VictorJuiz/thesis huggingface dataset:
Cell Physiology of Innate Immunity and Its Subversion by Intracellular Pathogens

Innate immune cells are embodied by their dynamic and responsive nature. In addition to housekeeping functions, they actively survey for danger by sampling their local niche, migrate into and out of the parenchyma of various tissues in response to minute chemical cues, secrete both pro- and anti-inflammatory cytokines to either provoke or resolve inflammation, and deftly counter infectious threats with a unique microbicidal toolkit. Of paramount importance to innate immunity is phagocytosis, the receptor-mediated uptake of extracellular particles (pathogens, effete cells, debris). The resulting membrane-bound intracellular compartment −the phagosome− undergoes a cascade of biochemical transformations to create a hostile, degradative lumen that is normally incompatible with microbial life. By presenting portions of their findings to lymphocytes, a means to couple innate and adaptive immune systems is borne out. To perform their many functions, innate immune cells rely on intricate signal transduction pathways that result in equally intricate changes in cell behaviour. At the heart of this is a specialized class of membrane second messengers called phosphoinositides that couple extracellular cues to intracellular protein recruitment, membrane transport, and actin cytoskeletal reorganization. From an evolutionary standpoint, pathogenic organisms noted the effectiveness of these pathways and developed means to overcome them, thereby disarming a fundamental function of the innate immune system. In this dissertation, I explore how human pathogens manipulate both the actin cytoskeleton of phagocytes to promote intracellular survival, and how they employ sophisticated toxins to manipulate phosphoinositide signaling for their selective advantage. Chapter 1 reviews fundamental aspects of the cytoskeleton and lipid metabolism in the context of immune cells; pathogenic organisms which evolved remarkable means to manipulate the underlying biology of these systems are highlighted. The overarching aims and hypotheses of my work are described in Chapter 2 and in Chapter 3, I detail how the secretion of a bacterial effector into macrophages by Burkholderia cenocepacia modifies phagosome maturation via local actin polymerization. Finally, Chapter 4 uncovers an unprecedented mechanism by which a bacterial effector delivered by Salmonella species synthesizes an important phosphoinositide signaling molecule. This work contributes to understanding several fundamental cellular pathways and their complex manipulation by human pathogens.

Keywords: host-pathogen
lipid biosensors
lipid signaling
membrane traffic
phagocytosis
phosphoinositides
Advisor: Grinstein, Sergio
Brumell, John
Exploring the Theranostic Potential of Gas Vesicle Protein Nanobubbles

Halophilic archaeabacterial gas vesicles (GVs) are a class of protein nanobubbles isolated from buoyant, aquatic microorganisms. The hollow chamber of GVs enables them to be readily visualized by ultrasound (US) waves. Extensive research has gone into characterizing the imaging or therapeutic functions of GVs, but no work has sought to combine these functions to develop GVs as multifunctional theranostics. We hypothesized that GVs can serve as a scaffold to integrate therapeutics or tumor targeting ligands through covalent or noncovalent approaches. This thesis investigates the strategy of chemically conjugating therapeutics to the free amino groups on the GV shell, and explores the non-covalent complexation of GVs with bispecific linkers to introduce tumor-targeting function to GVs. The first study demonstrated that covalently modifying the surface of GVs with the photosensitizer called chlorin e6 (Ce6) transformed them into light-sensitive, photoactive nanobubbles (Ce6-GVs) with potent cancer-cell killing effects. The second study used bispecific adapters to noncovalently link monoclonal antibodies that bound Ce6-GVs, in order to target Ce6-GVs to cancers overexpressing the tumor antigen called carcinoembryonic antigen (CEA). The third study focused on the surface modification of Ce6-GVs using GV specific antibodies covalently modified with another tumor targeting ligand called folate. Overall, the results of these studies support the hypothesis that GVs can be repurposed into nanoscale theranostics for cancer. GVs can be manipulated in diverse ways for diagnostic or imaging purposes, which warrants further investigation on GVs and other ligands or tools that may be useful to develop them into beneficial biologics.

Keywords: Cancer
Chlorin e6
Gas Vesicles
Nanobubbles
Photodynamic therapy
Ultrasound
Advisor: Gariepy, Jean
Two Left Feet: A Study of Multispecies Musicality in British Women's Sport

The division between the study of human cultures, human minds, and animal behaviours and biology in academic scholarship exacerbates the assumption that music is exclusively human and that the human is singularly musical. In an attempt to avoid this simplified linkage between human music cultures and human biology, my research explores the interrelationship between (a) the “music-like” socialities underpinning sustained interspecies encounters, and (b) the human constructions of musicality (or unmusicality) that generate social allegiances and facilitate the strategic navigation of hierarchical power structures within multispecies environments. My dissertation examines two interspecies sports in the UK—equine freestyle dressage and canine heelwork to music—in which horses and dogs are trained predominantly by women to perform skills on command to the accompaniment of a music track. Drawing together perspectives on the animal from continental philosophy, ethology, gender studies, and critical theory, this multi-sited, multispecies ethnography aims to rethink the category of music through the animal and, conversely, the category of the animal through music. My argument is that the social bonds generated amongst freestyle dressage and heelwork to music’s sportswomen at shows are related to the interactions negotiated between the women and their horses/dogs during training and competition, both of which emerge from the interspecies performers’ music-like “expressions of desire” mediated sonically, visually, and tactilely between individuals through time. However, in order to engender these social bonds of community across human spectators as well as navigate the hierarchies of difference that govern their lives as mostly white, British, middle-class women, riders and handlers must place conditions on their animal partners’ expressions of desire as part of their construction of horse and dog (un)musicalities in social discourse. This latter characteristic of musical sociality, I argue, appears to be exclusive to the human.

Keywords: animal studies
British leisure culture
ethnomusicology
gender studies
social bonding
sport
Advisor: McLeod, Kenneth
The Proof Complexity of Integer Programming

Proof complexity provides a promising approach aimed at resolving the P versus NP question by establishing the nonexistence of propositional proof systems which admit short proofs of every tautology. Proof complexity suggests an incremental program of proving lower bounds on the size of proofs in successively stronger proof systems as a means of building towards a resolution to the central question. The complexity of specific proof systems is also deeply connected to the analysis of practical algorithms. A proof system corresponds to a family of efficient algorithms. Thus, lower bounds for a proof system reveals the limitations inherent to the associated algorithms. In this thesis we develop and study proof systems which formalize modern algorithms for integer programming.Our contributions are as follows. A major conjecture in proof complexity is that random k-CNF formulas are hard to prove in every proof system. This conjecture has been confirmed for a number of proof systems [ChvatalS88, SegerlindBI04, AlekhnovichR01, Schoenebeck08]. One notable exception is the Cutting Planes system, which formalizes classical algorithms for integer programming. In this thesis we confirm this conjecture for Cutting Planes. Modern algorithms for integer programming, known as branch-and-cut, improve upon Cutting Planes by combining it with a branch-and-bound procedure. We introduce Stabbing Planes as an elegant proof system which formalizes branch-and-cut algorithms. In doing so, we show that Stabbing Planes can simulate Cutting Planes and surprisingly, that a partial converse exists as well. Using this converse we are able to obtain exponential lower bounds on branch-and-cut, as well as exhibit small Cutting Planes proofs of any systems of linear equations over a prime finite field, generalizing [DadushT20]. One striking feature of these Cutting Planes proofs of linear equations is that their depth far exceeds worst-case. This suggests that these formulas may yield a supercritical size/depth tradeoff for Cutting Planes --- formulas for which short proofs require depth beyond worst-case. We make two contributions towards this. First, we develop a geometric technique for proving depth lower bounds and apply it to a ``semantic'' generalization of Cutting Planes. Second, generalizing [Razborov16], we establish supercritical size/depth tradeoffs for Cutting Planes.

Keywords: Complexity Theory
Integer Programming
Proof Complexity
Advisor: Pitassi, Toniann
Three Essays on the Role of Information in the Development of Early-stage Startups

Entrepreneurs bring novel ideas to market, ideas that are the engine of economic growth. In the early stages of firm development, however, entrepreneurs face significant uncertainty with respect to both the quality of ideas and the path to commercializing them. Whereas scholars have extensively studied the nature of risky ideas, the uncertain path to firm development has received little attention. The three chapters of this dissertation explore three ways in which information can reduce this uncertainty and increase the probability of entrepreneurial success. In the first chapter, I explore the differences in the types of information provided by angel investors and venture capitalists, two major suppliers of risk capital to early-stage startups. I also examine how these different information types are related to investors' prior experience. I find that angels are more likely than venture capitalists to provide information on entrepreneurial experiments that test important product and market hypotheses. On the other hand, venture capitalists are more likely to provide information on market sizing and business planning. Evidence suggests that angel investors' higher operating experience gives them a skill advantage over venture capitalists in designing and running experiments. In the second chapter, Ajay Agrawal and I report evidence that the impact of information from mentors is not uniform across firms, suggesting that some entrepreneurs absorb information from mentors more than others. I characterize these as high versus low learners and show that information from mentors on task prioritization has a much greater effect on high learners. In the third chapter, Kevin Bryan, Mitchell Hoffman, and I examine the effect of quality signals in the context of startup recruiting. Human capital is one of the most important determinants of firm performance. However, early-stage startups face significant difficulty in attracting job applicants. In a Randomized Controlled Trial, we find that workers' access to signals about the quality of firms' technology and business models substantially affect how they rank startups, and hence the ones they apply to. We also find that workers' beliefs about startups' growth potential are strongly influenced by information about the quality of the firm's core technology and business model.

Keywords: Entrepreneurship
Experimentation
Hiring
Information Asymmetry
Mentorship
Startups
Advisor: Agrawal, Ajay K
Measurements of Greenhouse Gases from Near-infrared Solar Absorption Spectra

This thesis presents improvements to retrievals of greenhouse gas concentrations, with a focus on CO2 and the Arctic. Near-infrared solar absorption spectra were collected at the Polar Environment Research Laboratory (PEARL) in Eureka, Nunavut as part of the Total Carbon Column Observing Network (TCCON), extending the data record to July 2020. Data processing was improved by the application of solar zenith angle corrections to account for pointing offsets of the solar tracker. Issues related to surface pressure records were resolved. TCCON measurements were used to validate simulations of CO2 and CH4 by GEM-MACH-GHG, a model in development at Environment and Climate Change Canada. Vertical profile retrievals of CO2 from TCCON spectra were evaluated, using improved spectroscopy and line shapes. CO2 profiles were obtained from sequential retrievals in five spectral windows using synthetic and real spectra. A sensitivity study showed that the leading source of uncertainty in the retrieved CO2 profiles is errors in the a priori temperature profile as small as 2°C between 600-850 hPa. To distinguish the effect of errors in the instrument alignment and spectroscopic parameters from other error sources, CO2 profiles were retrieved using an a prioriprofile built from coincident in-situ measurements. With real spectra, the deviations in retrieved CO2 profiles were larger than typical vertical variations of CO2. Remaining errors in the forward iiimodel limit the accuracy of the retrieved profiles. Implementing a temperature retrieval or correction is critical to improve CO2 profile retrievals. A study was conducted in support of the proposed Canadian satellite mission AIM-North. The ReFRACtor algorithm was adapted to generate synthetic spectra for a Fourier transform spectrometer and a grating spectrometer. Retrievals were performed on these synthetic spectra to estimate the precision and accuracy of retrieved XCH4, XCO, and XCO2, in different conditions.Over a standard scene corresponding to a boreal forest, the retrieval precision for the given instrument characteristics was ~0.6% for XCH4, ~8% for XCO, and ~0.4% for XCO2. These results can be used by the AIM-North team to decide whether the instrument design should be adapted to meet the mission’s precision and accuracy goals and thresholds over specific scenes.

Keywords: arctic
carbon cycle
carbon dioxide
fourier transform spectrometer
optimal estimation
remote sensing
Advisor: Strong, Kimberly KS
Wunch, Debra DW
Monogenic Fields with Odd Class Number

We prove an upper bound on the average number of 2-torsion elements in the class group monogenised fields of any degree n ≥ 3, and, conditional on a widely expected tail estimate, compute this average exactly. As an application, we show that there are infinitely many number fields with odd class number in any even degree and signature. This completes a line of results on class number parity going back to Gauss.

Advisor: Shankar, Arul
Difunctionalizations of Alkynes in the Domino Synthesis of Heterocycles

The Lautens group has investigated the use of metal catalysts for the domino synthesis of heterocycles. These strategies aim at generating products with high atom economy and minimal generation of waste. This thesis consists of three chapters describing the synthesis of various heterocycles in this fashion using both metal- and non-metal-catalyzed methodologies. Chapter 1 describes a palladium-catalyzed cycloisomerization of 1,6-diynes for the synthesis of silylated 2-azafluorenes. This reaction occurs via a palladium-hydride addition and C–H bond functionalization cascade. Originally, we desired to generate carbohalogenation products via the reductive elimination of a C–Pd(II)–X species, however, the corresponding intermediates demonstrated higher aptitudes for C–H activation. The synthetic utility of the products was investigated, and several mechanistic experiments were performed. Chapter 2 focuses on a palladium-catalyzed synthesis of dihydrobenzoindolones via an ortho C–H bond functionalization and alkyne insertion process. The reaction forms three new C–C bonds and generates products in high yields and excellent regioselectivities using unsymmetrically substituted alkynes. Chapter 3 describes the intramolecular chloroacylation of alkyne-tethered carbamoyl chlorides for the synthesis of E-3-(chloromethylene)oxindoles. Initial attempts to synthesize methylene oxindoles using nickel catalysts revealed that fluorinated alcohols promote this process in the absence of a metals or other additives. The products were obtained in high yields and excellent E-selectivity, and their synthetic versatility was demonstrated via a series of derivatizations, including the synthesis of nintedanib. Isomerization and halide-exchange experiments were performed to gain further insight into the reaction mechanism. Furthermore, analogous reactivity was extended towards the synthesis of chlorinated methylene pyrrolidones and 2-quinolinones. Chapter 4 describes future directions of the previous chapters. Mechanistic experiments, new substrate classes, asymmetric variants, among other related and unexplored areas of research are discussed.

Keywords: Carbohalogenation
Cycloisomerization
C–H Functionalization
Domino reactions
Hexafluoroisopropanol
Palladium catalysis
Advisor: Lautens, Mark
Police as Institution of Public Force. A Research Agenda

An agenda for legal research on the police is sketched. Adopting a public law account of state authority, mainstream approaches in legal scholarship are criticized. Legal scholarship has been narrowly focused on the regulation of policing through the enforcement of constitutional rights by the courts, using the exclusionary rule of wrongfully obtained evidence. This approach disregards the institutional dimension of police forces and their interactions with other state agencies, thereby providing a reductionist image of the police. This limitation can be overcome by redirecting analysis towards the intra-organizational production of police practices within a given territory. The last section offers a case study by developing a genealogy of the Chilean police.

Keywords: exclusionary rule
institutional design
police
state authority
Advisor: Chiao, Vincent
The Bidirectional Relationship Between Invariant Natural Killer T Cells and the Intestinal Microbiota

Invariant natural killer T (iNKT) cells are innate T cells that recognize lipid antigens presented by CD1d. Upon activation, these cells can rapidly secrete a wide array of cytokines and chemokines to bridge and influence both innate and adaptive immune responses. As a result, iNKT cells are key players in the maintenance of tissue homeostasis and a promising immunotherapeutic target for various diseases. While the regulation of iNKT cell development and function by host factors has been rigorously investigated, only few studies have described the involvement of microbial factors in these processes. In this work, we aimed to characterize the influence of the intestinal microbiota on iNKT cell homeostasis and the reciprocal effect of iNKT cells on microbiota composition. First, we investigated the effect of microbial alterations on iNKT cell function during intestinal inflammation. We showed that engraftment of a proinflammatory microbiota can exacerbate chemically induced colitis in mice by imprinting iNKT cells with a procolitogenic gene signature and altering their response to activation. Second, we examined the impact of microbial status on iNKT cell homeostasis and how microbial presence is communicated to these cells. Using germ-free and pet store mice, we found that the gene expression, subset distribution and cytokine production of iNKT cells are significantly altered in the absence of the microbiota and upon increased microbial exposure. In addition, we showed that microbial signals are potentially conveyed to iNKT cells in a TCR-independent manner. Finally, we demonstrated that iNKT cells and/or CD1d has a marginal impact on the composition of the microbiota. Collectively, this work contributes to the understanding of the crosstalk between iNKT cells and the gut microbiota.

Keywords: CD1d
colitis
Invariant natural killer T cells
microbiota
Advisor: Mallevaey, Thierry
Tales from the Canadian Tax Code: The Policy and Politics of Federal Tax Expenditure Instrument Choice

Drawing from 30 in-depth interviews of elite policy actors, this project seeks to add to extant rich descriptions of Canadian federal tax expenditures through a policy instrument choice analysis of the durability of political executives’ interest in tax expenditures. The project proposes a new concept of the politics of Canadian federal tax expenditures. More specifically, the data collected suggests that the use of tax expenditures is motivated by the logic of institutional leapfrogging, which expresses itself in the form of: i) bureaucratic bargaining; ii) public opinion responsiveness; iii) evasive federalism; and iv) government responsiveness to citizenry policy fatigue. The concept of institutional leapfrogging denotes efforts by federal political executives (i.e. Members of Cabinet and their senior advisors) as well as civil service elites to use tax expenditures to deliver visible and popular policy outcomes to the public with minimal interference from other political or governmental actors and institutions (i.e. Members of Parliament, departments of government, and political executives in the provincial-territorial order of government). While I believe that existing understandings of tax expenditures as a politically rational instrument choice are correct, this study departs from earlier conceptual models by examining how such political self-interest is uniquely conditioned by broader Canadian political phenomena. To structure these arguments, I provide background on existing sub-fields of Canadian tax expenditure research and make the case for turning the orientation of federal tax expenditure research upstream in the policy process, toward policy instrument choice theory. I provide an overview of the project’s dependent variable, including a survey of select statistical analyses of Canadian federal tax expenditures. I outline the four independent variables that I hypothesize influence Canadian federal tax expenditure adoption. I then proceed to outlining my research approach, including the methods adopted for elite interviews, as well as the methods used for Hansard and media analysis. Next, I review my research findings, exploring how the project’s data speaks to the causal and intersecting relationship between my independent variables and the durability of tax expenditures. Finally, I offer conclusions on the project’s significance to Canadian political scientists and outline several areas of future research.

Keywords: Canada
Federalism
Instrument Choice
Public Opinion
Tax
Tax Expenditure
Advisor: White, Linda