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Next Generation Chemoproteomic Platforms for Functional Diagnostics and Small Molecule Drug Discovery
No full textTargeting the proteome to treat diseases has been a long-standing goal in biomedical research. Yet less than 3% of the human proteome have FDA approved drugs against them. This is largely because over 35% of the proteome remains poorly understood. Moreover, we need to identify those proteins within the proteome that directly drive disease. To uncover new therapeutic targets, we must assess the activity of the proteins under relevant backgrounds—not just their abundance. Furthermore, many disease-driving proteins are still considered "undruggable," underscoring the need for innovative strategies to therapeutically target these challenging proteins. Here we report single cell Activity Dependent Proximity Ligation (scADPL) which integrates automated microfluidic single-cell capture and nanoliter-volume handling to translate activity of proteins into multiplexed, amplifiable oligonucleotide barcodes. Activity-based probes targeting serine hydrolases and cysteine proteases were used to profile a panel of six enzymes known to be associated with cancer aggressiveness. Using the single-cell ADPL (scADPL) workflow on cancer cell lines and primary breast cancer organoids, we identified an activity signature that correlates with metastatic progression in breast cancer. This platform enables measurement of activity signatures at the single-cell level, allowing us to distinguish signals from cancer cells versus normal cells—signatures that would be masked in bulk analyses. Additionally, the low sample input requirement makes it possible to profile patient-derived cells under physiologically relevant conditions, helping to identify true disease drivers. To enable efficient targeting of traditionally undruggable proteins, we developed a high-throughput chemoproteomics screening platform called In-situ Proximity Amplified Rapid Chemoproteomics (SPARC). SPARC employs activity-based probes to convert protein engagement into a barcoded DNA signal that is amplified and quantified. Drug binding to the target protein leads to signal loss or signal gain, indicating inhibition or activation of target protein. Using SPARC, we identified inhibitors and activators for a panel of five full-length kinase-GFP fusion proteins in their native, intracellular context. In addition to detecting drug–protein interactions, SPARC provides multiple layers of information that help reduce false discovery rates and accelerate drug development. It captures protein localisation and abundance, allowing us to distinguish true target engagement from changes in protein levels. SPARC is also coupled with a viability assay to assess whether observed effects are due to specific interactions or general cytotoxicity from off-target effects. Overall, these chemoproteomic platforms advance drug discovery by enabling the identification of disease-relevant targets through scADPL and the rapid discovery of modulators—activators or inhibitors—of these targets using the SPARC screening pipeline
Work Outside: How Novel Collaborations Construct Innovative Financial Markets, Change Organizations, and Advance Careers
No full textThis dissertation examines how novel, cross-boundary collaborations among professionals give rise to novel markets, reshape organizations, and redirect careers. Focusing on securitization structured finance, it explores how buyers, sellers, bankers, lawyers, accountants, trustees, ratings agencies, consultants, and regulators co-construct what I call collaboration-induced markets (CIMs). While some collaborations merely facilitate transactions, high-impact collaborations structure a broader market field—establishing templates, infrastructures, incentives, and expectations that outlast any single deal. Why would professionals step outside of their firms and spend time and money on uncompensated work or uncertain initiatives? Drawing on comparative-historical analysis, in-depth interviews, longitudinal deal-level data, and immersive fieldwork, I show how such work outside serves as a vehicle for advancing market structures, organizational development, and professional standing. These collaborations take shape in a variety of settings—from informal meetings, formal industry working groups, on regulatory panels, at conference happy hours, and in elite social circuits—revealing a patterned ecology of seemingly peripheral but powerful activity. Work Outside contributes a novel mechanism for understanding market creation and organizational change: not as a top-down mandate or a reactive adaptation, but as an emergent response to collaborative market creation activities by organizational entrepreneurs operating at the interstices of firms, industries, and institutions. The dissertation offers a new theoretical lens on the sociology of markets, organizations, professions, and innovation—showing how professionals, by working outside, shape the futures of both their organizations and the broader economy
Reviving, Reimagining, and Reclaiming Cuba’s Colonial Musical Past in the Twentieth and Twenty-First Centuries
Get PDFThis dissertation explores the use of the past in the present through processes of heritage, focusing on Cuba’s revival in the twentieth and twenty-first centuries of its colonial-era Catholic sacred music. Within this repertory dating from the eighteenth century, I focus on the revival of the music of Esteban Salas y Castro, the Cuban-born chapel master considered Cuba’s first composer. This revival, which takes place via the interconnected study and performance of colonial sacred early music, is an important means through which Cuban cultural authorities have enrolled the fraught colonial past in nationalist endeavors to foster heritage and local identity in place. Examining the use of this repertory since the early-mid twentieth century opens a window onto Cuba’s changing relationship with its colonial past, from its independence from Spain in 1898 through the present day. I examine how major inflection points in Cuba’s history—moments of social change and uncertainty for the Cuban people—have seen a coalescing in the production of Cuban heritage that turns to the colonial past to navigate the present, particularly a revival of the island’s early music via research and performance. Through a combination of ethnographic and archival research methods, this dissertation explores three such moments of change that align with its three central chapters: the 1930s–40s, the 1940s–60s, and the 1990s–present. This view of Cuba’s past and present illuminates how intellectuals and cultural officials have championed elements of colonial art in pursuit of an anti-imperial Cuban history and culture. I unpack how cultural figures and artifacts from the colonial, imperial past—the Church of San Francisco de Paula and Esteban Salas chief among them—are taken up for Cuban anti-imperialist ends. I explore throughout this dissertation how and why colonial sacred music has been revived alongside and within colonial sacred architectural spaces, and reflect through ethnographic accounts the realities of these revival and heritage processes as they continue in Cuba’s challenging present-day conditions and as they confront an uncertain future
Trust Broken, Logic Switched: Sexual Harassment and the Strategic Shift in Rationality for Entrepreneurs
No full textStandard economic models predict that reputational mechanisms should discipline misconduct in markets. However, empirical reality often shows the opposite: in cases of sexual harassment, the costs are borne not by perpetrators but by victims, who disengage from opportunities, thereby reproducing structural inequality. Employing a hybrid Test and Explore experiment with Japanese entrepreneurs—a group uniquely reliant on relational trust due to weak institutional protections—this study investigates the underlying logic of their investor choices when faced with this threat. The findings reveal a core tension. On one hand, a confirmatory (test) analysis shows entrepreneurs assign an immense, yet calculable, cost to harassment, with a Willingness-to-Pay (WTP) of ¥16.35 million to avoid a problematic investor—a sum exceeding highly valued assets like network access. On the other hand, an exploratory analysis finds that this calculative logic seems to collapse under a specific condition: when no trustworthy alternative is available. In this context, 76.5% of entrepreneurs opt for categorical rejection, a choice insensitive to financial incentives. This paper argues that this tension is resolved by a model of dual rationality. A dignity-based logic is activated when trustworthy alternatives are absent, acting as a non-negotiable precondition for market engagement. It complements the calculative logic that governs choices once this precondition for dignitary safety is met. This study offers a plausible micro-level mechanism through which individually rational choices, drawing on different logics depending on the context, may in aggregate contribute to broader patterns of market disengagement and social inequality
The Day the Icon Fell: Relic Conquest in the Fourth Crusade
Get PDFDuring the Fourth Crusade, Latin knights, originally bound for Egypt, laid siege to Constantinople, the capital of the Eastern Roman Empire. The city was eventually sacked. A short-lived Latin empire was installed to rule over the empire, and a great horde of valuables was taken back to the West. Among this booty were many holy relics. Upon their reception, these holy artifacts required justification and explanation for how they came to be where they were. The Sack of Constantinople is now remembered as a confused tragedy: an unprovoked crusade that pitted Christian against Christian. In these hagiographic sources, however, we see the narrative that contemporary Latin churchmen preferred to give the Fourth Crusade. Focusing on a particularly prolific battle in which the crusaders seized a famous Greek icon, this paper examines how focusing on the seizure of relics allows these sources to paint the Fourth Crusade as a divinely ordained conflict. This contradicts most modern accounts and many of the most famous contemporary sources
The Embodied Epistemology of Rasa: Recentering Interoception and Sensory Cognition in Classical Indian Aesthetic Theory
Get PDFThis thesis argues that rasa theory, an Indian classical aesthetic framework describing both the distilled emotional “flavors” experienced by an audience and the performative process by which they are evoked, offers a robust and underrecognized model of embodied cognition. Through a combination of autoethnographic reflection, fieldwork with practitioners of kūṭiyāṭṭam, a Sanskrit theatre tradition in Kerala, India dating back to the 10th Century CE, textual analysis of the Nāṭyaśāstra and The Dhvanyaloka of Anandavardhana with the Locana of Abhinavagupta, foundational Sanskritic texts on dramaturgy and aesthetic philosophy, and interdisciplinary engagement with cognitive science, I examine rasa not as a metaphor for mood or emotion, but as a structured epistemological process. The project traces how performance traditions across India cultivate rasa through embodied discipline, somatic resonance, and aesthetic transmission, and demonstrates how these practices align with and often exceed contemporary theories of intersubjectivity, entrainment, and affective cognition. Rasa emerges as a method that insists on the centrality of bodymind processes in the construction of shared knowledge. By returning to the visceral moment of rasa, as both object and event, this thesis claims aesthetic experience as a legitimate and rigorous site of knowing
