VictorJuiz/thesis huggingface dataset:
Engineering a robust and scalable platforn for the production of IEILC1-like NK cells, a novel solid tumor immunothereapeutic modality
Keywords: Bioengineering.

While surgery, radiation, and chemotherapy have been the gold standards of cancer treatment for decades, they are severely limited in certain aspects -- not all tumors are operable, and chemotherapy and radiotherapy can damage healthy tissues as well as the cancer cells. Targeted therapy and immunotherapy were hailed as solutions to this, but they also have drawbacks of their own. The first is that they can be extremely expensive, which leads to financial toxicity, and the second is that they can sometimes cause cytotoxicity to healthy tissues or even occasionally kill the patients they are meant to treat. Natural killer (NK) cell-based therapies solve both issues as they exhibit an optimal safety profile and can be given off-the-shelf to lower the cost of production, but their success has been mostly restricted to liquid tumors. Solid tumors account for 90% of all cancer diagnoses and are significantly more difficult to treat due to a variety of factors such as tumor heterogeneity, the immunosuppressive tumor microenvironment (TME), and poor immune cell trafficking. Here, I present our work designing NK cells with optimized functionalities for solid tumor indications. We have previously identified a novel population of NK cells within head and neck squamous cell carcinoma (SCC) patients that maintain an activated and highly proliferative phenotype within the TME and resemble intraepithelial group 1 innate lymphoid cells (ieILC1s) due to their expression of CD49a and CD103. In earlier work, we were able to induce moderate levels of CD49a and CD103 expression on peripheral blood NK cells through injection of the NK cells into subcutaneous tumors or co-culture with live tumor cells -- but these cells were not thoroughly studied in vitro or in vitro, and this functional evaluation is critical for designing solid tumor therapeutics. We designed cell culture systems that can reliably differentiate peripheral blood NK cells into highly pure, clinically relevant doses of ieILC1-like NK cells. This platform design involved comparing media conditions, cytokine exposure, feeder cell ratios, seeding density, and many other variables. We then assessed the ability of these ieILC1-like NK cells to kill target cells, produce inflammatory cytokines, interact with tumor-targeting antibodies and chimeric antigen receptors, and infiltrate solid tumors. Our results show that ieILC1-like NK cells exhibit high cytotoxicity, high production of cytokines, and tumor infiltration rates up to ten times higher than other NK cell products that are currently being tested in the clinic. This cytotoxicity can be enhanced by using antibodies or chimeric antigen receptors in manners similar to conventional NK cells. Furthermore, we established the role of the surface integrin CD103 as a critical molecular regulator of tumor invasion by NK cells. This work represents an important step forward in the design of affordable and accessible cell therapeutics for solid tumors
Engineering quantum entanglement by coherent Rydberg dressing
Keywords: Applied Physics.

Ensembles of neutral atoms enable state-of-the-art measurements of time, acceleration, and electromagnetic fields. Introducing entanglement among the constituent atoms offers a route to enhancing the precision of these measurements. One proposed approach to generating the requisite entanglement relies on the off-resonant optical coupling of one ground state to a highly excited electronic state. This technique, known as Rydberg dressing, enables local and dynamical control of interactions between neutral atoms. In this thesis, I present the engineering of Rydberg-dressed interactions by single-photon coupling to nP states in a cesium atomic clock. Optimizing the coherence of these many-body interactions is a major challenge; in order to understand and minimize dissipation mechanisms, I show sensitive measurements of percent-level noise processes, comparable to the projection noise of our atomic ensembles. Finally, I present the creation of a squeezed spin state by local interactions that achieves a factor of 0.79(6) reduction in phase variance below the standard quantum limit. The results of this thesis seek to inform the design of future experiments that will use coherent Rydberg-dressed interactions for a wider range of applications in quantum sensing and simulation
Engineering Spin Squeezing with Local Interactions
Keywords: Physics
Quantum metrology
Spin squeezing
Quantum entanglement
Spin waves
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Thesis

Quantum metrology uses entanglement as a resource to enhance measurement precision, most commonly through spin squeezing. While spin squeezing with all-to-all interactions is a well-studied phenomenon, spin squeezing with local interactions remains a largely open problem. On the other hand, local interactions are indeed more natural to realize in a wide range of physical systems, such as ultracold neutral atoms, Rydberg-dressed atomic gases, electric and magnetic dipolar quantum gases, and solid-state spin ensembles. We provide a general theoretical framework for studying canonical approaches to spin squeezing in the presence of local interactions in terms of spin waves. We propose a gap-protected countertwisting (CT-GP) Hamiltonian, which introduces an isotropic “gap-protection” coupling term to the canonical countertwisting Hamiltonian to mitigate the degrading effect of local interactions. Using the discrete truncated Wigner approximation (DTWA) for simulating dynamics of large spin-½ ensembles, we conduct a numerical study comparing metrological gain attained with the CT-GP (gap-protected countertwisting) and XXZ (gap-protected one-axis twisting) Hamiltonians, with respect to spatial dependence of interactions, spatial distribution of spin-½ sites, and strength of gap protection. We find that CT-GP is advantageous over XXZ in terms of both optimal squeezing and time to optimal squeezing. Furthermore, we find that increasing the strength of gap protection enhances the squeezing, having a similar effect as increasing the interaction range. To obtain the full metrological benefit of the CT-GP Hamiltonian, we propose and analyze an echo protocol that approaches the Heisenberg scaling with system size. We also study how to engineer and trotterize the CT-GP Hamiltonian using different native interaction terms relevant to various physical platforms.
Enhancement of functionality in complex oxides through growth in the [111] direction
Keywords: Materials Science and Engineering.

Transition metal oxides are a particularly interesting class of materials because they exhibit tunable properties due to the coupling of the lattice, spin, orbital, and charge degrees of freedom. In this thesis, I explore the potential to tune their properties through growth in the [111] direction. The enhancement of functionality of materials grown in the (111)-orientation could expand the current toolbox used to design novel computing devices. The growth of LaNiO3 thin films on (111)-oriented LaAlO3 results in a unique strain state in the first few unit cells at the substrate/film interface. This strain, consisting of an expansion of the out-of-plane lattice parameter in the first few interfacial unit cells, results in insulating behavior at the substrate/film interface, the emergence of the anomalous Hall effect, and changes in the chemical valence. Notably, these changes are distinct from those observed in ultrathin (001)-oriented LaNiO3 films. This makes it clear that the strain introduced by the substrate in (111)-oriented films has the potential to greatly alter the properties of the first few unit cells of film grown on it. These thin films are also indirectly observed to be antiferromagnetically ordered. While antiferromagnetism can be difficult to directly measure, I provide evidence that these films are entirely magnetically ordered and that there is no net ferromagnetic moment. These results suggest growth in the [111] direction alters the magnetic structure of LaNiO3. Next, I explore the enhanced interfacial ferromagnetism enabled in (111)-oriented CaMnO3/CaRuO3 superlattices. These superlattices have a larger total moment and a thicker interfacial ferromagnetic phase present in the CaMnO3 as compared to (001) superlattices as well as the emergence of ferromagnetism in CaRuO3 layers. Further, an enhancement of the Curie temperature shows that growth direction can change this important engineering specification: the temperature at which magnetic ordering occurs. These changes are likely due to the differences in the orbital overlap across the (111) interface and suggest that magnetic structure can be tuned by growth direction--particularly for G-type antiferromagnets. In sum, the superlattices support the conclusion that growth of complex oxides in the (111) orientation results in an enhancement of the functionalities observed in (001)-oriented films
Enhancing the safety and efficacy of engineered cell therapies using protease-regulated platforms
Keywords: Bioengineering.

Chimeric antigen receptors (CARs) are synthetic modular proteins that allow for directing immune cell reactivity towards a molecular target of interest, such as a cancer-associated antigen. CAR-T cells have demonstrated remarkable clinical activity in patients with refractory hematologic malignancies, leading to ten FDA-approved therapies to date. There is much hope that next-generation platforms leveraging synthetic biology and genetic engineering will expand this class of therapeutics to solid tumors, where toxicity risks and limited efficacy are major barriers to progress. However, current platforms for enhancing CAR potency are at risk for increased toxicity, while those that are designed for safety exhibit diminished potency. In this thesis, I first report on SNIP, an extensively optimized CAR ON switch that dually enhances safety and efficacy of T cells and is regulated by an FDA-approved small molecule. SNIP CARs outperformed conventional CARs in numerous orthotropic solid tumor models. Through phenotypic and functional studies, we show that enhanced activity of SNIP CARs is due to diminished T cell exhaustion and greater generation of memory T cells. In an on-target, off-tumor toxicity model we developed, we show that SNIP CAR activation can be tuned to fall within a therapeutic window in which T cell cytotoxic activity can be directed at tumor cells expressing high levels of antigen while sparing healthy tissue that expresses lower levels of antigen. Next, I report on STASH Tag, a drug regulated system for regulating the subcellular localization of a protein of interest. In order to meet the multiple obstacles facing CAR-T cells in solid tumors, next-generation smart therapies need to be multi-specific, resistant to exhaustion, and maintain their fitness in a hostile tumor microenvironment. Engineering next-generation therapies with these enhanced capabilities will require the introduction of additional genetic modules that often do not fit within the payload capacity of a single vector, or use a combination of gene engineering techniques (e.g. lentivirus + CRISPR), necessitating the use of multiple vectors. For my last thesis project, I report on STASH Select, a simple platform technology for enriching cells that have been engineered with multiple vectors using a single-step selection that results in high purity/yield and is compatible with current GMP cell manufacturing workflows and closed loop systems
Environmental and genetic regulation of gene expression via exercise and ancestry
Keywords: Genetics.

Differential gene expression contributes to variation in complex traits and disease. The regulation of gene expression is dynamic and multifactorial, governed by the genome, epigenome, environment, and interactions between these levels. Genetic association studies link phenotypic differences to specific genetic factors, identifying putative genetic mechanisms underlying disease. Ancestry contributes to genetic and environmental factors that manifest in population differences ranging from gene expression to disease incidence. Therefore, ancestry must be carefully accounted for when performing genetic association studies in heterogeneous cohorts to avoid spurious results arising from confounding population structure. In Chapter 2, an admixed subcohort of the Genotype-Tissue Expression (GTEx) Project is leveraged to compare variant-specific local and genome-wide global ancestry adjustments in the context of genetic association studies. We provide a local ancestry map of the admixed GTEx subcohort and report generally concordant results between local and global ancestry-based adjustments, identifying distinct advantages and disadvantages of each approach. Among environmental factors impacting gene expression, exercise elicits strong but transient effects that reflect a coordinated, whole-body response. Regular exercise promotes wide-ranging health benefits, substantially reducing the risk of cardiovascular, metabolic, and neurological pathologies, among others. However, the multi-tissue molecular mechanisms underlying these adaptive responses are incompletely understood. To address this gap, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to develop multi-omic molecular maps of the acute and chronic endurance and/or resistance exercise responses across tissues in rats and accessible tissues in humans. All MoTrPAC data will be made publicly available (https://motrpac-data.org/). Chapter 3 presents MoTrPAC's complete multi-tissue, multi-omic endurance exercise training data resource from young adult male and female rats, encompassing 211 datasets across 19 tissues, 25 molecular assays, and 4 training time points. We identify 35,439 molecular features that respond to training in at least one sex over the training time course and perform integrative analyses to describe alterations in whole-body homeostasis, mitochondrial biogenesis, metabolism, immune responses, and tissue structure. The benefits of regular exercise necessarily manifest through repeated acute exercise bouts. Therefore, Chapter 4 presents preliminary analyses of multi-tissue gene expression data from an acute endurance exercise study in young adult male and female rats, representing a fraction of what will be another powerful MoTrPAC data resource. The work presented in Chapter 2 will be relevant for future genetic analyses of the diverse MoTrPAC clinical cohort. In totality, this work contributes to our understanding of the interplay between genetics, exercise, and disease
Epicureanism and the death of the soul in the high middle ages
Keywords: History.

Epicureanism and the Death of the Soul in the High Middle Ages demonstrates that from the twelfth to the fourteenth century discussion and debates about the death of the human soul took place from the highest to the lowest social levels of Latin Christendom. The evidence examined reveals that the discussion tended to focus upon the moral consequences of holding that the human soul died with the body. Epicurus's famed mortalism, coupled with his ethic based on pleasure made him and his philosophy a touchstone within medieval conversations about these issues. In many sources, a belief that affirming the death of the soul would lead to amoral behavior on the part of mortalists is on display, as is the fear that the presence of contemporary mortalists—often branded "Epicureans"—would threaten key aspects of medieval society, such as politics, the church, and the universities. The sources analyzed exhibit a fear that new social, institutional, and economic developments taking place from the twelfth to the fourteenth century were leading their contemporaries to abandon the Christian faith and embrace a "worldly" and/or "carnal" life. The sources further show that Dante's decision to condemn Epicurus and all those who embraced his teachings in his Inferno X triggered a debate among early humanists that led to a renewed interest in the ancient Greek philosopher
Epidemiology, natural history, and cancer prevention of non-alcoholic fatty liver disease
Keywords: Epidemiology and Population Health.

Non-alcoholic fatty liver disease (NAFLD) is defined by the presence of excessive hepatic steatosis (> 5%) in the absence of other identifiable causes, including excessive alcohol use and viral hepatitis. It is a major cause of chronic liver disease globally with a prevalence of 29.8% and 35.7% for the United States. NAFLD also carries a substantial health, economic, and patient reported outcome burden. The overall goal of this dissertation is to use different statistical and epidemiological methods to study the epidemiology, natural history, and cancer prevention of NAFLD. In the first part of the dissertation, we applied the meta-analysis method to estimate the prevalence, incidence, clinical characteristics, and outcome of NAFLD in the Asian population. The evidence can assist stakeholders in understanding disease burden of NAFLD in Asia. In the second part, we investigated the prevalence and outcome data for non-obese NAFLD for the multiethnic US population and discovered that non-obese individuals with NAFLD had significantly higher all-cause mortality than obese individuals with NAFLD. Finally, we applied the causal inference method to determine the association between statin initiation and the risk of live cancer among patients with NAFLD. These chapters demonstrated NAFLD is truly becoming a global disease burden and future studies should be devoted to investigating the prevention and treatment of NAFLD
Equivariant algebraic K-theory of profinite Bieberbach group actions
Keywords: Mathematics.

This thesis considers the equivariant algebraic K-theory of the actions of certain groups, which are profinite analogues of Bieberbach groups, on certain inverse systems of algebraic tori. The significance of these groups is that it is known that they can be used to approximate the absolute Galois groups of fields containing an algebraically closed subfield, due to work by G. Carlsson and R. Joshua, and these actions are used to build an object used to prove the representational assembly conjecture proposed by G. Carlsson. We prove an analogue of the Gersten spectral sequence in the case of a finite group action on a scheme, and develop a related technique, which is a modified version of the Gersten filtration, to handle these profinite group actions. We then carry out explicit calculations in equivariant algebraic K-theory using this technique
Eroding Autonomy: An Analysis of Russian and Belarusian Media Coverage of the 2020 Belarusian Pro-Democracy Protests
Keywords: Stanford Global Studies, Center for Russian, East European Studies, Russia, Belarus, News Media
Text
Thesis

This paper analyzes the evolution of Russian and Belarusian state-owned and state- influenced media coverage of the 2020 pro-democracy protests in Belarus. The pro-democracy protests came during a difficult time in Belarus-Russia relations, as President Lukashenka had become closer to the European Union and was blaming Russia for his declining popularity, but the two countries rapidly renewed close ties in the aftermath of the protests. My analysis finds that Russian coverage was overall consistently negative but shifted from focusing on the election and protests themselves to framing them as part of geopolitical conflict with the West. Belarusian media coverage shifted from positive to negative and converged with Russian media coverage as journalists were brought into Belarusian state media from Russia after hundreds of Belarusian journalists walked out in support of the pro-democracy protests.
Essays in corporate finance theory
Keywords: Business.

This dissertation consists of three pieces of research in theoretical corporate finance. The first one studies multi-agent design problems. Agents are concerned about each other's decisions and can communicate strategically with each other. The principal would like to motivate agents' participation decisions by affecting their communication. I employ such a multi-agent perspective on economic design to understand practices such as syndication. The second and the third ones take a more applied approach and study agency problems in specific corporate finance settings. They shed light on information design in corporate governance and dynamic interactions in special purpose acquisition companies (SPACs), respectively
Essays in economics : Finnish manufacturing development, optimal default choices, and occupational mobility after WW1
Keywords: Economics.

My dissertation covers contributions to several subfields of economics -- in Chapter 1, I study a pertinent question in labor economics and development economics (the trade-off between labor and capital in manufacturing development) through the lens of economic history, in Chapter 2 I turn to behavioral economic theory by solving for the optimal choice of defaults in situations where agents might be behaviorally biased, and in Chapter 3 I turn back to economic history and labor economics by studying occupational mobility after World War 1 in Britain. The unifying frame to this dissertation lies in an attempt to theoretically ground my empirical work and to make empirically relevant my theoretical work
Essays in financial economics
Keywords: Business.

With quantitative easing (QE), central banks buy long-term government bonds to lower long-term interest rates. QE removes from the market both the investment risk associated with ownership of the bonds and also the transaction services conveyed by these bonds, which include facilitating the matching of buyers and sellers in the bond market. To the extent that it lends its stock of bonds back to market participants, a central bank replaces these transaction services. In contrast, by not lending its bonds, the central bank further lowers long-term rates by increasing the scarcity of these transaction services. This amplification of the impact of QE on long-term rates through reduced bond lending allows the European Central Bank to achieve its QE rate objective more easily because the alternative of even greater purchases of bonds could be politically contentious