VictorJuiz/thesis huggingface dataset:
Contributions to Data-Driven Combinatorial Solvers

Discrete optimization problems appear in everyday life, with a wide range of applications including airline scheduling, telecommunications network design and healthcare. Modern solvers are intricately crafted to perform well on average across this wide range of applications. This generality is at odds with their emerging applications where the solver is rapidly queried with slightly modified versions of the same problem. Data-driven algorithm design provides a potential solution to this dilemma by tuning various aspects of the solver via machine learning to the desired distribution of a particular domain. Several attempts have been made towards this goal, yet many challenges lie ahead of its adoption in modern solvers. In this dissertation, we identify some of these challenges and propose methods to alleviate or circumvent them. First, we contribute the first ML-based exact model counter by improving the branching heuristic of a conventional solver in a data-driven manner. We show that the resulting solver takes fewer steps in solving unseen similarly distributed instances and can extrapolate to larger instances from the same problem family, sometimes leading to orders of magnitude speedups over the conventional solver. Second, we investigate the potential of contrastive learning in ML-based solvers. Given the NP-hard nature of these problems, the cost of acquiring labels is quite expensive. We show that, by using only 1% of the labelled data, contrastively-trained representations can achieve comparable test accuracy to fully-supervised representations. This positions contrastive learning as a formidable technique for data-driven solver design. Third, we propose a framework based on Monte Carlo tree search for efficient “backdoor” discovery in integer linear programming. The study of backdoors can reveal novel structural properties of these problems and provide insights into their hardness. Lastly, we show how ML can in turn benefit from the discrete mathematics domain. We show how a type of formal logic can be used to express multi-task, temporally extended instructions to reinforcement learning agents. We prove that the resulting agents have theoretical advantages over baseline methods. Particularly, we show that our agent does not suffer from myopia, where the individual subtasks are solved optimally but the combined solution is suboptimal.

Keywords: Combinatorial Optimization
Contrastive Learning
Integer Programming
Machine Learning
Reinforcement Learning
Advisor: Bacchus, Fahiem
McIlraith, Sheila Ann
Investigating the In vivo Effects of Osteoblast-specific Oerexpression of Gαs and Gαq/11 on Bone Formation and Remodeling during Fracture Repair

G proteins mediate a multitude of physiological processes by transducing extracellular signals from G protein-coupled receptors to various intracellular signaling cascades. Of particular importance in bone are GαS that raises cAMP levels by activating adenylyl cyclase and Gαq/11 that increases intracellular calcium levels via activation of phospholipase C. Using transgenic mice that overexpress either GαS (Gs-Tg) or Gαq/11 (G11-Tg) in osteoblast lineage cells, previous work in our lab has demonstrated that alterations in GαS and Gαq/11 levels in the skeleton can have profound effects on bone mass, microarchitecture, mineral density, and quality. It remains unclear, however, how variation in GαS and Gαq/11 levels affects bone regeneration and repair. To test our hypothesis that increasing Gαs and Gα11 in osteoblasts leads to differential fracture healing responses, we performed stabilized tibial osteotomy in male Gs-Tg and G11-Tg mice at 8 weeks of age and examined the progression of fracture healing by Micro-CT, histomorphometry, and gene expression analysis over a 4-week period. Gs-Tg mouse fractures exhibited diminished cartilage formation, increased callus mineralization, increased bone formation, and improved material stiffness. Histological analyses also revealed excess fibroblasts along the newly formed woven bone surfaces and elevated osteocyte density at the times of increased bone formation and elevated osteoclastic bone resorption in the bone remodeling stage. Coincident with enhanced osteogenesis, elevated osteoblastic Wnt secretion and Wnt/B-catenin signaling was evidenced by quantitative reverse transcription PCR and immunofluorescence staining implicating increased Wnt signaling activation as a mechanism by which increased GαS levels promote osteogenesis and induce fibrosis during bone repair in Gs-Tg mice. In contrast, normal endochondral healing progressed in G11-Tg mice. However, their reduced osteogenic differentiation capacity led to diminished formation of highly mineralized bone and poor structural integrity of healing bone. The lack of changes in osteoclast parameters and osteoclast marker expression suggested that the G11-Tg fracture repair phenotype is driven by osteogenic abnormalities. Overall, our results confirm our hypothesis that GαS and Gαq/11 differentially regulate bone formation and remodeling during fracture repair and highlight that osteoblast GαS and Gαq/11 levels play a significant role in determining the pattern, rate, and extent of fracture healing.

Keywords: Biomechanics
Fracture repair
G protein
Osteoblast
Advisor: Mitchell, Jane
Grynpas, Marc
Efficient Algorithms for Smulations of Quantum Chemical Systems

Even though the physical equations that model chemical systems are known, the complexity of solving, and sometimes even representing such equations, escalates exponentially with the system size for an arbitrary chemical system. However, many different approximations can be made and efficient algorithms found for the accurate description of some chemical systems of interest with reasonable computational effort. In this work, we propose efficient algorithms for the solution of three problems of chemical interest, namely: the electronic structure problem using quantum computers, the simulation of chemical reactions on metallic surfaces, and modelling the absorption of solar radiation by light harvesting molecules. All of the proposed algorithms work within larger frameworks. We start by discussing the importance of each given problem, after which we cover the necessary background for all the used frameworks and show the details on how our proposed algorithms make these frameworks more efficient.

Keywords: Electronic structure
Hamiltonian simulation
Metallic surface
Nonadiabatic dynamics
Quantum computing
Solar light absorption
Advisor: Izmaylov, Artur F
Developing a Diagnostic Approach to Multi-Dimensional Poverty

Resource accumulation benefiting some people over others has been naturalized throughout human social evolution, even when its acquisition caused widespread suffering, disease, and premature death. The first religious orders, humanitarians, and indeed nurses, all emerged in response to this widespread exploitation and misery. In our globalized and technologically advanced world, there is widening inequality, deepening impoverishment, complex threats to health and security, and increasing uncertainty. As clinicians, we seek to assist people living in multi-dimensional states of suffering, yet our tools and methods are insufficient. Poverty measures often focus on monetary impoverishment alone; most are not meant to be broad or diagnostic in nature; political barriers and other perverse incentives limit the scope of poverty case finding; practice barriers (not least, time) limit case finding in the clinic; and often we focus on symptoms and surface manifestations of poverty – not the root causes. Grounded on an ontological foundation of critical realism and guided by an epistemology of critical theory, this study seeks to address this practice gap by synthesizing existing poverty measures and approaches via a literature scoping review; collecting primary data from health providers and clients through a generic qualitative research study; and constructing a novel diagnostic approach to multi-dimensional poverty with an emphasis on clinical utility. During eight months of data collection in urban Toronto, semi-structured interviews were carried out with 11 healthcare professionals and 6 clients, as well as a multidisciplinary focus group of 5 clinicians. Findings revealed that respondents held diverse perspectives on the definition of “poverty”, what to do about it, and what provider and client roles ought to be. Respondents also helped prioritize life domains, proposed ways to measure complex aspects of life, and suggested settings where a diagnostic approach to poverty would be useful. Based on these findings, I propose the Survival – Orientation – Self-Actualization (S.O.S.) Diagnostic Approach, a novel multi-dimensional measure infusing elements of the nursing process, person-centered care, and ethical triage to better guide poverty case finding and praxis in the clinical setting. The study concludes by offering suggestions on application to practice, informing policy, and suggestions for future research.

Keywords: Diagnosis
Health Assessment
Multi-dimensional poverty
Nursing
Person Centered-Care
Triage
Advisor: Gastaldo, Denise
Odd Electron Transition Metal Hydride and Amine Complexes and their Associated Proton/Electron/Hydrogen Atom Reactivity

This thesis is focused on furthering our understanding of the thermodynamics associated with metal hydrides and coordinated amines, namely the acidity, electrochemistry, and M-H and MN-H bond strengths. This understanding will improve catalyst development and should make industrial processes more sustainable and environmentally benign. In chapter 2, literature-reported electrochemistry of metal-hydride complexes is combined with estimated acidities of the oxidized species, in order to examine trends in electrochemical reversibility, acidity, and metal-hydride bond strength. It was found that oxidations to acidic metal hydrides tend to be irreversible due to proton loss. On the other hand, regions of electrochemical reversibility are usually associated with more reducing, less acidic complexes. In addition, the ligand acidity constant (LAC) method of estimating the pKa of metal hydrides and dihydrogen complexes is applied to paramagnetic metals. It was found that the LAC method generally works well for paramagnetic complexes, even though it was empirically derived from pKa of diamagnetic hydrides. Using the work from chapter 2 as a guide, a series of paramagnetic manganese(II) hydride com- plexes were synthesized, as discussed in chapter 3. This series is of the type trans-[MnH(L)(dmpe)2]+ were L is PMe3, C2H4, or CO. All of these complexes were studied by frozen solution EPR spec- troscopy. However, at room temperature, the trans ligand was found to determine the radical stability, and in cases of instability, the decomposition products. trans- PMe3 provides steric bulk and basicity, which stabilizes the radical. The trans-C2H4 complex decomposed by loss of ethylene and ethane, which ultimately yielded the homoleptic tris-dmpe complex and other unidentified side- products. The trans-CO complex provided little steric bulk and was more acidic, such that this complex cleanly lost 1/2 H2 in MeCN to give the MnI product [Mn(CO)(MeCN)(dmpe)2]+. In chapter 4, the focus is on coordinated amines, specifically a secondary amine in a tri-dentate phosphorous-nitrogen-nitrogen (PNN) ligand, which is coordinated to iron and rhodium. This case study used cyclic voltammetry and NMR to measure the acidity, electrochemistry, and MN-H bond dissociation free energies for the complexes.

Keywords: Hydride
Inorganic
Paramagnetic
Transition Metals
Advisor: Morris, Robert H.
Reaction Discovery through Amphoteric Functional Groups: From Fluorophores to Peptides

Functional groups with multiple electrophilic and nucleophilic sites facilitate the synthesis of complex molecular scaffolds and the development of new chemical reactions. This thesis classifies functional groups based on the relative position and nature of their reactive atoms and studies their chemical transformations as well as the applications of the molecules generated. Chapter 2 discusses the use of sodium cyanoborohydride as a C1 borylated building for synthesizing borindolizines, a class of fluorescent boron-containing heterocycles. Borindolizines exhibit scaffold-dependent fluorescent emissions spanning the entire visible spectrum (violet to red) and a high Stokes shift. A computationally-guided scaffold screen is performed, allowing for the rational design and synthesis of a family of fluorophores with tunable emission wavelengths, including a red-emissive isoquinoline-based borindolizine. Chapter 3 explores the redirection of an established 1,3,4-oxadiazole-forming reaction towards the synthesis of pyrazolyl-heteroaryl-containing rings from readily available amino-azoles in a single synthetic step. The heterocycle-forming reagent N-isocyaniminotriphenylphosphorane (Pinc) possesses an amphoteric isocyanide capable of engaging both nucleophilic and electrophilic reaction partners during the reaction and a nucleophilic iminophosphorane. The redirected reaction rapidly generates chiral bis(heteroaryls) from linear peptides and commercially available azole amines that can have wide-ranging applications as small molecule probes, organocatalysts, and ligands. In Chapter 4, the monomer-dimer equilibrium observed in amphoteric aziridine aldehyde dimers is probed by introducing hydrogen-bond donors and acceptors. The synthesis of functionalized aziridine aldehydes displaying a breakdown of the dimeric character of aziridine aldehydes is conducted, and the first observation of a predominantly monomeric aziridine aldehyde is made. Finally, a mechanistic tool is developed by leveraging the homochiral nature of aziridine aldehyde dimers based on the non-linear effect observed through monomer enantiomeric excess values in scalemic mixtures of dimers.

Advisor: Yudin, Andrei K
Systematic Characterization of Human 14-3-3 Paralogs Reveals Highly Similar Interaction Specificities and Uncovers their Role as Chaperone-like Molecules

Human 14-3-3 proteins are a family of seven highly conserved phospho-serine/threonine binding domains. They interact with hundreds/thousands of structurally and functionally diverse protein clients, thereby acting as central hubs of many signaling networks. However, how each 14-3-3 paralog differs in client specificity is not known for most clients because interaction specificity differences have never been quantitatively assessed on a large scale for the full complement of 14-3-3 paralogs. Furthermore, due to the lack of systematic functional screens, it is not known how most client proteins are regulated by 14-3-3s. Here, I used affinity purification coupled to mass spectrometry (AP-MS), proximity biotinylation (BioID2), and LUminescence-based Mammalian IntERactome profiling (LUMIER) to generate quantitative and directly comparable interactomes of all seven human 14-3-3 paralogs. I also used a high-content immunofluorescent imaging approach to uncover the effect of disrupting 14-3-3 interactions on client protein localization. The resulting networks revealed that all paralogs, with the exception of 14-3-3σ, have extremely similar or nearly identical interaction specificities. Furthermore, I found that loss of 14-3-3 binding leads to coalescence of a large fraction of clients into discrete foci or clusters in a client-specific manner, suggesting a central chaperone-like function for 14-3-3 proteins. Consistent with this, engraftment of 14-3-3 binding motifs to non-clients suppressed their aggregation or phase separation. This is also supported by the enrichment of features in 14-3-3 interactors that promote aggregation and phase separation. Finally, I showed that 14-3-3 proteins negatively regulate the localization of the RNA-binding protein SAMD4A to cytoplasmic granules and suppress its activity as a translational repressor. Ultimately, I was able to generate the most comprehensive framework for deciphering differences in interaction preferences between 14-3-3 paralogs. Furthermore, my work was able to greatly expand on the functional consequences of 14-3-3 binding in human cells, revealing that 14-3-3 proteins have a more prominent role as chaperone-like molecules than previously thought.

Keywords: 14-3-3
Chaperones
Mass-spectrometry
Microscopy
Phase separation
Protein interactions
Advisor: Taipale, Mikko
Online Decision-Making in a Randomized Environment: Stochastic Matching and Adaptive Random Graph Processes

In the first part of the thesis, we consider an online version of the stochastic matching problem. The stochastic matching problem is a generalization of the classical maximal matching problem in which the edges are associated with known edge probabilities which model their likelihood of existing. The algorithm must probe potential edges to reveal which ones exist, while respecting a limited budget for how many probes it can make. In the online variant of the problem, the vertices of the graph are revealed and processed by the algorithm sequentially. We introduce a new linear program to design and analyze combinatorial algorithms which work in greater generality than that of previous works, and which also yield the best-known competitive ratios. Afterwards, we consider a related online stochastic matching problem called the prophet matching problem with edge arrivals. In this model, the edges of the graph are processed by the algorithm sequentially. To attain improved competitive ratios, we design online contention resolution schemes for the matching polytope with state-of-the-art selectability bounds. In the second part of the thesis, we consider online decision-making in the context of random graph processes. In the semi-random graph process, a collection of edges is randomly drawn in each step, and the online algorithm then gets to add precisely one of them to the current graph. Through intelligent decision-making, the objective of the algorithm is to force the graph to satisfy a fixed graph property with high probability in as few rounds as possible. We provide upper and lower bounds on the performance of the optimal algorithm when the property corresponds to being Hamiltonian or to containing a perfect matching. We next introduce a formal definition of an adaptive random graph process which generalizes both the semi-random graph process, as well as the Achlioptas process. In this model, we define a condition called \textit{edge-replaceability} which we prove is sufficient for a property to have a sharp threshold. We apply our result to the semi-random graph process to show that the properties of being Hamiltonian and of containing a perfect matching each have a sharp threshold.

Advisor: Borodin, Allan
Takemitsu’s Solo Guitar Music Inspired by Visual Art: Informed and Imaginative Interpretation and Performance

The guitar music of Japanese composer Tōru Takemitsu presents a unique contribution to the solo guitar repertoire. Like much of his creative output, his guitar music features some ambiguous inspiration from extra-musical sources. The purpose of this study is to uncover information on the connection between Takemitsu’s guitar pieces and the works of visual art for which they are named; additionally, this information is incorporated into a multi-level approach to interpretation and performance. The methods include first establishing an approach to the problem from the perspective of the performer through a framework built upon hermeneutic methods, literature on the role of the performer, performer’s analysis (John Rink), analogy of score as script, and reflections on the practice-based learning process on the guitar. The suggested approach is then applied to two case studies, Takemitsu’s All in Twilight (1987), and Equinox (1993). The approach includes producing translations of pertinent Japanese texts, conducting interviews with two professional guitarists (Tanenbaum and Fukuda), and investigating the artists Klee and Miró and the works of visual art after which each piece is named. The results show that for each case the viewing experience, evocation of the title, and aesthetic of the artwork inspired Takemitsu’s creativity. This manifested in various associations and references to concepts and fascinations of the composer, including the conflation of dream and water themes, nocturnal references, the subconscious mind, transitions of nature, the end of life, and the space between dualities of day and night, life and death, and sound and silence. The composer embedded these associations in part through intertextual reference to previous works of his own and those of major influences Messiaen and Debussy, with overlapping motivic material, contours, and harmonies. The results of each case study present an informed and imaginative interpretation, rather than an authoritative reading. The information on the visual artists, artworks, and extensive reflections on the technical execution of the pieces on the guitar may be used by students and professionals as a guide toward their own interpretations of the case-study pieces and further related works by this and other composers.

Keywords: extra-musical
guitar
hermeneutics
interpretation
performance
Takemitsu
Advisor: McFadden, Jeffrey
Making a Beautiful Difference: How Teachers Support Students with Learning Challenges in Rural Nepal

The growing demand for high-level English education in south Asia has created a network of private schools, promising better results and outcomes for students than local-language government schools. This in turn creates an expectation that all children should be able to access this type of schooling, and an environment where academic achievement is prioritized for a variety of complex reasons. Typically within these systems, students who did not succeed in school were pushed out early, or held back repeatedly over multiple years. However, with the global push to ensure access to education to all of the world’s children, children who struggle academically are spending more and more years in a classroom, despite their lack of perceived success. How do teachers support students who are struggling academically within a system which emphasizes academic achievement, and which measures success based on a strict series of exams? The purpose of this research was to explore the experiences of teachers in supporting students who struggle academically in a small community in rural Nepal, and explore the process of creating a positive model of support for students at the study school. I interviewed teachers and explored ideas related to the supports and barriers they faced in supporting struggling students, the value of education to their community, and the changes they felt were needed to better support students with learning challenges. I took a qualitative case study approach based in narrative and ethnographic traditions, and collected data through individual interviews and group discussions with the participants, as well as through the analysis of field texts, including the use of reports, journals and photographs. I analyzed the data using thematic analysis and organized in relation to an initial, and then revised, conceptual framework that included a variety of influences impacting the teachers in their work. I used narrative and story throughout to contextualize and discuss the findings, and discuss implications for theory, practice and further research.

Keywords: Development
Education
Nepal
Schools
Special Education
Teachers
Advisor: Joshee, Reva