to evaluate the in vivo performance of heart valve transplantation via multicentric studies including centers from across the United States, as well as through the development of a dedicated registry aimed at the long-term follow up of heart valve transplant recipients

Perceived Benefits and Risks of Emotional Self-Disclosure in Therapy and Online Spaces

Emotional self-disclosure, talking about one’s private thoughts and feelings, has been central to help-seeking and help-receiving since Freud. Previous research has explored how tendencies to self-disclose in therapy are influenced by personality traits such as shame, guilt, and attachment style; it has also suggested that client self-disclosure influences therapy outcomes. Relatively little research has explored how individuals conceptualize different “targets” of self-disclosure—that is, individuals or groups to whom they choose to reveal personal information. Common targets of emotional self-disclosure have included individual and group therapy since their invention as interventions in the early 20th century, as well as family and other close relationships. More recently, anonymous and non-anonymous social media and conversational AI have gained attention as possible emotional self-disclosure targets. The present study examined how personality and demographic characteristics may be associated with emotional self-disclosure preferences. A previously validated therapy research measure was adapted and used to gather self-report data via MTurk from 671 participants about how rewarding and risky they would find emotionally self-disclosing towards different targets, including more relational targets such as therapists and family, and less relational targets such as anonymous social media and AI. Initial analysis revealed personality and demographic traits that contribute towards self-disclosure preferences. Further analysis segregated participants into three groups based on level of therapy experience: none, low, high. Latent profile analyses of these three groups revealed multiple psychologically distinct subclasses. Findings suggested that preferences for self-disclosure targets are highly differentiated, with individuals weighing both psychological and social risk and reward factors in deciding where to self-disclose. Individuals high in trait shame and insecure attachment showed no preference for more relational targets over less relational targets. These “omni-disclosers” appeared in each therapy experience-level group, as did “relational-preferrers” who on average were less socially anxious and less ashamed. The results highlighted the context-sensitive nature of modern help-seeking and reflect a world in which engaging in emotional self-disclosure on anonymous social media and with conversational AI is increasingly normal, even among those engaged in other supports such as therapy. Directions for future research and applications for therapy training, digital intervention design and ethics, and public mental health outreach were discussed

The Sonic Architecture of Interdictor: Matter, Structure, and Code

This dissertation examines composer Marek Poliks’s Interdictor—a sound installation of 558 computer fans on an aluminum hull—as a “reconversion piece” that leverages institutional resources to stage a strategic exit from the neoliberalized New Music field. Through a tripartite analysis, it first maps the field’s hollowed-out conditions, then performs a technical autopsy showing how the work’s C++ code materializes a logic of algorithmic precarity. Finally, a reception study reveals how critiques of the work’s “emptiness” inadvertently validate its core function: to devalue the field’s capital through a performed departure. This framework is tested and expanded through the creative component, Drinking Brecht, a collaborative work of experimental theatre created under the banner of Sister Sylvester (Kathryn Hamilton). Where Poliks’s model is one of alienating exit, this project explores collectivist, embodied participation. While the piece centered Hamilton’s voice as the primary storyteller, our collaborative process—engaging my own compositional practice and the artistic contributions of Jessie Cox, Ellery Trafford, and Hamilton’s too—became a site to consciously negotiate authorship across differences of gender, race, and artistic discipline. The piece thus functions as an open laboratory, representing a different form of Bourdieusian struggle that challenges monolithic authorship through a shared, yet critically examined, creative practice. Together, these case studies chart the complex and often contradictory strategies artists deploy within a reconfigured cultural economy

The Reinvention of the Sexual: Radical Sexual Cultures, Politics, and Queer Marxism in Cold War Brazil and Cuba

The Cold War in Latin America is marked as much by the spread of leftist revolutionary political organizations and Cuban-inspired guerrillas as by the emergence of radical sexual cultures and politics throughout the region. From Brazilian alternative media and activisms to Cuban painting, sex education, and cinema, in my thesis I study homosexual and gender and sexual non-normative intellectual and artistic production, forms of political action, sex education initiatives, and queer Marxist cultural and political practices in Brazil and Cuba between the 1970s and the early 1980s. In Chapter One, I examine the centrality that the critique of guerrilla sexual politics and socialist cisheteronormativity had in pioneering 1970s homosexual intellectual and cultural production in Brazil and Cuba. I build an archive for this chapter structured around the Brazilian homosexual newspaper Lampião da Esquina and the work of Cuban painter Servando Cabrera Moreno. In Chapter Two, I move on to an analysis of the actual existing alternative radical sexual politics emerging in the late 1970s in both countries and aiming to transform Brazilian and Cuban societies. My focus in this chapter is on a memoir written by Monika Krause, the head of the Cuban Sex Education Program, on the relationship between Cuba and East Germany in the field of sex education, and on the theoretical production and politics of the Homosexual Faction of the Brazilian Trotskyist organization Socialist Convergence. In Chapter Three, I examine why the interrogation of the relation between cisheteronormativity, racialization, and the production of labor took central stage in the formulations of rising black activists and artists in Brazil and Cuba. In this chapter, I focus on the early 1980s intellectual production of the Brazilian black homosexual activist group Adé Dúdu, and on One Way or Another, the posthumous feature-length film of Cuban revolutionary filmmaker Sara Gómez. Queer Marxism plays a double role in my thesis. It is the main field of research in which I situate my dissertation and an object of inquiry within my own archive. Above all, I show in my thesis that the questioning of continuities between twentieth-century socialist gender and sexual epistemologies and politics with bourgeois idealism, of patriarchal social reproduction, and of a racialized brand of cisheteronormativity structuring the division of labor weaves together my archive. Finally, I also argue that the liberationist-form of cultural and political action is not enough to trace the radical sexual cultures and politics of Latin America, nor the broader struggle for sexual freedom that overcame Cold War divisions between capital and twentieth-century socialism. Often informed by existing internationalist networks and shared political commitments, my argument is that a dematerialized consideration of gay liberationism fails to grasp how local dynamics of accumulation and dispossession and revolutionary challenges to them distinctively shaped the political imaginary of the radical sexual cultures and politics emerging in Cold War Latin America

Neoliberalismo global: arte, tiempo y feminismos en Argentina. 1990s-2000s

Esta investigación examina las relaciones entre el neoliberalismo, la globalización y las artes en Argentina durante el auge de las políticas neoliberales en los años noventa y hacia su desestabilización con la crisis social y económica de comienzos del siglo XXI. En un contexto artístico sin un mercado consolidado ni industria cultural a gran escala, el trabajo propone un acercamiento teórico y analítico a los efectos micropolíticos del neoliberalismo global, centrado en la formación de subjetividades, de modos y de prácticas de vida en la sociedad y en las artes. El estudio aborda diversos ejes: la circulación de discursos sobre globalización y tecnología en periódicos y revistas culturales; el surgimiento de espacios de formación artística independientes de la educación oficial y en diálogo con el ámbito internacional; un conjunto de prácticas artísticas impulsadas por premisas feministas; y los impactos de la crisis económica sobre estas dinámicas. Entre los casos analizados se encuentran la Beca Kuitca y el Taller de Barracas, surgidos entre 1991 y 1994, orientados al formato de clínica de arte y a promover el intercambio entre artistas y alianzas internacionales. El estudio se concentra en las obras allí producidas, las discusiones entre artistas y los encuentros impartidos por figuras como Roberto Jacoby y Jorge Gumier Maier, quienes cuestionan los fundamentos del modelo de clínica. Asimismo, la tesis se enfoca especialmente en la producción de las artistas Alicia Herrero y Ana Gallardo. El análisis aborda un entramado crítico, basado en premisas feministas, que en la obra múltiple de las artistas vincula colonización, patriarcado y contemporaneidad mediante prácticas pictóricas, objetuales, performáticas y de autogestión. La investigación traza así el despliegue de una visión y una práctica conflictivas y críticas dirigidas a los procesos de globalización neoliberal desde Argentina y revela un mapa marcado por contradicciones asociadas al monopolio contemporáneo y colonial del saber, a la configuración consumista de la sociedad neoliberal, a la historia y el tiempo como entidades mutables y a la precarización atravesada por desigualdades de género

Liturgy of Empire: Reading the Mozarabic Rite in Early Modern Europe, 1500–1800

Liturgy of Empire examines the European reception of the neo-Mozarabic rite created under the patronage of the Archbishop of Toledo, Francisco Jimenez de Cisneros (1495-1517), in relation to the history of the Mozarabs of Toledo, the development of bibliophilia and libraries, the scholarly study of medieval liturgy, and the crusading ideology of Spanish expansionism in the Mediterranean. During the emergence of Spain’s global empire, the editions of the Mozarabic rite entered collections throughout Europe. The provenance of the copies (studied here for the first time) reveals their mediation of knowledge about Iberian history and the political contexts for their acquisition

The Film Poem: Lyric Poetry and the Origins of Documentary Film

This dissertation considers the use of lyric poetry and lyricism as one of the originary frameworks of early documentary cinema. Through close analysis of both public and archival materials, I demonstrate how an array of influential filmmakers—among them Paul Strand, Charles Sheeler, John Grierson, Pare Lorentz, and Dziga Vertov—recognized lyric poetry as nonmimetic and nonnarrative—a form of epideictic encounter and display that (1) makes direct claims about the world as it (2) foregrounds the ethos and agency of the speaker. These filmmakers, active during the 1920s and 1930s, paired “actuality footage” with lyric intertitles that demonstrated to audiences the epideictic force of their images. In Manhatta (1921), Strand and Sheeler self-consciously matched images of downtown New York City with excerpts from Walt Whitman’s Leaves of Grass, an act that belies the influence of William Carlos Williams in light of the film’s overlapping channels of lyricized evidence and commentary. Grierson, a pioneering force in the British documentary movement, was himself an amateur poet whose lyrics and writings on poetry prefigure his documentary productions and later collaborations with W. H. Auden. Similarly, the poets and critics writing for the modernist magazine Close Up, among them Roger Burford and H.D., theorized a number of early documentary films as the first “film poems.” Each chapter considers the particular lyric traditions that influenced these early conceptions of documentary media. Although previous scholarship has theorized forms of “poetic documentary,” the present study considers some of the ways in which lyric poetry shaped the development of different modes, including more “expository” forms that are typically considered to be antithetical to lyric expression. As such, I argue that the epideictic force of documentary film is a likely product of the nascent genre’s early engagement with lyric poetry

Essays on Informational Efficiency of the Financial Markets

This dissertation studies the effects of informational frictions and information acquisition on asset prices and investor decision-making. Chapter 1 build models for capital market opening based on the noisy rational expectations equilibrium (NREE) framework. To reconcile the mixed empirical evidence on whether domestic investors have an advantage over foreign investors in domestic stock market tradings, I distinguish soft information, which is qualitative and cannot be transmitted if the receiver is not physically present, and hard information, which can be stored in the form of data, purchased, and transmitted regardless of the presence of the receiver. The models feature a mismatch of data processing technology level and availability of soft information. Furthermore, the partial opening model also features a mismatch between the accuracy of hard information and foreign investability of shares. The equivalent data amount and the information spillover rate governs domestic and foreign institutional investors' data choices, respectively. Sufficiently, when the unit precision of hard information for foreign investable shares directly from processing data for them exceeds that indirectly acquired through processing data for foreign non-investable shares, foreign institutional investors would exhaust data processing capacity on foreign investable shares. The proportion of foreign institutional investors and their technology level both need to be large enough to overcome the dilution of soft information. Given that the signal-to-noise ratio increases, if the domestic investors learn more about foreign investable shares or the proportion of foreign investors is larger than a threshold, then the average precision of dividend innovation for foreign investable shares increases. In the full opening model, the average posterior precision of dividend innovation changes in the same direction as the signal-to-noise ratio for all shares. The case of China is characterized by a very small proportion of foreign investors, a large proportion of domestic individual investors, a large disparity between domestic and foreign data processing technology, and high precision of soft information. Foreign institutional investors would allocate their data processing capacity in both type of shares, and the signal-to-noise ratio for foreign investable shares decreases. Domestic institutional investors are also induced to learn slightly less about those shares, and thus the average posterior precision of dividend innovation decreases. In the full opening counterfactual, the signal-to-noise raios for both type of shares increase. Chapter 2 fills a gap in the theory literature of NREE models by studying the effects of learning about future demand shocks. Learning about future demand shocks makes price more informative in the future but less informative now. Ex-ante utility improves through what I term as the future uncertainty channel: on the aggregate level, fundamental information acquisition decreases, which makes dividends more risky and leads to higher risk premium; on the individual level, the investor is more certain about the asset payoff in the future due to the signal about future demand shocks she acquires today. As a result, her ex-ante utility improves. Chapter 3 zooms in on the learning process and highlights a specific subprocess---the perception process. Agents take the same sensory information as inputs, direct them through different perceptual sets and thus form different perceptual information, which is then used to update posterior beliefs. Biased perceptual sets thus lead to persistent disagreement among agents, while set revision corrects any perceptual bias and allows agreement to be reached. Depending on the intensity of perceptual shocks, agents' sensitivity to perceptual shocks and their initial entrenchment levels, there could be overreaction or underreaction in the price to sensory information in the markets. When overreaction happens, the trading volume also increases