VictorJuiz/thesis huggingface dataset:
Computational Modeling of Drug Resistance: Structural and Evolutionary Models

Active site mutations that disrupt drug binding are an important mechanism of drug resistance. Such resistance causing mutations impair drug binding, thus reducing drug efficacy. Knowledge of potential resistance mutations, before they are clinically observed, would be useful in a number of ways. During the lead prioritization phase of drug development, this knowledge may direct the research team away from candidate drugs that are most likely to experience resistance. In the clinical setting, knowledge of potential resistance mutations could allow the development of treatment regimens, with drug cocktails likely to maximize efficacy. In this thesis I present a structure-based approach to predict resistance and its evolution. This method utilizes a two-pass search, which is based on a novel protein design algorithm, to identify mutations that impair drug binding while maintaining affinity for the native substrate. The approach is general and can be applied to any drug-target system where a structure of the target protein, its native substrate and the drug is available. Furthermore, it requires no training data for predictions and instead predicts resistance using structural principles. Finally, I use approximate force-field calculations from MMPBSA and simple assumptions about the relationship between binding energy and fitness to build fitness landscapes for a target protein under selective pressure from either a single drug or a drug cocktail. I use a Markov-chain based model to simulate evolution on this fitness landscape and to predict the likely evolutionary trajectories for resistance starting from a wild-type. The structure-based method was used to probe resistance in four drug-target systems: isoniazid-enoyl-ACP reductase (tuberculosis), ritonavir-HIV protease (HIV), methotrexate-dihydrofolate reductase (breast cancer and leukemia), and gleevec-ABL kinase (leukemia). This method was validated using clinically known resistance mutations for all four test systems. In all cases, it correctly predicts the majority of known resistance mutations. Furthermore, exploiting the relationship between binding energy, drug resistance and fitness of a mutant, evolution was simulated on the HIV-protease fitness landscape. This hybrid evolutionary model further improves the resistance prediction. Finally, good agreement between these evolutionary simulations and observed evolution of drug resistance in patients was found.

Keywords: Drug Resistance
Algorithms
Protein redesign
computational evolution
Advisor: Lilien, Ryan
Moses, Alan
Understanding the Molecular Mechanism of Mgm1 Function in Mitochondrial Dynamics

Given the debilitating effect that mitochondrial dysfunction has on human health, it is important to understand mitochondrial dynamics that are vital for the maintenance of mitochondrial function, genome, morphology, and quality control. Mitochondrial dynamics result from a balance in mitochondrial fusion and fission. Although the mechanism and regulation of mitochondrial fission are largely elucidated, less is known about mitochondrial fusion. Mgm1 is a protein that mediates mitochondrial fusion in yeast. However, the molecular mechanism of Mgm1 function in mediating mitochondrial fusion is unclear. In this thesis, first, I show that Mgm1 contains a lipid-binding domain by demonstrating that purified Mgm1 has lipid-binding activity and by identifying mutations in conserved residues that abrogate these interactions. Second, I show that Mgm1 assembles into hexameric rings and undergoes nucleotide-dependent structural transitions that, I believe, initiate membrane fusion. Lastly, I demonstrate that Mgm1 exhibits membrane-remodeling activities that are crucial for the tethering and lipid-mixing steps in the membrane fusion event. Together, I propose a mechanistic model of Mgm1 function in mediating mitochondrial fusion that advances the fields of mitochondrial biology, cellular protein-membrane dynamics, and the etiology of neurodegenerative diseases.

Keywords: Mitochondria
Mechanoenzyme
Dynamin-related protein
Membrane fusion
Advisor: McQuibban, G. Angus
Neural Substrates Related to Constructing Novel Events

This dissertation explored the cognitive processes and neural substrates underlying the simulation and construction of novel mental representations, by manipulating factors influencing construction ability. Across four experiments, subjects constructed novel events by relating multiple cue words to a single context word in order to make a coherent representation. Experiments 1 and 2 tested whether memory deficits related to age and amnesia due to medial temporal lobe lesions affect event construction performance. Both older adults and patients with amnesia showed deficits in event construction, with poorer performance at increasing mnemonic loads. Moreover, older adults’ construction ability was associated with memory performance, suggesting that associative encoding processes are crucial for simulation tasks. Experiments 3a and 3b examined whether semantic congruency between items and context influences event construction and subsequent memory. In Experiment 3a, younger adults constructed imagined events with from cue words that were typically or atypically related to the context word. Atypical events were less coherent, and were rated as poorer in quality and more difficult to construct. Experiment 3b also showed an advantage for typical trials on a cued recall test, suggesting the congruency of an imagined event with prior knowledge has a strong influence on its subsequent retrieval. Experiment 4 used fMRI to determine the neural correlates of imagining. Constructing imagined events activated the hippocampus, medial prefrontal regions, and default mode network regions in comparison to a baseline condition. Moreover, clusters of activation in the anterior hippocampus were positively correlated with construction task performance across all task conditions, whereas activity in the medial frontal poles varied with individual differences in the typicality of imagined events. Posterior hippocampus was associated with the novelty of imagined events, but did not correlate strongly with the anterior hippocampus or task performance. Taken together, these studies suggest that these regions are crucial when constructing a novel imagined event, regardless of the nature of the stimuli. In particular, the hippocampus may be necessary to bind items during the construction process, especially as representations become increasingly complex.

Keywords: memory
imagination
cognitive neuroscience
hippocampus
Advisor: Moscovitch, Morris
Contentious Cosmopolitans: Black Public History and Civil Rights in Cold War Chicago, 1942-1972

This dissertation looks at how teachers, unionists, and cultural workers used black history to offer new ways of thinking about racial knowledge from a local level. Numerous efforts to promote and teach this history demonstrated how dissident cosmopolitan political currents from previous decades remained relevant to a vibrant and ideologically diffuse African American public sphere despite widespread Cold War dispersions, white supremacist reactions, and anticommunist repressions. My argument proceeds by demonstrating how these public history projects coalesced around a series of connected pedagogical endeavors. These endeavors included the work of school teachers on Chicago's South side who tried to advance curriculum reforms through World War II and afterwards, the work of packinghouse workers and other union-focused educators who used anti-discrimination campaigns to teach about the history of African Americans and Mexican Americans in the labor movement and to advance innovative models for worker education, and the activities of important cultural workers like Margaret and Charles Burroughs who politicized urban space and fought for greater recognition of black history in the public sphere through the advancement of their vision for a museum. Collectively, these projects expressed important ideas about race, citizenship, education and intellectual labors that engaged closely with the rapidly shifting terrains of mid-20th Century civil rights and international anti-colonialisms. Ultimately, this dissertation offers a social history about how cosmopolitan cultural work in public history and similar forms of knowledge production were at the intersections of political realities and lived experience in U.S. urban life.

Keywords: African American Studies
Civil Rights
Black History
Public History
Cold War
U.S. Communism
Cultural Workers
Cosmopolitanism
Race
Chicago
Midwest
Mid-20th Century
Southside
United States
Urban
Politics
Advisor: Halpern, Rick
Ways of Hearing in Sophokles: Auditory Spaces and Social Dynamics in the Elektra, Philoktetes, Trachiniai, and Oidipous Tyrannos

It has long been known that sight was a crucial component of the fifth-century Athenian theatre. And while that is true, it can also be argued that aurality, the ability to hear and be heard, is an equally important aspect of Athenian drama. This dissertation strives to reclaim a place for hearing in studies on tragedy generally and on Sophokles in particular. Adopting terms from radio theory and media theory, I suggest that Athens was both an acoustic space and an aural community. In the course of an examination of four tragedies, I engage with the following question: how do the characters in these plays hear? Analyzing each play in turn, I show how hearing can occur physically, socially, publically and politically respectively. For Elektra, hearing is a physical and psychic blow; for Philoktetes, hearing is how he connects with the world around him and how he tries to reconnect with people; for Deianeira, hearing is a dangerous phenomenon capable over overturing her own predictions and capable of causing her to lose control of the final shape of her aural reputation; for Oidipous, hearing is an expression of his political status and ultimately a cause of his fall from power. The results of this study show that, in each case, the act of hearing is an invasive process in which the sonant object, mobile and semi-autonomous, can intrude upon new spaces, stage and body alike. This dissertation contributes to a growing body of literature on aurality in tragedy and enhances our understanding of the interconnections between hearing, society, politics, and the individual.

Keywords: Sophokles
hearing
Advisor: Wohl, Victoria
Piezoresistance in Polymer Nanocomposites

Piezoresistivity in conductive polymer nanocomposites occurs because of the disturbance of particle networks in the polymer matrix. The piezoresistance effect becomes more prominent if the matrix material is compliant making these materials attractive for applications that require flexible force and displacement sensors such as e-textiles and biomechanical measurement devices. However, the exact mechanisms of piezoresistivity including the relationship between the matrix polymer, conductive particle, internal structure and the composite’s piezoresistance need to be better understood before it can be applied for such applications. The objective of this thesis is to report on the development of conductive polymer nanocomposites for use as flexible sensors and electrodes. Electrically conductive and piezoresistive nanocomposites were fabricated by a scalable melt compounding process. Particular attention was given to elucidating the role of matrix and filler materials, plastic deformation and porosity on the electrical conduction and piezoresistance. These effects were parametrically investigated through characterizing the morphology, electrical properties, rheological properties, and piezoresistivity of the polymer nanocomposites. The electrical and rheological behavior of the nanocomposites was modeled by the percolation-power law. Furthermore, a model was developed to describe the piezoresistance behavior during plastic deformation in relation to the stress and filler concentration.

Keywords: Piezoresistance
Nanocomposites
Nanoparticles
Electrical Conductivity
Pressure Sensing
Advisor: Naguib, Hani
Biddiss, Elaine
Carrefour discursif : Les jeunes issus de l'immigration et l'école franco-ontarienne

Le contexte social actuel est caractérisé par les effets des processus qu’on attribue à la mondialisation tels que la diversité, l’(im)migration et la mobilité. Ces processus dits mondialisés ont un impact sur les individus, les populations et les institutions ; cela influence les idées de l’éducation en général et de façon plus spécifique la mission et le fonctionnement des écoles de la minorité linguistique francophone. Cette étude de cas ethnographique, sociolinguistique et critique, explore les expériences des jeunes issus de l’immigration dans une école de langue française à Toronto (Canada). Les deux principales questions de recherche sont les suivantes : 1) comment les jeunes issus de l’immigration se positionnent-ils par rapport à l’école de langue française en milieu minoritaire ? ; 2) comment l’école de langue française doit-elle se réinventer pour être plus inclusive de sa clientèle qui est de plus en plus diversifiée aux niveaux linguistique, socio-économique et ethnoculturel ? L’argument central avancé soutient que l’école de langue française en situation minoritaire est en décalage entre la vision et le fonctionnement de la langue à l’école et en dehors de l’école. Ce décalage entre l’idéologie et la réalité linguistique crée des inégalités pour certains membres de la clientèle scolaire plus que pour d’autres, et surtout pour les jeunes immigrants. Les thèmes analysés comprennent l’attrait et le choix des écoles de langue française pour les immigrants (chapitre 5), l’accès au bilinguisme dans le sens canadien (à savoir avec l’anglais) chez les élèves immigrants (chapitre 6) et le rôle de la langue dans les activités des jeunes (chapitre 7). Les résultats de la recherche indiquent que l’accès au bilinguisme en milieu scolaire francophone n’est pas équitable pour tous, que les programmes scolaires ne sont pas nécessairement adaptés aux besoins et aux attentes de la clientèle issue de l’immigration et que les jeunes immigrants rencontrent des obstacles importants à l’école et dans leurs parcours postsecondaires à cause du manque de capital, notamment de capital linguistique. La thèse se termine avec un résumé des implications de la recherche pour les programmes scolaires, pour les rapports école-communauté et pour les parcours postsecondaires chez les jeunes immigrants. Elle fournit également des recommandations pour les divers acteurs intéressés par l’éducation francophone en situation minoritaire.

Keywords: jeunes
immigration
francophonie
école
ethnographie
sociolinguistique
minorité linguistique
Advisor: Heller, Monica
Enhancing Knowledge Building Discourse in Early Primary Education: Effects of Formative Feedback

This research focuses on a Knowledge Building pedagogical approach and investigates ways to boost students’ competencies in knowledge creation processes, specifically their ability to contribute productively to high-level explanation-seeking discourse. This study uses a design-based methodology to explore how pedagogical and technological innovations can enhance students’ ways of contributing to knowledge building discourse, and examines whether expanding students’ contribution repertoire helps them to advance community knowledge in general. Gains associated with a Knowledge Building approach for secondary and post-secondary students are widely documented. This research adds to this body of literature by showing how a Knowledge Building approach can be productively engaged at the early primary level. This work also contributes to studies exploring automated feedback and assessment tools that can help boost student capacities for building new knowledge. The research was conducted in three main phases. The first phase mapped the ways that students from Grades 1-6 (n = 102) contribute to their naturally occurring Knowledge Building discourse in order to provide baseline data for subsequent design experiments. The following two phases corresponded to two design iterations that involved work in Grade 2 science and that tested different types of formative feedback. Design Cycle 1 (n = 42) focused on testing supports to boost low-frequency contribution types. Design Cycle II (n = 43) aimed to reproduce and improve results from the first iteration. In both design cycles, pedagogical supports included whole-class metadiscourse sessions, while technological supports consisted of contribution and content-oriented feedback tools that offered students a meta-perspective on their own discourse, including Word Clouds (Cycle 1), Concept Clouds (Cycle 1-2), visualizations produced by the Metadiscourse Tool (Cycle 1-2), and verbal scaffolds (Cycle 1-2). Analyses of data revealed that these supports helped students to significantly increase their engagement with targeted contribution types, diversify their general contribution repertoire, and advance collective knowledge beyond that attained by their peers in prior years. This research provides empirical evidence that Knowledge Building inquiry can be effectively engaged at the primary level, and offers usable artifacts tested and shown to be conducive for helping young students raise the level of their Knowledge Building discourse.

Keywords: Knowledge building
formative feedback
early primary
knowledge building environments
knowledge building discourse
Advisor: Scardamalia, Marlene
Regret-based Reward Elicitation for Markov Decision Processes

Markov decision processes (MDPs) have proven to be a useful model for sequential decision- theoretic reasoning under uncertainty, yet they require the specification of a reward function that can require sophisticated human judgement to assess relevant tradeoffs. This dissertation casts the problem of specifying rewards as one of preference elicitation and aims to minimize the degree of precision with which a reward function must be specified while still allowing optimal or near-optimal policies to be produced. We demonstrate how robust policies can be computed for MDPs given only partial reward information using the minimax regret criterion. Minimax regret offers an intuitive bound on loss; however, it is computationally intractable in general. This work develops techniques for exploiting MDP structure to allow for offline precomputation that enables efficient online minimax regret computation. To complement this exact approach we develop several general approximations that offer both upper and lower bounds on minimax regret. We further show how approximations can be improved online during the elicitation procedure to balance accuracy and efficiency. To effectively reduce regret, we investigate a spectrum of elicitation approaches that range from the computationally-demanding optimal selection of complex queries about full MDP policies (which are informative, but, we believe, cognitively difficult) to the heuristic selection of simple queries that focus on a small set of reward parameters. Results are demonstrated on MDPs drawn from the domains of assistive technology and autonomic computing. Finally we demonstrate our framework on a realistic website optimization domain, per- forming elicitation on websites with tens of thousands of webpages. We show that minimax regret can be efficiently computed, and develop informative and cognitively reasonable queries that quickly lower minimax regret, producing policies that offer significant improvement in the design of the underlying websites.

Keywords: Decision Making
Robust Optimization
Preference Elicitation
Artificial Intelligence
Planning under Uncertainty
Markov Decision Processes
Advisor: Craig, Boutilier
Effective Heuristic-based Test Generation Techniques for Concurrent Software

With the increasing dependency on software systems, we require them to be reliable and correct. Software testing is the predominant approach in industry for finding software errors. There has been a great advance in testing sequential programs throughout the past decades. Several techniques have been introduced with the aim of automatically generating input values such that the executions of the program with those inputs provide meaningful coverage guarantees for the program. Today, multi-threaded (concurrent) programs are becoming pervasive in the era of multiprocessor systems. The behaviour of a concurrent program depends not only on the input values but also on the way the executions of threads are interleaved. Testing concurrent programs is notoriously hard because often there are exponentially large number of interleavings of executions of threads that has to be explored. In this thesis, we propose an array of heuristicbased testing techniques for concurrent programs to prioritize a subset of interleavings and test as many of them as possible. To that end, we develop: (A) a sound and scalable technique that based on the events of an observed execution, predicts runs that might contain null-pointer dereferences. This technique explores the interleaving space (based on the observed execution) while keeping the input values fixed and can be adapted to predict other types of bugs. (B) a test generation technique that uses a set of program executions as a program under-approximation to explore both input and interleaving spaces. This technique generates tests that increase branch coverage in concurrent programs based their approximation models. (C) a new heuristic, called bounded-interference, for input/interleaving exploration. It is defined based on the notion of data-flow between threads and is parameterized by the number of interferences among threads. Testing techniques that employ this heuristic are able to provide coverage guarantees for concurrent programs (modulo interference bound). (D) a testing technique which adapts the sequential concolic testing to concurrent programs by incorporating the bounded-interference heuristic into it. The technique provides branch coverage guarantees for concurrent programs. Based on the above techniques, we have developed tools and used them to successfully find bugs in several traditional concurrency benchmarks.

Keywords: Concurrent Software
Testing
Advisor: Farzan, Azadeh