VictorJuiz/thesis huggingface dataset:
Characterizing nonlinear properties of complex signals across time

Many real world systems consist of multiple parts and processes that nonlinearly interact with each other at different time scales. Data generated by such systems often contain self-similar structures with proportional scaling of statistical properties across time-scales. It is well known that such structural richness is not captured by conventional statistics like the mean and variance. Development of methods of nonlinear dynamics that quantify complexity, self-similarity, and scaling properties of empirical signals have had a profound impact on our understanding of systems in various scientific domains. In particular, our understanding of physiological systems has undergone a paradigm shift from homeostasis to notions of operation far from equilibrium in physiological regulatory networks. A commonly used methodology for quantifying the scaling relationships is fractal analysis, which estimates the power law exponent, H of time-series fluctuations versus time scales. However, many real world time series are determined by a multitude of exponents which has led to development of multifractal analysis methods. The cornerstone of multifractal analysis has traditionally been the multifractal spectrum which is akin to a probability density of all scaling exponents in the signal. Multifractal spectra are useful for comparing the distributions of exponents in signals. However, a multifractal spectrum does not provide any information about the temporal evolution of scaling structures and therefore, it is less useful in studying dynamic scaling structures. I introduce a set of tools for investigation of scaling structures across time. In particular, I propose scaling maps as a tool that augments the multifractal spectrum with temporal information and then develop a methodology for partitioning of a time series into segments of homogeneous scaling structures. In an attempt to quantify the differences in time local scaling properties of groups of time series, I then introduce Holder histograms as a better representation of time-localized scaling properties scaling structures and propose a feature extraction methodology and statistical tests that lend themselves to quantified comparison of multiple groups of time series in terms of determining their scaling regimes and their temporal dynamics. I then empirically demonstrate the application of the developed methodology on a set of simulated and real world datasets. Result show the ability of the method in recovering scaling modes of complex signals and the quantified discriminative capability of local temporal scaling structures.

Keywords: Detrended fluctuations analysis
Holder exponent
Multifractal analysis
multifractal spectrum
Multiscale entropy
Advisor: Chau, Tom
Kushki, Azadeh
Essays in Labour Economics

This thesis uses novel data sets to examine the process of human capital accumulation at different points in the life cycle. Chapter 1 decomposes total childhood exposure effects – the causal effect of growing up in a better area – into separate school and neighborhood components. To do so, it brings together two research designs. First, I implement a spatial regression-discontinuity design based on institutional rules that assign different default schools to students of different linguistic backgrounds to estimate school effects. Second, I study students who move across neighborhoods in Montreal during childhood to estimate total exposure effects by exploiting variation in the timing of moves. I focus on measures of long-term educational attainment outcomes such as university enrollment. I find that total exposure effects are large, and that between 50 and 70% of the long-term benefits of moving to a better area are actually due to access to better schools rather than to the neighborhoods themselves. In chapter 2, joint with Graham Beattie and Philip Oreopoulos, we introduce a novel method for collecting a comprehensive set of non-academic characteristics to explore which measures best predict the wide variance in first-year college performance unaccounted for by past grades. Students whose first-year college average is far below expectations (divers) have a high propensity for procrastination and are considerably less conscientious than their peers. Divers are more likely to express superficial goals, hoping to 'get rich' quickly. In contrast, students who exceed expectations (thrivers) express more philanthropic goals, are purpose-driven, and are willing to study more hours per week to obtain the higher GPA they expect. Chapter 3 estimates the effect of linguistic enclaves on language skills. Using rich longitudinal data, I find that enclave size significantly impedes language acquisition, albeit the effect is smaller than cross-sectional models suggest. An unusually rich set of variables is used to generate bounds on the effect of enclaves and a complementary instrumental variable approach confirms the robustness of the results. Enclaves are unrelated to formal language course take-up rates, indicating that they affect language learning via social interactions among friends and colleagues rather than through formal education.

Keywords: economics of education
immigration
language skills
neighborhood effects
post-secondary education
school quality
Advisor: Oreopoulos, Philip
Structural and mechanistic characterization of the core mammalian Hippo tumor suppressor pathway

The Hippo Tumor Suppressor Pathway regulates eukaryotic cell growth by sensing and integrating diverse signals of cell contact, cell shape, cell density, and tissue organization. The canonical core of the Hippo pathway consists of a kinase cascade, in which upstream MST1/2 kinases phosphorylate and activate downstream LATS1/2 kinases. Activated LATS1/2 then phosphorylate and inhibit transcription coactivators, YAP and TAZ, thus silencing growth, proliferation, and anti-apoptosis. Dysregulation of the Hippo pathway leads to tissue overgrowth, tumors, and cancers. In my Ph.D., I focused on investigating the molecular basis of how the core Hippo pathway is regulated. One of the major questions that I have addressed in this thesis is the molecular mechanism of how MOB1 protein coordinates the interactions between the upstream MST1/2 kinases and the downstream LATS1/2 kinases. A second theme that I have investigated is the structural basis for the auto-inhibitory mechanism in NDR1, a paralog of LATS1/2. To accomplish these aims, I employed a combination of biochemistry, biophysics, proteomics, and structural biology approaches. In the first chapter, I systematically examine the phosphorylation dependent interactions between MST1/2 kinases and MOB1, and determine the phosphopeptide binding specificity of MOB1. I demonstrate that autophosphorylation of MST1/2 kinase provides multiple MOB1 binding sites, which in turn contributes to a redundancy of MST1/2-MOB1 interactions in cells. In the second chapter, I quantitatively assess how phosphorylation of MOB1 regulates its interactions with both the upstream MST1/2 kinases and the downstream LATS/NDR family kinases in vitro. Using interaction proteomics, I validate the significance of the in vitro studies and also discover that the MOB1 phosphorylation dependent recruitment of phosphatase PP6 and Rho guanine exchange factors (DOCK6-8) differ in key respects from that elucidated for MST1/2 kinases. In the third chapter, I describe the crystal structure of NDR1 kinase domain (paralog of LATS1/2), revealing its auto-inhibitory atypically long activation segment. I present a novel NDR1 activation mechanism, in which MOB1 binding and mutagenesis by disrupting the auto-inhibition operate independently yet additively to relieve NDR1 auto-inhibition. Together, the results of these studies illustrate and support a sophisticated communication network in the core Hippo pathway mediated by MOB1.

Keywords: biochemistry
biophysics
cancer biology
Hippo pathway
signal transduction
structural biology
Advisor: Sicheri, Frank
Molecularly Linked Gold Nanoparticle Films As a Platform for Studying the Influence of Strong Coulomb Interactions on Charge Transport through a Metal-Insulator Transition

Low temperature charge transport properties of butanedithiol-linked gold nanoparticles films are investigated and the importance of strong Coulomb effects through percolation metal-insulator transition is studied. Butanedithiol-linked gold nanoparticle films are tuned through the metal-insulator transition through film thickness and signatures of strong Coulomb effects are observed throughout the transition. In particular, 1) films in the thin limit are observed to be insulators (conductance, g, goes to zero as temperature, T, goes to zero), and conductance follows g = Aexp[(-To/T) 1/2] at low T, where A and To are temperature-independent variables. This behaviour is predicted by the Efros-Shklovskii Variable Range Hopping model, and comes from the optimization of electron tunnelling process (favouring short distances) and on-site Coulomb charging barrier of the metal clusters (favouring long distances). Additionally, 2) films in the thick limit behave as metals ( g goes to non-zero as T goes to zero), and g = go + βT 1/2 at low T, where go is conductance due to inelastic scattering and β is a constant. A T1/2 term is predicted by a correction of the conventional Fermi Liquid Theory by Altshuler and Aronov, in which electron-electron interactions are enhanced by disorder. And finally, 3) films at intermediate thickness, near the metal-insulator transition and just barely beyond the metallic regime, exhibit a zero-bias conductance peak. This phase is reminiscent of an exotic metallic phase seen in transition metal compounds near the metal-insulator transition, and is predicted by the Hubbard model near the metal-insulator transition in which Coulomb charging and charge delocalization effects are important, resulting in strong electron correlations. In this regime in which electron correlations are strong, transition metal compounds are known to exhibit many exotic behaviours (such as high Tc superconductivity in cuprates, and colossal magnetoresistance in manganites); molecularly linked nanoparticle films provide a new platform to understand such important strong electron correlation phenomena.

Keywords: Charge Transport
Chemical Physics
Coulomb Interactions
Metal-Insulator Transition
Nanomaterials
Strong Electron Correlation
Advisor: Dhirani, Al-Amin
The effects of environmental and physical stress on energy expenditure, energy intake, and appetite

Body weight loss occurs frequently in military personnel engaged in field operations. When this weight loss is rapid, or extensive it is associated with health and performance decrements. While the nature of military work does not allow for energy expenditure (EE) to be freely altered, energy intake (EI) can be increased to match EE and prevent weight loss. Therefore a primary objective of the current dissertation was to develop a physiological and empirical basis to facilitate informed estimates of the EI that would be required to offset the EE demand of military tasks during field operations. Three different approaches were undertaken: 1) The energy costs of 46 infantry tasks were measured; the results should reduce the dependency on less accurate predictions. 2) The impact of ambient temperature on EE of the tasks was minimal (~3%) when the ambient temperature was between -10°C and 30°C. This indicates that caloric supplementation of field rations on account of temperature is likely unnecessary during short-term operations occurring within this temperature range; and, lastly 3) A simple algorithm based on accelerometry and heart rate was developed to assess EE in the field. The application of this algorithm should improve EE/EI matching. Unfortunately military personnel engaged in arduous field operations usually experience an energy deficit, even when food availability is adequate. Voluntary anorexia can ultimately thwart nutrition optimization in the field, therefore the role of appetite was also explored. While hormonal responses pointed towards appetite suppression with increased physical activity levels (with a partial blunting of that response in the cold) and subjective appetite was the lowest in the heat and highest in the cold, actual EI was unchanged regardless of ambient temperature or whether the participant was sedentary or active. This research demonstrated that even in the most favourable scenarios military personnel engaged in typical infantry tasks may under eat and plunge into a negative energy balance. These results suggest that factors other than food availability and palatability, such as policy or procedural changes should be considered in addressing voluntary anorexia in the field in military personnel.

Keywords: Accelerometry
Ambient Temperature
Appetite Hormones
Energy Expenditure
Energy Intake
Military Activities
Advisor: Jacobs, Ira
The Role of Cell Mechanics in Embryonic Wound Repair: Staggered Contraction at the Leading Edge

Epithelia are physical barriers against pathogens. Therefore, the ability of multicellular organisms to self-repair epithelial wounds is critical for survival. In embryos, wound repair is mediated by the assembly of a contractile supracellular cable at the wound margin composed of filamentous actin and the molecular motor non-muscle myosin II. It has been proposed that the contraction of the actomyosin cable acts as a "purse-string" to coordinate the movement of cells into the damaged area. Here, I analyze the physical basis of the "purse string" in Drosophila embryos. Using quantitative image analysis I found that, opposing the idea of a uniform "purse string", the distribution of cytoskeletal molecules at the wound margin is heterogeneous with areas of high and low protein density. Furthermore, I showed that mutants for the non-receptor tyrosine kinase Abelson (Abl) display a homogeneous distribution of actin at the wound margin that results in slow wound repair. To investigate the role of actomyosin heterogeneity in wound healing I used biophysical tools to quantify that forces around wounds are also heterogeneous, and patches of the wound edge with heterogeneous actomyosin levels contract faster than homogeneous patches. I developed a mathematical model of wound repair that predicted that actomyosin heterogeneity benefits wound closure if myosin dynamics are directed by tension and strain. To test this idea in vivo, I inhibited stretch-activated ion channels during wound closure, which resulted in disrupted myosin dynamics and impaired tissue repair. Together these results suggest that, instead of a "purse-string", staggered contractility regulates myosin dynamics to coordinate cell movements and to drive fast wound healing.

Keywords: Cell mechanics
Computer Modelling
Cytoskeleton
Epithelial morphogenesis
Quantitative Image Analysis
Wound healing
Advisor: Fernandez-Gonzalez, Rodrigo
Fetal Magnetic Resonance Oximetry

Fetal magnetic resonance oximetry has the potential to improve upon current, ultrasound-based methods for the diagnosis of fetal hypoxia. Unlike ultrasound, which detects hypoxia by measurement of adaptive blood fow changes, MRI is directly sensitive to blood oxygen content. This phenomenon is exploited in a variety of MRI techniques, which are well established for postnatal imaging, such as Blood Oxygenation Level Dependent (BOLD) MRI and vascular relaxometry/susceptometry. The objective of this thesis is to improve the accuracy of these techniques for fetal oximetry applications. Correct estimation of blood oxygen content from relaxometry/susceptibility data requires an accurate biophysical model and calibration, which provide the relationship between MRI properties (i.e. T1, T2, and susceptibility) and blood properties (hematocrit, Hct, and oxygen saturation, sO2). While such relationships are established for adult blood, data on fetal blood properties is sparse. Fetal blood differs from adult blood in several respects, most notably in the structure of hemoglobin, the oxygen transport protein. Chapters 2 and 3 therefore provide a comprehensive characterization of the MRI properties of fetal blood at 1.5T and 3T eld strengths. A potential source of error in fetal oximetry comes from uncertainty in the fetal hematocrit. Postnatal oximetry protocols typically estimate sO2 only, and either assume a normal population value for the hematocrit, or measure it by routine blood sampling. Measuring fetal Hct is challenging, requiring risky and invasive blood sampling procedures. To address this problem, Chapter 4 describes a novel approach, which uses vessel T1 and T2 measurements to jointly estimate Hct and sO2. While Chapters 2-4 focus on correct estimation of blood properties from MRI derived biophysical parameters, Chapter 5 examines the accuracy of the MRI measurements themselves. Along with a description of current techniques, Chapter 5 investigates the robustness of fetal vessel T1/T2 measurements in the face of pulsatile flow and absence of a fetal ECG signal with which to synchronize the acquisition. Finally, Chapter 6 discusses the future of fetal magnetic resonance oximetry. This includes exploring strategies to improve the robustness of current measurements and investigating the potential role for BOLD MRI in the assessment of fetal hypoxia.

Keywords: blood
fetal
hypoxia
magnetic resonance imaging
oximetry
Advisor: Sled, John G.
Macgowan, Christopher K.
Automatic Cellularity Assessment in Surgical Specimens After Neoadjuvant Therapy of Breast Cancer

The goal of this research is to develop methodologies to automatically assess residual tumor cellularity in surgical specimens after neoadjuvant chemotherapy for breast cancer. At present pathological examination of the tissue sections after surgery is the gold-standard to estimate the residual tumor. Currently, tumor cellularity is manually estimated by pathologists from hematoxylin and eosin stained slides. The quality, and reliability of estimates might be impaired by inter-observer variability. For the past decade, pathology labs have been transforming their work flow by converting their physical tissue specimen into digital format enabling sample images to be archived, stored, and processed digitally. Furthermore, efficient computer algorithms can be employed to make the most of the embedded information in digital tissue slides and to detect important knowledge from within them. In this thesis, image analysis and machine learning techniques have been used to identify regions that contain clinically relevant information and to automatically estimate residual cancer cellularity from within regions of interest and whole slide images of breast cancer specimen. Methods developed in this thesis have been applied on actual complete patient cases and have been compared with other state-of-the-art techniques. In particular, for assessing cellularity of residual tumor, intra-class agreement coefficients of 0.74 (95% CI of [0.70, 0.77]) and 0.75 (95% CI of [0.71, 0.79]) were found between pathologists and the automated method respectively, while the agreement coefficient between the participating pathologists was found to be 0.89 (95% CI of [0.70, 0.95])

Keywords: Breast Cancer
Image Processing
Machine Learning
Neoadjuvant Therapy
Residual Cancer Burden
Advisor: Martel, Anne L
White Therapists’ Enactments And Mitigations Of Cultural Countertransference Responses In The Cross-Racial Dyad: An Interpretative Phenomenological Analysis

As cities across North America become increasingly racially diverse, the need for mental health professionals to purvey culturally sensitive and effective treatment is critical. White therapists, in particular, working in cross-racial dyads may encounter unique challenges to meet this need. Indeed, among other things, psychological vulnerabilities and racial biases of self and other underlying cultural countertransference enactments may interfere with White therapists’ abilities to provide effective treatment to racialized individuals. This study focuses on exploring White therapists’ lived experiences enacting and/or mitigating the infusion of cultural countertransference responses within the cross-racial dyad. In addition, this study seeks to understand how participants make sense of and contextualize the emergence of these countertransference processes including the manner by which race intersects and interacts with gender – and other sociocultural identities – to influence therapists’ deportment in the cross-racial dyad. Participants were 10 self-identified White therapists living and working in Canada with significant experience helping racialized individuals. Interpretative phenomenological analysis was the methodological approach deemed most suitable to investigate this subject. The findings suggest that cultural countertransference enactments were common among White therapists while working in cross-racial dyads, many of which were identified by the presence of anxiety and/or avoidance strategies. Many participants also reported instances in which they were ostensibly able to counter the tendency to enact cultural countertransference responses. Instead, at times, they reported approaching the treatment process more deliberately and with enhanced awareness such that unintended infusions of potentially harmful dynamics were mitigated. Participants pointed to intersections of gender with race as well as various familial, social, and educational factors that they believed contextualized the emergence/mitigation of these enactments. Unique contributions of this work as well as study limitations, implications, and recommendations for future research are discussed.

Advisor: Moodley, Roy
Priming Human Mesenchymal Stromal Cells to Enhance their Regenerative Potential

MSCs show promise for cell therapy due to their immune-suppressive and regenerative properties. Consequently, MSCs have been widely used in an increasing number of clinical trials to treat a variety of pathological conditions including cardiovascular diseases and disorders with dysregulated immune function. The outcome of prospective MSC therapy trials however, has shown marginal benefit warranting further investigation to develop strategies to enhance their therapeutic potential. The latter requires better understanding of the mechanisms by which MSCs exert their effects, and studying MSCs under conditions resembling the in vivo microenvironment will help to develop such understanding. The focus of this thesis is to explore the effect of a collagen-based matrix (successfully used in bioengineering approaches for tissue regeneration including for cardiac repair) and Toll-like receptor (TLR) stimulation (providing an in vitro model of an inflammatory environment and widely used for priming MSCs in vitro) on the regenerative properties of MSCs. The first aim of this study (discussed in Chapter 3) involves a comparative analysis of the regenerative properties of MSCs cultivated as a monolayer or on collagen scaffolds, or activated with TLR3 or TL4 agonists. I found that MSCs developed a more cardioprotective phenotype on scaffolds, although no functional changes were detectable when analyzing MSCs in a bioengineered model of heart tissue. The findings of this chapter provide a mechanistic explanation for the potential contribution of MSCs primed with cardiomyogenic cues or TLR agonists. In the second aim (discussed in Chapter 4), signaling through TLR3 was dissected and the effects on MSC phenotype were investigated. The knowledge created in this aim provide some insight into the dynamics of TLR3 signaling, which can be further used to develop preconditioning strategies. In Aim 3 (discussed in Chapter 5), the effects of TLR3 and TLR4 activation on immunomodulatory function of MSCs were further explored. I discovered that activation of either TLR3 or TLR4 enhanced the capacity of MSCs to generate regulatory T lymphocytes. The findings in this aim are applicable to a variety of settings, including tissue regeneration, organ transplantation and autoimmune disorders in which boosting immune suppression can prevent disease development and/or progression.

Keywords: 3D
Cardiac
Mesenchymal Stromal Cells
MSC
TLR
Treg
Advisor: Keating, Armand
Radisic, Milica