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Development of CD70 CAR-NK Cells with TGF-β Sensor-Controlled and Tumor-Directed IL-12 Expression against Clear Cell Renal Cell Carcinoma
No full textChimeric antigen receptor (CAR)-engineered T and NK cell therapies have shown promising success in treating hematological malignancies, yet their efficacy in solid tumor remains limited due to poor infiltration and reduced expansion and persistence in the tumor microenvironment (TME). To address these major challenges, we engineered a novel TGF-β sensor-controlled and tumor matrix-directed IL-12 secreting CD70 CAR-NK cell and evaluated it against clear cell renal cell carcinoma (ccRCC). In vitro studies confirmed that CD70 CAR-NK cells exhibited more potent tumor antigen-specific cytotoxicity, and both secretory and collagen-binding IL-12 enhanced killing efficiency by two folds against ccRCC cell lines. IL-12 secreting CD70 CAR-NK cells also demonstrated increased IFN-γ production and degranulation. Mice study indicated that these engineered NK cells effectively suppressed tumor growth in vivo. To further counteract TGF-β-induced immunosuppression within the TME and ensure controlled IL-12 release for improved clinical safety, we designed a novel TGF-β sensor based on SMAD-binding motifs. We showed that the TGF-β sensor successfully upregulated EGFP reporter protein expression in a TGF-β dose-dependent manner. Positioning the sensor on the reverse strand with IL-12 secretion domain precisely regulated IL-12 release upon TGF-β1 stimulation with minimal leakage. In vitro studies revealed that TGF-β sensor-controlled IL-12 secreting CD70 CAR-NK cells displayed superior tumor-killing capacity comparable to IL-12 secreting CD70 CAR-NK cells even at a low transduction rate. Overall, this study described a novel strategy to overcome the immunosuppressive TME and enhance tumor-specific killing in CAR-NK cell therapy while ensuring safety, supporting it as an effective therapeutic approach against ccRCC.Graduate Educatio
Essays on Health and Economic Outcomes over the Life-Course
Get PDFThis dissertation studies how health and health policies impact economic outcomes like earnings, employment, disability application, and wealth accumulation throughout the life course. The first two chapters focus on the role of childhood health in shaping life-long economic inequality. The third paper focuses on outcomes after disability onset in midlife and the role of employer-sponsored health insurance.
Chapter 1 investigates the role of childhood health on economic outcomes over the life-cycle using uniquely detailed data from the Health and Retirement Study with a linkage to Social Security administrative earnings records. I first present several key facts about the role of childhood health in long-term economic outcomes: childhood health is associated with substantial gaps in earnings and employment throughout the prime working years; gaps peak in midlife when poorer childhood health is associated with a 7.5 percentage point reduction in employment and a reduction of $6,000 in earnings; and these gaps translate to substantial gaps in wealth in retirement. I then implement a quasi-experimental approach using variation in access to the measles vaccine upon its introduction to test for a causal effect of childhood health on later-life economic outcomes. While I find no evidence for a causal link between the measles vaccine and later life outcomes, my results reflect a need to better understand the specific channels through which childhood health effects persist.
Chapter 2 extends on work in Chapter 1 and investigates the role of childhood health in shaping racial economic inequality over the life course. Many of the same structural and systemic barriers that impact racial economic disparities have also produced disparities in child health among Black Americans, and childhood health has consistently been shown to be a predictor of labor market and human capital outcomes later in life. Using data from the Health and Retirement Study with a linkage to Social Security Administration earnings records, I find that poorer childhood health is associated with disproportionately large reductions in earnings and employment for Black respondents over the life course compared to White respondents. In Oaxaca-Blinder decompositions, I find that up to 2.4% of the earnings gap and 12.2% of the employment gap in my sample can be attributed to childhood health, with the contribution being greatest in midlife. Conversely, childhood health has little role in shaping Black wealth or the Black-White wealth gap, likely reflecting the greater influence of other factors in shaping these outcomes. These results highlight a small, but potentially important impact of childhood health as well as the need to continue addressing structural barriers to racial economic equality in the U.S.
Chapter 3 (with Nicole Maestas and Kathleen Mullen) studies the potential for “employment lock”, a phenomenon where individuals are reluctant to leave their current job due to fear of losing their employer-sponsored health insurance coverage, among workers experiencing the onset of a new disability. We use prospective longitudinal data on newly disabled older workers from the Health and Retirement Study to examine the effect of employer sponsorship of health insurance (ESHI) on post-onset employment and disability insurance claiming. We compare outcomes of workers with ESHI and no access to another coverage source immediately prior to onset with outcomes of two comparison groups: individuals with ESHI who also have access to an alternative coverage source, those who are covered by coverage source other than ESHI prior to onset. We find limited evidence of “employment lock” only when restricting to newly disabled older workers. We find no evidence that ESHI impedes application for Social Security Disability Insurance, but ESHI is associated with higher rates of disability receipt for newly disabled older workers.Health Polic
Differentiable Programming for Problems in Statistical Mechanics and Biophysics
Get PDFThis thesis explores how differentiable programming -- a paradigm that leverages automatic differentiation (AD) for scientific computing -- can be used to advance modeling and design in soft matter and biophysics. Traditional applied mathematics relies on hand-crafted models, approximations, and domain-specific numerics. However, recent advances in hardware acceleration and AD frameworks originally developed for deep learning have transformed the landscape of scientific computing, enabling exact and efficient computation of gradients in complex models.
I demonstrate how this computational shift enables novel capabilities across several domains. I first show how AD enables otherwise intractable analytical calculations. Specifically, I use AD to efficiently evaluate partition functions and assembly yields in systems of anisotropically interacting particles. I then apply this framework to compare calculations under existing models of protein-protein interactions with experimentally-determined assembly yields of de novo proteins. Inspired by this example of poor model generalization, I then focus on AD as an optimization tool for physics-based models. I devise a framework for directly differentiating the aforementioned assembly yield calculation, allowing me to fit protein force fields to target assembly yields via gradient-based optimization. I then extend these techniques to thermodynamic models of nucleic acids, showing that parameters in the popular "nearest neighbor" model describing secondary structure thermodynamics can be fit to data via gradient descent, enhancing predictive power. I also apply differentiable molecular dynamics to design functional colloidal systems.
For some physics-based calculations, direct differentiation for modeling or design is infeasible. One such cause is that a calculation is differentiable in principle but computationally prohibitive to unroll. In the face of this, I leverage and extend novel methods for stochastic gradient estimation to develop a framework for fitting coarse-grained force fields to experimental data. In the second limiting case, a calculation may be inherently discontinuous due to discrete control variables. One example of this is designing RNA sequences with respect to the aforementioned nearest neighbor model, for which I introduce an algorithm to compute the expected partition function over a probability distribution of RNA sequences, enabling gradient-based RNA design. Building on these advanced methods for stochastic gradient estimation and this probabilistic sequence representation, I develop a general method for inverse design in molecular simulations by introducing a notion of expected Hamiltonians. I demonstrate how this enables the rational design of intrinsically disordered proteins, DNA sequences, and even improved particle linking algorithms.
I conclude with a forward-looking perspective on promising applications of these methods, opportunities for future methods development, and proposed directions for novel interfaces between computation, mathematics, and physics.Engineering and Applied Sciences - Applied Mat
Regulating Commerce: Law and Economic Life in the Late Ottoman Empire
No full textRegulating Commerce narrates how a distinct Ottoman jurisdiction for adjudicating
commercial life emerged in the nineteenth century, and how this legal system worked in practice.
The nineteenth century was a period of intense legal and economic change in the Ottoman
Empire during the period known as the Tanzimat. This dissertation investigates the intersection
of these two fields by studying a new legal institution: the Ottoman commercial court (Tr. ticāret
maḥkemesi, Ar. maḥkamat al-tijāra). One of the major, yet underexplored, transformations of
nineteenth century Ottoman commercial life was how sharīʿa courts lost their jurisdiction over
commercial litigation. The process began at the start of the nineteenth century and by the 1860s
there were over a hundred specialized commercial courts in operation across the empire. These
were, in turn, incorporated as a distinct part of the state’s new Niẓāmiyya legal infrastructure.
Like other parts of this emerging system, commercial law relied on new courts, new codes and
new procedures. Unlike other courts, it was staffed by a mixture of bureaucrats and merchants
who took up state appointments to regulate local commercial life.
This development has conventionally been associated with European influence. This
dissertation, however, situates commercial regulation within the larger project of nineteenth
century Ottoman bureaucratic reorganization as the state responded to new and expanding
commercial practices. It introduces the rare and virtually unexplored registers of a working
provincial commercial court in Damascus, between 1885 and 1900, to investigate how this legal
system fit into a local economic context and to reconstruct how it operated. Closely reading these
registers in conjunction with law codes, Ottoman state documents, legal commentaries, treatises
on Islamic law, late Ottoman law journals, biographical dictionaries, architectural histories,
travel narratives and provincial yearbooks, this study highlights the neglected role that
merchants, bureaucrats, scribes, notaries and a wide variety of litigants played in defining the
practical legal boundaries of late Ottoman economic life. At the same time, the project
demonstrates how legal practice – in particular the role of documentary evidence and the
emergence of professional legal intermediaries in the court room – can be used to highlight
significant continuities and changes with the Ottoman sharīʿa court tradition that have been
missed by conventional narratives. In doing so, the project tells the story of late Ottoman legal
reform in a new way, through the actors who substantively engaged with commercial law.Middle Eastern Studies Committe
Exploring Acoustic Couplings to the SiV center in diamond
Get PDFThe negatively charged Silicon Vacancy (SiV) center in diamond has shown extraordinary promise for quantum information applications, in particular quantum networking, due to its long-lived spin memory and high-cooperativity spin-photon interface. In addition to these excellent demonstrations towards quantum networking, the SiV center has also been demonstrated to exhibit a large susceptibility to acoustic phonons. While this susceptibility is typically considered a drawback for necessitating low-temperature operation, it also presents an opportunity to study the strong interactions of SiV centers with acoustic fields. In this thesis, we will discuss several results that focus on the integration of SiV centers with diamond nanostructures with interesting acoustic properties. Through this integration, we will show both how the SiV center can be used as an unprecedented probe of these engineered acoustic environments and conversely how controlling the acoustic environment can be used to unlock new potential for SiV center based quantum networks. Together, these results point towards the SiV center as an exciting candidate for realizing novel hybrid quantum systems composed of photon-mediated quantum networks in the optical domain and phonon-mediated quantum systems in the microwave domain.Engineering and Applied Sciences - Applied Physic
Know Thy Herd: The lives of sheep and goats from Tepe Yahya, Iran, and the benefits of multi-methodological approaches
No full textThis dissertation examines caprine management practices at Tepe Yahya, an archaeological site in southeastern Iran, from the Neolithic to the Bronze Age, c. 5500 to 2000 BCE. Tepe Yahya was occupied across several millennia and, despite its small size, was a crucial waypoint between local and regional political entities east and west. Richard Meadow’s 1986 dissertation documented 19,000 bone fragments. I expand on his work in identifying the importance of caprines to the Tepe Yahya inhabitants using methods unavailable in the 1980s. Four hundred and five caprine mandibular fragments were analyzed for age profiles based on tooth wear, species identification using morphology and ZooMS, and carbon and nitrogen isotopic analysis. Using these complementary methods on a single set of bones increases the data resolution from each fragment, creating a larger, more in-depth dataset from which to interpret past caprine management.
This information allows for interpreting different potential culling strategies practiced by the people at Tepe Yahya. Using Zooarchaeology Mass Spectrometry (ZooMS), sheep and goats can be accurately distinguished from one another through observable differences in their collagen proteins. Employing this method allows for the inclusion of mandibles that would otherwise be indistinguishable at the species level and, therefore, unable to contribute to investigations of species-specific use. ZooMS is a beneficial methodological complement to morphological identifications for expanding the number of accurately identified mandibles. I use stable isotope analysis of bone collagen to delve further into the lives of the Tepe Yahya sheep and goats. Carbon isotopes in bone and tooth enamel reflect animal diets and the types of plants they consume. Nitrogen isotopes elucidate diet and environmental aridity. The heterogeneous dietary composition of the Tepe Yahya caprines suggest that animals did not come from species-specific herds, but mixed herds under a range of managerial practices.
Sexing enamel amelogenin has the potential for wide-scale applications in caprines. Obtaining sex demographics of this set of Tepe Yahya caprines to accompany the species, age, and dietary data would provide an unparalleled look into herd management. I conduct a pilot project to develop best protocols and test the accuracy of enamel amelogenin sex determination for goats (Capra) and sheep (Ovis), which have not yet been investigated using this method. Increasing the data gathered from each bone reveals more about the animals and elucidates previously invisible nuances of human-animal relationships in archaeological contexts. Our pilot project demonstrates that while sex determination with SEAMS is possible, the limited recovery of sex-specific peptides makes it unreliable. Developing a strategy for targeting the desired AMELX and AMELY peptides will improve the success of the method.
I demonstrate the continued value of this assemblage by showcasing new data obtained from these caprines. ZooMS helped refine the age profiles for sheep and goat, adding identifications to the older and fragmentary animals in the assemblage, revealing differences in slaughter patterns between the species. The additional dietary information provided by the carbon and nitrogen stable isotopic analysis highlights the wide range of dietary practices undertaken by all caprines and not grouped by species or age. This project is the beginning of further investigations into these animals, which will continue to make contributions to the field of zooarchaeology.Anthropolog
Light Transport through Disordered Materials: Experimental and Computational Approaches
Get PDFDisordered materials are abundant in our world, and they can have complex interactions with light. Understanding these interactions is important for both engineering new optical materials and for developing new methods of imaging materials. To engineer new optical materials, I use a combination of experiments and computational modeling to investigate how light moves through disordered materials that both scatter and absorb. For imaging disordered materials, I demonstrate that a fundamental understanding of how light scatters from the interface allows us to extract information from interferometric scattering imaging experiments and use that information to understand the dynamics of the system.
In the first half of this thesis, I examine the interaction between absorption and scattering in disordered systems and explore how understanding this interaction can be used to tailor their optical properties. I first examine inverse photonic glasses composed of a porous polymer film with varying amounts of embedded absorber. In these systems, scattering can increase the optical path length and potentially increase absorption. I quantify absorption enhancement by comparing simulated optical properties of this system to those of a non-scattering absorbing polymer film and a layered system with spatially separated absorption and scattering. I compare the calculated absorption enhancement to the theoretical limits and to measurements of experimental systems. These comparisons allow us to propose design rules for optimizing absorption enhancement within photonic glasses. Next, I explore the optical properties of microgeode systems. Microgeodes are hollow silica shells encapsulating silicon nanowires. The multiple refractive indices and length scales within these systems in principle allow for the tailoring of optical properties across a wide spectral range. To explore how the response can be tailored, I characterize the optical properties of individual microgeodes and bulk collections of microgeodes, and I describe how the interaction of absorption and scattering of the different components affects the optical properties.
In the second half of the thesis, I use interferometric scattering microscopy (iSCAT) to measure the structure and dynamics of disordered films. iSCAT is a noninvasive, label-free imaging technique that records the interference of scattered light with a reference plane wave, similar to interferometry but without the need for extensive alignment of the instrument. I show how iSCAT reveals heterogeneous dynamics of surfactants breaking down phase-separated grease films and how it can provide insights into these dynamics. Lastly, I develop an analysis technique to extract quantitative film topography from recorded iSCAT interference data, adapting both holographic reconstruction and interferometry techniques to do so.Engineering and Applied Sciences - Applied Physic
Entrenched Orientalism: Insidious Anti-Asian Racism in Contemporary Hollywood Films
Get PDFThis thesis investigates Hollywood’s subtle and pervasive use of anti-Asian stereotypes and racialized narratives in contemporary cinema, revealing how the industry disguises systemic racism under the façade of diversity and progressivism. Despite claims of inclusivity, Hollywood continues to perpetuate harmful stereotypes such as the Yellow Peril, White Savior, Lotus Blossom, Dragon Lady, Asexual Asian Man, Model Minority, and Techno-Orientalism, all of which reinforce White superiority while marginalizing Asians and Asian Americans.
Through close textual analysis of Shang-Chi and the Legend of the Ten Rings (2021), Plane (2023), and Ghost in the Shell (2017), this study demonstrates how these films replicate colonial hierarchies by framing Whiteness as morally and intellectually superior. Each film uses racial tropes and Orientalist imagery to exoticize, fetishize, or erase Asian identity, revealing how post-racial rhetoric conceals structural inequity.
Drawing upon scholars such as Edward Said, Nancy Wang Yuen, Jane Chi Hyun Park, and David C. Oh, this thesis exposes how the illusion of inclusion in modern cinema sustains rather than dismantles racial hierarchy.
Ultimately, this research argues that Hollywood’s post-racial mask continues to serve White hegemony, transforming anti-Asian prejudice into aesthetic pleasure. True representation demands not cosmetic diversity, but the dismantling of White-centered power structures within the American film industry.Extension Studie
Mechanisms of cysteine regulation of liver cholesterol metabolism and adipose tissue thermogenesis
No full textCysteine is a rare and highly conserved amino acid whose biological significance arises from the distinct chemical reactivity of its thiol (–SH) group. This intrinsic reactivity allows cysteine contained within both small molecules and proteins to regulate redox homeostasis, antioxidant defense, and critical metabolic signaling pathways. Moreover, cysteine’s chemical versatility makes it an ideal target for selective covalent modification by electrophilic small molecules. This thesis explores mechanisms that regulate cysteine metabolism and the extent to which they can be targeted for therapeutic benefit in the context of metabolic disease. First, to uncover proteins that regulate cysteine metabolism I deploy a method termed Metabolite-Protein Covariation Architecture (MPCA), a mass spectrometry-based approach to systematically explore metabolite-protein interactions in living tissues. Using MPCA, we uncovered a previously unknown cysteine-sensitive regulatory pathway involving the E3 ligase adaptor protein, leucine-rich repeat-containing 58 (LRRC58), which mediates proteasomal degradation of cysteine dioxygenase 1 (CDO1), the enzyme controlling cysteine catabolism toward taurine synthesis. Stabilization of CDO1 upon LRRC58 depletion reduced the total cysteine pool by shifting metabolism to elevated taurine production, resulting in a significant reduction of hepatic cholesterol in vivo. In the second study, I focus on cysteine residues within proteins that can be therapeutically targeted to promote adipocyte thermogenesis. I discover and characterize ZNL-06-030, a cysteine-targeted covalent small molecule that activates thermogenic adipocyte G protein-coupled receptors (GPCRs). ZNL-06-030 induces thermogenesis via Gs-dependent cyclic AMP signaling, protein kinase A activation, enhanced lipolysis, and mitochondrial respiration. Preliminary findings nominate orphan receptors GPR6 and GPR12 as potential targets, although further validation is necessary to fully elucidate receptor specificity. Together, these findings uncover new mechanisms for regulation of cysteine biology and suggest new avenues for regulation of metabolic physiology.Biological and Biomedical Science
On the linguistic development of Irish Traveller Gammon-Cant (‘Shelta’) and other Gaelic-based argots
No full textThis dissertation explores the historical development of the language of the Irish Travelling Community (Mincéirí, Pavees). Known variously as ‘Cant’ or ‘Gammon’, and termed ‘Shelta’ solely within academic circles, the compromise form ‘Gammon-Cant’ is adopted here. This language is spoken exclusively by members of the traditionally nomadic Travelling Community and is largely unknown within the ‘Settled’ population.
Well-known, however, is that a significant portion of the Gammon-Cant lexicon emerged via the historical application of deliberate phonological alterations (‘metaplasms’) to existing Gaelic wordforms (e.g. Ir. mac ‘son’ ⪢ GC. cam, via consonantal transposition or ‘metathesis’). Such is typical of ‘argots’, distinct varieties of speech that pertain to speaker groups of restricted membership, while maintaining a structural relationship with the language(s) of the wider community. This dissertation provides a detailed re-assessment of the evolution of the Gammon-Cant lexicon and suggests that a historical chronology of metaplasmic alterations can be inferred from the available data. Its methodological approach also highlights the equally central role of non-metaplasmic, ‘regular’ sound change in the language’s formation.
The study further investigates the relationship between the Gammon-Cant language and other Gaelic-based argots, with particular focus on the Beurla Reagaird of the indigenous Scottish Highland Travellers and the Béarlagair na Saor jargon of the Irish peripatetic stonemasons, arguing that a direct phylogenetic connection to Gammon-Cant is probable for the former, but not the latter. In terms of the language’s ultimate origins, this dissertation challenges ‘antique’ theories which allege that Gammon-Cant has its roots in medieval cryptological practices. It also contests ‘recent’ theories that endorse a late date of formation following the spread of Irish-English bilingualism in Ireland to account for its present usage of English-based morphosyntax.
Employing principles of the Comparative Method of Historical Linguistics, this study argues that there is no clear evidence of either phonological archaism or scholastic influence in the historical development of the Gammon-Cant lexicon, as maintained by ‘antique’ origin theories. Instead, it proposes that the language was most likely formed in a purely oral setting, among speakers who had native fluency in an Early Modern form of the (Irish) Gaelic language. Adopting analytical models from the field of Contact Linguistics, this dissertation further argues that the English-based component of modern Gammon-Cant can be satisfactorily explained as a secondary development following prolonged language contact with English. Extensive comparison with other mixed languages and argots is made throughout, with a view to demonstrating that the Gammon-Cant language has undergone a structural shift (in both its phonological and morphosyntactic character) from primarily Gaelic-based to English-based. Such parallels further support the claim that Gammon-Cant fits comfortably within a wider typology of argotic speech.Celtic Languages and Literature