VictorJuiz/thesis huggingface dataset:
Targeting the MYC Oncoprotein by Disrupting the MYC-PNUTS Interaction

Despite the knowledge that the MYC protein family is a potent driver of multiple oncogenic malignancies, no targeted therapy against MYC exists for patient care. One major obstacle for conventional drug development is that MYC is an intrinsically disordered protein, that only upon binding to protein partners adapts a conformation. One of the recently identified MYC protein interactors is the Protein Phosphatase 1 (PP1)/PP1 Nuclear Targeting Subunit (PNUTS) complex. Inhibition of PP1 leads to the hyperphosphorylation and degradation of MYC, thus making this complex a potential vulnerability of MYC-driven cancers. As protein phosphatases are promiscuous enzymes with multiple substrates, we placed our focus for developing a MYC-specific inhibitor on the interaction of MYC with the regulatory protein PNUTS. To this end we took two approaches: i) characterizing the MYC-PNUTS interaction structurally; and ii) demonstrating that disruption of this interaction is detrimental to tumour growth.First, we identify the MYC-PNUTS interaction. PNUTS interacts directly through the PNUTS amino-terminal domain (PAD) with the MYC homology Box 0 (MB0) of MYC. The latter is a highly conserved region, shown to be important for MYC oncogenic activity. We also demonstrate that mutation of key residues on either protein disrupts this interaction and leads to elevated phosphorylation of MYC in human cells. Leveraging the MYC-PNUTS structural information, we designed a proof-of-principle study, in which we show that overexpression of the PAD provokes disruption of the MYC-PNUTS complex in human cells. Moreover, we find that disruption of this complex affects MYC-driven transcriptional programs, and alters breast cancer cell proliferation, transformation, and xenograft growth. Taken together, the work presented in this thesis lays the groundwork for developing novel, targeted therapeutics against the to date deemed ‘undruggable’ MYC oncoprotein. Considering the omnipresence of MYC dysregulation in human cancers, these findings hold the promise of ultimately developing a MYC-PNUTS inhibitor and benefiting many cancer patients.

Keywords: Cancer Therapeutics
Dominant Negative
MYC
PNUTS-PP1 phosphatase
Protein-Protein Interaction
Advisor: Penn, Linda Z
Measurement of Electroweak VVjj Production in Semileptonic Final States in pp Collisions at √s = 13 TeV with the ATLAS Detector

Vector boson scattering (VBS) is a rare process in the electroweak sector of the Standard Model, and it has not been observed at over $5\sigma$ significance in many of its final states until the 139 fb$^{-1}$ dataset was taken at the Large Hadron Collider (LHC). This thesis presents the precision measurement of VBS-enhanced electroweak $VVjj$ production in semileptonic final states, using the full 139 fb$^{-1}$ $pp$ collision dataset taken at $\sqrt{s}=13$ TeV with the ATLAS detector at the LHC. To model background contributions, Monte Carlo simulations corrected with data in dedicated control regions are used, and a new recurrent neural network approach is introduced to increase signal-to-background separation.Three channels are considered, with 0, 1, or 2 leptons (electrons or muons) in the final state, and a signal significance of $6.0\sigma$ is reached where $6.5\sigma$ has been expected, with a simultaneous fit in all three channels. With the same dataset, a fiducial cross-section of $\sigma^{\text{fid,obs}}_{\text{VVjj}} = 21.7\pm2.0\text{(stat.)}^{+3.4}_{-3.3}\text{(syst.)}$ fb is measured where a cross-section of $22.3 \pm 1.7$ fb has been expected. This is the first time that a significance value above $5\sigma$ is reached for VBS-enhanced electroweak $VVjj$ production in this final state at the ATLAS experiment.

Advisor: Savard, Pierre
Pious: Why Meta’s Business Model Drives Intolerance

The rise of social media parallels a rise in distorted identity politics. The past decade has seen an increase in cases of ethnic fraud, polarizing populism, and corporate solidarity statements critiqued for capitalizing on social issues. While many critics blame these social phenomena on opportunistic individuals and businesses, this dissertation studies the role played by social media platforms: their business models, advertising datasets and ranking algorithms. I focus on Meta as a blueprint for subsequent social media platforms. I begin with my autobiography as a former QTBIPOC influencer, as a microcosm of the distorted identity politics amplified by social media infrastructures. I conduct a walkthrough of the Meta Detailed Targeting Tool (MDTT), paying close attention to how this tool fetishizes social difference: by stripping behaviors, interests and demographics down to fungible exchange value and market optimization. I argue that this process of fetishization rewards and conditions grammars of action that inherit the techniques, and problematic social dynamics, of Christian colonialism. This dissertation brings The Black Radical Tradition and anti-colonial critique to bear on social media scholarship, in order to investigate the following questions: 1) How does the MDTT shape behavior? 2) What are the motivations that compel identity politics? 3) Why have “morals” become so important to business? and 4) How can the framework of “piety” offer new theories and solutions for negative social media dynamics?

Keywords: Algorithms
Anti-colonial theory
Critical Race Theory
Facebook
Social Media
Advisor: Cowan, T.L.
The Properties of Dirac Materials: Strain, Magnetoelectrics and Krein-Hermiticity

The study of Dirac matter offers a cross section of some of the most dynamic topics in condensed-matter physics. Interest in Dirac-like dispersions in band structures dates back to the early days of solid-state physics; however, in the past decades, emergent Dirac-like behaviour in materials has become a focal point of condensed-matter physics, in no small part because of the new, topological appreciation of these gapless phases of matter. Since then, the field has witnessed an ever-increasing understanding of the exotic properties that emerge in Dirac matter. The present thesis furthers the exploration of Dirac-like physics in condensed-matter systems and the novel properties that stem from it. After a thorough overview of the physics underpinning these states of matter, we investigate the existence of strain-induced pseudomagnetic fields in nodal superconductors like the cuprates. We provide a realistic proposal to realize strain-induced Landau levels in a cuprate sample, a unique scenario that cannot be achieved with an ordinary magnetic field. We then turn to a study of the orbital Edelstein effect resulting from spontaneous symmetry breaking within a nodal-line semimetal. In this model, the onset of charge order endows the gapless lines with a mass; they then become sources of orbital magnetic moment. Hence, we exemplify how this magnetoelectric effect can serve as a proxy for symmetry breaking in certain Dirac semimetal phases. Finally, we develop a formalism of the Schrieffer-Wolff transformation in Krein-Hermitian Hamiltonians, which arise, among other contexts, as the single-particle Hamiltonians of bosonic Bogoliubov–de Gennes systems. These Hamiltonians are Hermitian with respect to an indefinite inner product, and the Krein-unitary transformation we formulate preserves their Krein-Hermiticity. In particular, we explain why an effective Hermitian Hamiltonian can, under certain conditions, be used to describe subsets of adjacent bands of a larger Krein-Hermitian Hamiltonian, a justification of which seems to have been lacking. We then apply our findings to study the generic codimension of Dirac-like band touchings in such systems, focusing on spin-wave excitations in quantum magnets.

Keywords: cuprate
Edelstein
Krein Hermitian
magnetoelectric
magnon
strain
Advisor: Paramekanti, Arun
Unlocking Cell Biology Through Development and Application of High-Throughput Microfluidic Cell Sorting

Studying biology through a high-throughput lens has enabled many advancements in academia and healthcare. Yet for cytometry, the analysis and sorting of cells, current tools necessarily face trade-offs between throughput, accuracy, and viability. Microfluidics, the highly controllable manipulation of fluids on the microscale, has potential to address these limitations. Herein, we present the development and application of an ultrahigh-throughput immunomagnetic microfluidic cytometry platform technology. The technology, termed microfluidic cell sorting (MICS), is capable of sorting 4.4x108 live cells/hour/device and contains reusable components and a user-friendly external set up to facilitate deployment to non-expert users. Device performance was validated using immortalized cell lines and was shown to be able to isolate clinically relevant quantities (108) of mature CD56dimCD16bright natural killer cells from primary samples in hours. To demonstrate further utility in cell biology, MICS was used to facilitate a genome-wide CRISPR screen in embryonic stem cells, a challenging cell type for sorting. This screen identified homeobox protein CDX-2 as a negative genetic regulator of mesoderm differentiation efficiency. Knock-out of CDX2 resulted in a 2-fold increase in mesoderm specification at day 6 and increased proportions of both hematopoietic stem cell and lymphocyte progenitors at later time points. Finally, MICS was used in combination with an unsupervised k-means clustering algorithm, to create a novel approach to phage display antibody discovery. This approach, termed Cellect, performs fab-antigen binding in a heterogenous mixture of antigen-expressing and background cells and chooses candidates for validation by identifying underlying motifs in primary protein structure that contribute to affinity. In a proof-of-concept screen pursuing Frizzled-7, a challenging oncology target, Cellect discovered antibodies with picomolar affinities and increased selectivity relative to first-in-class reagents in only two selection rounds. The approaches and findings presented in this work demonstrate that MICS is a high-throughput, high-precision cytometry tool with the potential to unlock new approaches to studying cell biology. In addition, the approaches used to develop the MICS technology provide novel contributions to microfluidics and adjacent research fields.

Advisor: Sargent, Edward
Causes and Consequences of Recombination Rate Variation

Recombination, the shuffling of alleles during meiosis, is a fundamental evolutionary process that is nearly ubiquitous across eukaryotes. By uncoupling linkage disequilibrium between harmful and beneficial mutations, recombination promotes more effective selection. However, recombination rate varies at multiple scales across nature, which has important implications for genome evolution at large. Here, I report four chapters that investigate recombination and genome evolution using the unicellular and facultatively sexual chlorophyte Chlamydomonas reinhardtii. I examine recombination rate variation at the level of populations, individuals, and across the genome itself. I show that recombination rates are consistent between populations and individuals, demonstrate evidence that recombination plays a role in reducing the effects of selection at linked sites, and estimate the rate of sexual reproduction in a wild population of C. reinhardtii. I also investigate recombination in a crossover-suppressed sex-determining region of the genome, and show how noncrossover recombination can still maintain effective selection, thus preventing long-term degeneration of these loci. Finally, I close off with a study pertaining to mutational biases introduced by environmental stressors in C. reinhardtii and demonstrate the effects of the former on adaptation. Altogether, my thesis addresses fundamental questions regarding recombination rate variation and adaptation in C. reinhardtii, and alongside existing detailed work on spontaneous mutation in the system, provides an empirical framework for understanding how these processes affect genome evolution over evolutionary time.

Keywords: Chlamydomonas
evolutionary genetics
mutation
population genetics
recombination
Advisor: Ness, Rob W
Chemistry and Reactivity of Lone Pair Bearing Electron Deficient Main Group Compounds

Due to concerns around the cost, abundance, and toxicity of precious metal systems used for various chemical transformations, substantial research has targeted cleaner and cheaper catalysts. Motivated by the discovery of frustrated Lewis pairs (FLPs) and their ability to reversibly activate H2, main group compounds have become attractive alternatives. Consequently, metal-free advancements have recently been reported for nitrogen fixation and the Fischer-Tropsch process. To continually develop these new advancements, new and robust Lewis acid compounds are of significant fundamental interest. This work explores the synthesis and reactivity of various electrophilic compounds based on carbon, phosphorus, and sulfur. The reactivity of electron-deficient N,N’-diamidocarbenes (DAC) was explored with various common main group Lewis acids with results showcasing their ability to stabilize unpaired electrons. These carbenes were shown to undergo nucleophilic substitution to the C6F5 rings of B(C6F5)3 leading to the stabilization of analogues of the B(C6F5)3•- radical anion. Furthermore, with other Lewis acids, such as Ph3C+, spontaneous radical formation was observed, a rare observation from the combination of a Lewis acid and a Lewis base. New base-stabilized phosphorus(III) polycationic species were prepared through the use of various ligands based on nitrogen and phosphorus. An air-stable P(III)2+ example bearing a terpyridine ligand was shown to be an effective catalyst towards the hydrosilylation or reductive hydrodeoxygenation of aldehydes, ketones, and olefins. Similarly, new P(III)3+ species stabilized by transannular interactions showed unusual ambiphilicity by these highly charged species. Finally, this strategy was used in the synthesis of new and robust base-stabilized thionylium dicationic (SO2+) species. Computational and experimental studies show that these compounds are moderate Lewis acids through S-N σ* orbitals, with comparable Lewis acidity to BF3 and PF5. These compounds were shown to be able to enact the C-F bond activations, with the loss of SOF2; and O2- abstraction reactions of phosphine oxides and CuO, with the loss of SO2. Furthermore, due to a high s-character of the lone pair of these SO2+ species, they were highly resistant towards the direct oxidation of the sulfur centre.

Keywords: Frustrated Lewis Pairs
Hydrosilylation
Lewis Acid Catalysis
Main Group
Polycationic Lewis Acids
Radical Chemistry
Advisor: Stephan, Douglas W
Development of High-temperature Thermoplastic Foams: Investigation on Foaming Behaviors of Sulfone Polymers

One of global efforts to address the growing environmental concerns pertaining to energy consumption in automotive and aerospace industries is to replace conventional materials with lightweight alternatives. In this regard, development of industrially viable high-temperature polymeric foams is of significant interest. Generating microcellular structures with lightweight thermoplastics would not only provide weight reduction but also tailorable properties based on the cell architecture. Furthermore, utilizing environmentally benign physical blowing agents, for instance CO2 and N2, to develop such structures would additionally reduce the environmental footprint of manufacturing processes. Despite the economic and the environmental advantages of high temperature polymeric foams, the development is still at its inception. There is a limited number of studies on the foaming of high temperature polymers and the majority are based on the two-step batch foaming process, in which cell nucleation was induced thermally through rapid heating. Although the results may be meaningful, it is not applicable to continuous foaming processes that utilize pressure quench as a means of inducing thermal instability. In this regard, the present dissertation is dedicated to investigating various aspects of processing high-temperature sulfone polymer foams and making a transition from small scale batch to continuous processes. The study commenced with fundamental research on the solution properties of sulfone polymers and CO2. Empirical as well as theoretical determination of gas solubility and observation on plasticizing effects of CO2 on the thermal behaviors of polysulfone (PSU) and polyethersulfone (PES) were conducted and discussed in relations to foaming. The one-step batch foaming process was employed to discern the effects of processing parameters on the foaming behaviors of PSU and PES. Uniform cellular structures exhibiting high cell densities ranging up to 1010 cells/cm3 were developed affirming that the pressure quench method was effective in producing high density foams. Subsequently, foam injection molding techniques were implemented for the continuous production of PSU foams. Impact and tensile properties of the foams were characterized and analyzed based on the parameters of cellular structures. Lastly, graphene nanoplatelet (GnP) was introduced in the processing of PES foams. The effectiveness of GnP as a cell nucleating agent, and the effects of cell structures on the electrical performance of the nanocomposites were investigated. Overall, the dissertation provides a comprehensive framework of high-temperature foam processing that focuses on process-structure-property relationships of sulfone polymer foams.

Keywords: Foam injection molding
High temperature thermoplastics
Microcellular foams
Nanocomposite
One-step batch foaming
Solubility
Advisor: Park, Chul B.
Data Fusion Methods to Support Travel Demand Modelling in Emerging Contexts

In the face of growing incomprehensiveness of traditional data sources, lack of behavioural information of emerging sources, and changing data requirements of advanced models, the dissertation investigates the feasibility of fusing data from multiple sources to generate richer, more comprehensive, and more representative information to support disaggregate travel demand modelling. It presents an econometric data fusion framework that is based on four dimensions: purpose of fusion, characteristics of input data, feature of fusion methods, and nature of outputs. It proposes a conceptual framework to integrate econometric data fusion with activity-travel model to create a consistent simulation system. The thesis presents four empirical investigations that implement parts of the proposed conceptual framework. The first two studies demonstrate the feasibility of fusing traditional data with emerging data to infer the missing semantic information of the latter. The first exercise proposes an econometric fusion method to infer trip purposes from GPS trajectories of ride-hailing services in Toronto by combining with travel survey and land use data. The inferred trip purpose pattern extends our understanding about ride-hailing demand and helps account for trip underreporting in travel surveys. The second investigation infers origin and destination zones of transit trips from smart card data by fusing with survey data, land use information, and network characteristics. This helps generate up-to-date demand data necessary for public transport planning and operations. The dissertation also demonstrates the feasibility of fusing multiple survey data to capture travel attitudes and preferences. The third analysis focuses on enriching a “core” travel diary survey with attitudinal information from “satellite” surveys via implicit fusion to evaluate the impacts of COVID-19 on passenger travel demand. The results highlight the ability of the imputed variables to support the estimation of an advanced econometric model. The fourth investigation proposes a model-based method to fuse repeated cross-sectional travel survey data based on the theory of rational inattention to capture travel preference evolution and enhance the forecasting robustness of discrete choice models. Taken together, the components of this dissertation lay the framework for producing rich and accurate input data for evidence-based transportation planning in the emerging context.

Keywords: Choice modelling
Data fusion
Econometrics
Emerging transportation services
Travel demand modelling
Advisor: Nurul Habib, Khandker M
Art for whose sake? Occupational Identity, Commercialization, and Innovation in the “Porcelain Capital” of China

When and how could experts translate the growing power of the audiences of their work (e.g., clients and customers), which existing research often characterizes as an occupational identity threat, into an opportunity for product innovation and identity reconstruction? I answer this question using a qualitative ethnography and a quantitative audit study of porcelain artists in China who have been forced to cater to market audience demands due to a market shift. I found that when facing challenging feedback from market audiences on their work, artists who distilled the core material element(s) of their work products that signify their occupational identity, and successfully experimented novel work products integrating their distilled material element(s) with audience feedback, innovated new artistic products and reconstructed their occupational identity. I further found that artists who did not go through the distilling and/or experimenting processes either quit the market or built strong segmentation between the work products that they created catering to audience feedback from their occupational identity through work product self-categorization, which helped protect their existing work and occupational identity. These findings contribute to a richer understanding of the role audience feedback, material objects, and innovation play in occupational identity processes, as well as the market implications of holding an unwavering occupational identity.

Keywords: Art
China
Identity
Innovation
Occupations and professions
Advisor: Zhong, Chen-Bo
Christianson, Marlys