VictorJuiz/thesis huggingface dataset:
Knowing Instruments: Design, Reliability, and Scientific Practice

This dissertation is an attempt to understand the role of instruments in the process of knowledge production in science. I ask: how can we trust scientific instruments and what do we learn about when we use them? The dissertation has four parts. First, I construct a novel account of “epistemic possibility,” the possibility of knowing, that captures the dependency of knowledge on action, and I introduce the notion of “technological possibility,” which depends on the availability of material and conceptual means to bring about a desired state of affairs. I argue that, under certain circumstances, technological possibility is a condition for epistemic possibility. Second, I ask how instruments become reliable. I argue that when the material capacities and conceptual functions of a scientific instrument correspond, the instrument is a reliable component of the process of knowledge production. I then describe how the instrument design process can result in just such a correspondence. Instrument design produces the material device, a functional concept of the device revised in light of experience, a measure of the closeness of fit between material and function, and practices of trust such as calibration routines. ii Third, I ask what we learn from instruments such as those used for experimentation and simulation. I argue that in experiments, instruments function to inform us about the material capacities of the object of investigation, while in simulations, instruments function to inform us about the conceptual model of the object of investigation. Fourth, I put these philosophical distinctions into historical context through a case study of Monte Carlo simulations run on digital electronic computers in the 1940s-70s. I argue that digital electronic computers made the practice of Monte Carlo simulation technologically possible, but that the new method did not meet existing scientific standards. Consequently, Monte Carlo design practices were revised to address the worries of potential practitioners.

Keywords: scientific instruments
scientific practice
computers
possibility
Advisor: Chakravartty, Anjan
Emergent Low Temperature Phases in Strongly Correlated Multi-orbital and Cold Atom Systems

This thesis considers various strongly correlated quantum phases in solid state and cold atom spin systems. In the first part we focus on phases emerging in multi-orbital materials. We study even-parity spin-triplet superconductivity originating from Hund's coupling between t2g orbitals and investigate the effect of spin-orbit interaction on spin-triplet and spin-singlet pairing. Various aspects of the pairing state are discussed against the backdrop of the spin-triplet superconductor Sr2RuO4. Motivated by the remarkable phenomena observed in the bilayer compound Sr3Ru2O7, which point to the formation of an electronic nematic phase in the presence of critical fluctuations, we investigate how such a broken symmetry state emerges from electronic interactions. Since the broken x-y symmetry is revealed experimentally by applying a small in-plane magnetic field component, we examine nematic phases in a bilayer system and the role of the in-plane magnetic field using a phenomenological approach. In addition, we propose a microscopic mechanism for nematic phase formation specific to Sr3Ru2O7. The model is based on a realistic multi-orbital band structure and local and nearest neighbour interactions. Considering all t2g-orbital derived bands on an equal footing, we find a nematic quantum critical point and a nearby meta-nematic transition in the phase diagram. This finding harbours important implications for the phenomena observed in Sr3Ru2O7. The second part is devoted to the study of the anisotropic bilinear biquadratic spin-1 Heisenberg model, where the existence of an unusual direct phase transition between a spin-nematic phase and a dimerized valence bond solid phase in the quasi-1D limit was conjectured based on Quantum Monte Carlo simulations. We establish the quasi-1D phase diagram using a large-N Schwinger boson approach and show that the phase transition is largely conventional except possibly at two particular points. We further discuss how to realize and to detect such phases in an optical lattice.

Keywords: strongly correlated electrons
unconventional superconductivity
quantum liquid crystal phases
frustrated spin systems
Advisor: Kee, Hae-Young
Role of Epithelium-specific ETS Transcription Factor-1 in Airway Epithelial Regeneration

Human epithelium-specific ETS transcription factor-1 (ESE-1), which is also known as E74-like factor-3 (Elf3) in mice, is strongly expressed in lung during fetal development and in certain lung cancers. The primary goal of the work presented in this thesis was to investigate whether ESE-1 is involved in regeneration of the injured lung epithelium by administering naphthalene to both wild-type (Elf3 +/+) and Elf3-deficient (Elf3 -/-) mice. However, optimal conditions for proper utilization of the naphthalene-induced lung injury model must first be established. Therefore, dose-response studies were initially conducted by administering three different doses of naphthalene to both male and female mice, as described in chapter 2. Although it is shown that the extent of naphthalene-induced Clara cell injury is dose-dependent in both male and female mice, female mice are more sensitive to naphthalene-induced injury than male mice independent of the dose. Furthermore, it is also demonstrated that these gender-dependent differences in naphthalene injury can subsequently influence downstream lung repair kinetics. In light of these findings, lung regeneration was examined in both sexes of both Elf3 +/+ and Elf3 -/- mice. As reported in chapter 3, the kinetics of bronchiolar epithelial cell proliferation and differentiation is delayed considerably in Elf3 -/- mice following naphthalene injury. Moreover, expression of transforming growth factor-beta type II receptor, which is a well-known transcriptional target gene of ESE-1 and is involved in the induction of epithelial cell differentiation, is significantly lower in the bronchiolar airway epithelium of Elf3 -/- mice as compared to Elf3 +/+ mice under steady-state conditions and during repair of naphthalene-induced damage. Collectively, these findings occur to a similar extent in both sexes of both Elf3 +/+ and Elf3 -/- mice, and suggest that ESE-1 plays an important role in regulating the kinetics of airway epithelial regeneration after acute lung injury.

Keywords: ESE-1
ETS
transcription factor
airway epithelial injury
airway epithelial regeneration
Advisor: Hu, Jim
Do Boards Matter? The Links between Governance, Organizational Monitoring and Alignment Capacity and Hospital Performance

No systematic research has been undertaken in Canada on the relationship between hospital performance, organizational monitoring capacity and board governance. This three-part dissertation aims to fill that gap. The conceptual framework elaborated in a theoretical paper and tested in two exploratory empirical studies proposes that boards reflect their institutions, with high performers exhibiting greater capacity to harmonize accountability needs and align governance decision-making and monitoring systems with external performance measurement and reporting requirements. Top team (board and management) characteristics, and governance practices, both proposed elements of “governance capacity,” are hypothesized to reflect and reinforce “organizational monitoring and alignment capacity” thereby contributing directly and indirectly to key aspects of hospital performance including quality of care, financial health and patient satisfaction. Using hierarchical regression analyses, six hypotheses were tested on a sample of 101 acute hospital corporations that participated in the 2005, 2006 and 2007 Ontario Hospital Report Research Collaborative. After controlling for hospital size, evidence of a statistically significant relationship was detected between organizational monitoring and alignment capacity and quality performance, and between one element of governance capacity, governance practices, and financial performance. A relationship was also detected between governance practices and top team characteristics, including diversity, education and turnover. These findings suggest that the relationship between hospital governance and performance is tenuous and that some aspects of performance may be more amenable to governance influence than others. In highly-regulated environments governance space is circumscribed and myriad stakeholders have a stronger pulse on singular aspects of organizational performance than the board. This study argues that the role of boards in environments of distributed governance is to mine the ‘accountability web’ for timely, multivariate intelligence on performance and use it to drive alignment, integration and performance improvement. The contribution of this research, its limitations, and implications for researchers, policymakers and hospital leaders are discussed.

Keywords: board
governance
hospital
performance
Canada
accountability web
Advisor: Lemieux-Charles, Louise
Reading the Histone Code: Methyl Mark Recognition by MBT and Royal Family Proteins

The post-translational modifications (PTMs) of histones regulate many cellular processes including transcription, replication, DNA repair, recombination, and chromosome segregation. A large number of combinations of PTMs are possible, with methylation being one of the most complex, since it is found in three states and is recognized in a sequence specific context. Methylation of histones at key lysine residues has been shown to work in concert with other modifications to provide a Histone Code that may determine heritable transcriptional conditions in normal and disease states. On the most basic level it is pivotal to understand how and by which proteins the numerous PTMs are recognized, as well as mechanisms for downstream signal propagation. To address this need we developed a high-throughput method that allows analysis of up to 600 PTMs in a single experiment. This approach was utilized to characterize macromolecules interacting with the specific modifications on histone tails and to screen for the marks that bound to Malignant Brain Tumor (MBT) proteins, important chromatin regulators implicated in cancer. All MBTs recognized either mono- or dimethyllysine histone marks, and using structure-based mutants we identified a triad of residues that were responsible for this discrimination. These results provide the foundation for the rational design of highly selective MBT inhibitors. Additionally, this thesis describes combinatorial recognition of histone modifications, as proposed in the original Histone Code hypothesis. We demonstrate that Tudor domains of UHRF1, a protein involved in epigenetic maintenance of DNA methylation, is able to read a dual modification state of histone H3 in which it is trimethylated at lysine 9 and unmodified at lysine 4. This study provides an elegant example of the combinatorial readout of histone modification states by a single domain. Together, our findings offer mechanistic insights into the recognition of methylated histone tails by MBT domains and Royal Family in general.

Keywords: Epigenetics
Histone modifications
Royal Family Proteins
NMR, x-ray crystallography
Advisor: Arrowsmith, Cheryl
Knowledge Building in Continuing Medical Education

Continuing medical education has been characterized as didactic and ineffective. This thesis explores the use of Knowledge Building theory, pedagogy, and technology to test an alternative model for physician engagement—one that emphasizes sustained and creative work with ideas. Several important conceptual changes in continuing medical education are implied by the Knowledge Building model—changes that extend the traditional approach through engagement in (a) collective responsibility for group achievements rather than exclusive focus on individual advancement and (b) work in design-mode, with ideas treated as objects of creation and assemblage into larger wholes and new applications, with extension beyond belief-mode where evidence-based acceptance or rejection of beliefs dominates. The goal is to engage physicians in “cultures of participation” where individual learning and collective knowledge invention or metadesign advance in parallel. This study was conducted in a continuing medical education End-of-Life Care Distance Education course, for family physicians, from 2004 to 2009. A mixed methods case study methodology was used to determine if social-mediated Knowledge Building improved physicians’ knowledge, and if so, what social network structural relationships and sociocognitive dynamics support knowledge improvement, democratization of knowledge, and a metadesign perspective. Traditional pre-/posttest learning measures across 4-years showed significant gains (9% on paired t-test = 5.34, p < 0.001) and large effect size (0.82). Social network analysis of ten 2008/2009 modules showed significant difference in density of build-on notes across groups. Additional results demonstrated a relationship between high knowledge gains and social network measures of centrality/distribution and cohesion. Correlation of posttest scores with centrality variables were all positive. Position/power analyses highlighted core-periphery sociocognitive dynamics between the facilitator and students. Facilitators most often evoked partner/expert relationships. Questions rather than statements dominated the discourse; discourse complexity was elaborated/compiled as opposed to reduced/dispersed. Themes beyond predefined learning objectives emerged and Knowledge Building principles of community responsibility, idea improvability, and democratization of knowledge were evident. Overall, results demonstrate the potential of collective Knowledge Building and design-mode work in continuing medical education, with individual learning representing an important by-product. There were no discernible decrements in performance, suggesting significant advantages rather than tradeoffs from engagement in Knowledge Building.

Keywords: Knowledge Building
Continuing Medical Education
Social Network Analysis
Collaborative
Advisor: Scardamalia, Marlene
Meaning, Media and Dwellings: The Public Image of the High-rise Toronto Condo

This research examines representations of condominiums in the real estate section of the Toronto Star from 1967 through 1997, and in the Star’s Condo Living section between 1997 and 2007. I depart from conventional approaches by evaluating the articles as well as the advertisements that comprise the real estate section, based on the assumption that the context in which these texts appear is significant: a major newspaper is not a neutral vehicle, and ads and articles—consumed together, as they are in a print newspaper—will interact in creating representations of condominiums. The Condo Living section in particular is seen to perform a number of brand-like activities, most obviously in positioning the Toronto high-rise condominium as a dwelling that is particularly well-suited to young, middle-class women. This occurs partly as a function of the frequency with which women are portrayed as condominium owners. Beyond this, however, I show how the advertisements and articles in Condo Living help remake the public image of the condominium by countering existing stigmas attached to high-rise living. The section also helps to differentiate the condominium from other dwelling types by emphasizing elaborate amenities and making claims to urbanity through high-profile cultural and entertainment events. Perhaps most importantly, I demonstrate how the leading present-day design aesthetic—a reworking of midcentury modernisms—came to thoroughly dominate the image and the built form of the recent-era condominium. Positioning the condominium as a design-led dwelling type had profound implications: due to the links between design and high-end fashion, health and beauty items, the condominium immediately became a member of an aspirational product category associated with women, wealth, style and glamour. In addition to positioning the condominium as ‘naturally’ suited to young single, women, it removed the condo from direct competition with the single-family house, allowing it to be perceived as a desirable and distinct—rather than denigrated—dwelling type.

Keywords: Condominium
Toronto
Marketing
Newspaper
Advisor: Hess, Paul M.
Characterization of Tumour-initiating Cells in Human Colorectal Cancer

It has been hypothesized that tumours are caricatures of normal tissue organization, where a minority cell population, the ‘stem cell’ of cancer, holds the exclusive ability for tumour propagation. These cancer stem cells (CSCs), or tumour-initiating cells, possess extensive self-renewal ability, through which they ensure maintenance of the tumourigenic clone. Such cells have been identified in various cancers, including colorectal, and have been proposed to be the source of tumour re-initiation following therapy. An important and currently unanswered question in solid tumours is whether all CSCs are equal or whether there is a gradient of potency within the CSC compartment. Using primary human colon tumour cells and sensitive in vivo functional assays, we have determined that colon CSCs are not uniform; rather, they vary with respect to their proliferative capacity, which is also linked to their response to chemotherapy. These findings hold therapeutic implications for colorectal cancer treatment since all types of CSCs must be eradicated to remove the risk of tumour relapse. While the CSC model may provide attractive answers to some challenging questions, it remains controversial. Ascertaining the importance of CSCs will come from targeted CSC therapies. Here we demonstrate that human colorectal CSC function is dependent on the self-renewal regulator BMI-1. Down-regulation of BMI-1 inhibits the ability of colorectal tumour-initiating cells to self-renew resulting in the abrogation of their tumourigenic potential. Treatment of primary colorectal cancer xenografts with small molecule BMI-1 inhibitors resulted in colorectal tumour-initiating cell loss with long-term and irreversible impairment of tumour growth. Targeting the BMI-1 related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer. Collectively, we have advanced the CSC field in two areas of importance. We show for the first time that the CSC pool encompasses a gradient of proliferative potential linked to chemotherapeutic response. Second, we provide critical proof for the clinical relevance of CSCs by inhibiting tumour growth through targeting of the self-renewal machinery. This body of work significantly advances our understanding of colorectal tumour-initiating cells.

Keywords: colorectal cancer
stem cell biology
Advisor: Dick, John E.
Epigenetic Silencing of Novel Tumour Suppressor Genes in Medulloblastoma

Medulloblastomas (MB) are the most common pediatric nervous system malignancy. Known mutations account for only a subset of MB cases. We hypothesized that CpG island methylation-mediated tumour suppressor gene (TSG) silencing contributes to MB pathogenesis, either alone, or in combination with genetic events such as loss of heterozygosity (LOH). We performed a microarray-based genome-wide screen of MB cell lines treated with 5-aza-2’deoxycytidine, identifying genes exhibiting increased expression following treatment. Using this strategy, we identified inhibitors of WNT signalling (SFRP1, SFRP2, and SFRP3) and an inhibitor of the HGF/MET signalling pathway (SPINT2) as putative TSGs silenced by promoter region methylation in MB. Methylation of the WNT signalling inhibitors SFRP1, SFRP2, and SFRP3 was identified using bisulfite sequencing and methylation-specific PCR (MSP). Stable re-expression of SFRP1, SFRP2, and SFRP3 reduced proliferation, impaired anchorage-independent growth, and limited WNT signalling activity. SFRP1 re-expression reduced tumour growth in vivo in xenograft models. Aberrant WNT signalling plays a role in the pathogenesis of a subset of sporadic human MB, as well as MB in cases of Turcot syndrome with germline mutations of APC. Activating mutations of β-catenin are also implicated in a subset of MB. We have identified for the first time an additional mechanism – loss of normal pathway inhibition by SFRP gene silencing – that contributes to MB pathogenesis. SPINT2 methylation was confirmed with bisulfite sequencing and MSP. Stable re-expression of SPINT2 reduced proliferation, impaired cell migratory ability, and decreased the capacity for anchorage-independent growth. In vivo, re-expression of SPINT2 reduced tumour formation in xenograft models. This study identified for the first time SPINT2 as a putative TSG in human MB, and further implicated aberrant HGF/MET oncogenic signalling in the pathogenesis of this disease. The efficacy of targeting the HGF/MET pathway as a novel therapeutic strategy was tested in vitro using the small molecule MET kinase inhibitor PHA665752. Treatment of MB cell lines with PHA665752 reduced cell proliferation, anchorage-independent growth, migration, and limited downstream signalling via the MAPK and PI3K/AKT pathways.

Keywords: medulloblastoma
epigenetics
Advisor: Rutka, James T.
Geometric Analysis on Solutions of Some Differential Inequalities and within Restricted Classes of Holomorphic Functions

Pars 1 and 2 are devoted to study of solutions of certain differential inequalities. Namely, in Part 1 we show that a germ of an analytic set (real or complex) admits a Gagliardo-Nirenberg type inequality with a certain exponent s>=1. At a regular point s=1, and the inequality becomes classical. As our examples show, s can be strictly greater than 1 even for an isolated singularity. In Part 2 we prove the property of unique continuation for solutions of differential inequality |\Delta u|<=|Vu| for a large class of potentials V. This result can be applied to the problem of absence of positive eigenvalues for self-adjoint Schroedinger operator -\Delta+V defined in the sense of the form sum. The results of Part 2 are joint with Leonid Shartser. In Parts 3 and 4 we derive the basic elements of complex function theory within some subalgebras of holomorphic functions (including extension from submanifolds, corona type theorem, properties of divisors, approximation property). Our key instruments and results are the analogues of Cartan theorems A and B for the `coherent sheaves' on the maximal ideal spaces of these subalgebras, and of Oka-Cartan theorem on coherence of the sheaves of ideals of the corresponding complex analytic subsets. More precisely, in Part 3 we consider the algebras of holomorphic functions on regular coverings of complex manifolds whose restrictions to each fiber belong to a translation-invariant Banach subalgebra of bounded functions endowed with sup-norm. The model examples of such subalgebras are Bohr's holomorphic almost periodic functions on tube domains, and all fibrewise bounded holomorphic functions on regular coverings of complex manifolds. In Part 4 the primary object of study is the subalgebra of bounded holomorphic functions on the unit disk whose moduli can have only boundary discontinuities of the first kind. The results of Parts 3 and 4 are joint with Alexander Brudnyi.

Keywords: Several complex variables
Unique continuation
Advisor: Milman, Pierre