VictorJuiz/thesis huggingface dataset:
Computational Methods of Inferring Context-specific MicroRNA Regulatory Networks

MicroRNA (miRNA) is a class of small endogenous non-coding RNA species, which regulate gene expression post-transcriptionally by forming imperfect basepair with the target sites primarily at the 3 prime untranslated regions of the messenger RNAs. Since the 1993 discovery of the first miRNA let-7 in worms, a vast number of studies have been dedicated to functionally characterizing miRNAs with a special emphasis on their roles in cancer. A single miRNA can potentially target ~400 distinct genes, and there are thousands of distinct endogenous miRNAs in the human genome. Thus, miRNAs are likely involved in virtually all biological processes and pathways including carcinogenesis. However, functionally characterizing miRNAs hinges on the accurate identification of their mRNA targets, which has been a challenging problem due to imperfect base-pairing and condition-specific miRNA regulatory dynamics. In this thesis, I developed several novel computational methods to elucidate the functional implications of miRNAs by inferring their context-specific regulatory roles in human transcriptional programs. Each method is established through an effective and integrative design by exploiting the static sequence-based information pertinent to existing knowledge of miRNA targeting and the dynamic information of miRNA activities using the recently available large data compendia, which interrogate genome-wide expression profiles of miRNAs and/or mRNAs across various cell conditions.

Keywords: Cancer
Gene regulation
Machine Learning
MicroRNA
Network analysis
Probabilistic models
Advisor: Zhang, Zhaolei
Quantum Measurement on a Budget

Quantum computation - the use of quantum systems as bits, or qubits, to perform computation - has been proven to be exponentially faster than what is thought possible with classical computation for several tasks. Quantum computers have the unique ability to store an amount of information that is exponential in the number of constituent particles used to encode that information. This property, which is arguably where quantum computers derive their power, makes it very difficult to characterize quantum systems. In order to fully characterize an unknown quantum state, a series of measurements must be performed on it and the state deduced from the results of those measurements. This process, called quantum tomography, is known to require exponential resources in the number of qubits. Both the number of measurements - the measurement complexity - and the number of times each measurement must be repeated - the sample complexity - present serious challenges when performing tomography. In addition, the measurement apparatus itself, which is usually a quantum system, must be characterized leading to even more experimental complexity. Here, I present three experiments which aim to reduce the experimental complexity of quantum tomography. The first aims to reduce the number of measurements needed to locate the decoherence-free subspaces of a noisy quantum channel. The process of locating these subspaces, which would normally require full process tomography, is performed with quadratically fewer measurement settings. The second experiment aims to characterize both an uncalibrated measurement apparatus and an unknown quantum state at the same time. With a specific model of measurement, it is found that an uncalibrated parameter of the measurement can be directly extracted using a single measurement. In the third experiment, I perform an experiment in which the optimal sample complexity for quantum state tomography is obtained using adaptivity: the ability to change measurement settings part way through an experiment. All three experiments were performed using the polarization degree of freedom of photons generated by spontaneous parametric downconversion. The source of photon pairs and the measurement techniques used are described in detail, along with the theory of quantum distinguishability and its relevance to tomography.

Keywords: Measurement
Advisor: Steinberg, Aephraim M.
Generalized Inverse Optimization with Application to Cancer Therapy

Inverse optimization has recently received a growing amount of attention as a data-driven approach to determining parameter values for an optimization problem. In this thesis, we study new inverse optimization methodologies that generalize the traditional method of solving inverse optimization problems and accommodate data that makes the standard method ill-posed. We apply the proposed methodologies to prostate cancer therapy data and provide novel insights for radiation therapy treatment planning. In the first part of the thesis, we briefly review recent theoretical development of inverse optimization and discuss how this thesis contributes to the literature. In the second part of the thesis, we describe a motivational example in radiation therapy treatment planning and illustrate the problem settings and clinical data. In the third part of the thesis, we develop generalized inverse linear optimization models. We characterize the relationship between the generalized models and the standard model in the literature. By building on the models in general inverse multiobjective optimization problems, we establish a new connection between inverse optimization and existing multiobjective optimization techniques. We show how our methods can be used for determining objective function weights for radiation therapy treatment planning. Next, we present a clinical application of the results from the previous part of the thesis, by proposing a statistical model that relates the objective function weights to a patient's anatomical characteristics. Using the statistical relationship, we propose a prediction model that infers objective function weights from patient anatomy and provide a proof of concept of automated, knowledge-based weight determination for radiation therapy treatment planning. Finally, we extend the theory of the second part of the thesis by developing generalized inverse convex optimization models. In the multiobjective optimization framework, we propose inverse convex optimization models that preserve the preference ordering among different objectives that is encoded by given data, and compare our models to existing inverse optimization models using prostate cancer therapy data. We present a unifying framework that encompasses many of the inverse optimization models in the literature.

Keywords: Cancer therapy
Inverse optimization
Multicriteria optimization
Operations research
Optimization
Radiation therapy treatment planning
Advisor: Chan, Timothy C. Y.
A Search for Supernova Type Ia Progenitors in the Magellanic Clouds

While it is generally agreed that type Ia supernovae are thermonuclear explosions of carbon-oxygen white dwarfs, there is still an ongoing debate whether the explosions originate from two white dwarfs merging (the double degenerate or DD scenario) or a white dwarf accreting material off of a normal star companion (the single degenerate or SD scenario). In addition, observed number of suitable progenitor systems is significantly smaller than what is required to match the observed supernova rate. White dwarfs with high mass transfer rates from their companion objects have been suggested as one type of type Ia supernova progenitor. I performed a survey looking for rapidly accreting white dwarfs (RAWD) in the central core of the SMC. I detect no candidate RAWD. The upper limits from this non-detection are 10 - 14 RAWD in the SMC, assuming they resemble the LMC source LHA 120-N 66 or fainter versions of Wolf-Rayet stars. I conducted a second survey of the SMC to identify new Symbiotic stars -- white dwarfs accreting off of a giant star companion, usually via winds. They are another possible type Ia supernova progenitor. All of the stars identified as candidates in the survey are false positives. We conclude that there are about 12 - 18 bright symbiotic stars in the SMC. Even under optimistic assumptions, this is too few objects to make up for the 25 - 130 missing SD progenitors in the SMC. I also briefly discuss LHA 115-S 18, a peculiar B[e] supergiant in the SMC, which was observed in the symbiotic star survey. S18 is both photometrically and spectroscopically variable. The system likely contains an approximately 12 solar mass B supergiant, along with a hot compact object. The identity of the hot object remains unclear since either a neutron star or a white dwarf could be formed through normal stellar evolutionary processes and are consistent with the observed properties of the hot object.

Keywords: cataclysmic variables
novae
Small Magellanic Cloud
Symbiotic stars
Type Ia Supernovae
White Dwarfs
Advisor: van Kerkwijk, Marten
Sox17 Regulates Dynamic Gene Regulatory Networks to Specify Cell Fates in Pluripotent Stem Cells

The gene regulatory networks (GRNs) driving mammalian extraembryonic endoderm (ExEn) and definitive endoderm (DE) specification are not well understood. To extend our understanding of mammalian endoderm specification, we used high-throughput genomic approaches in combination with in vitro gain of function studies to investigate the regulatory interactions of the endoderm GRN candidate Sox17. In our first study, we overexpressed Sox17 in embryonic stem cells (ESCs), driving cell fate conversion to an ExEn stem (XEN) cell-like state (Sox17-XEN), equivalent to embryo-derived XEN cells. To elucidate the dynamic networks activated by Sox17 during XEN conversion, we overlaid 352 promoter occupancy datasets onto RNA-sequencing (RNA-seq) time-series expression data and identified putative ExEn cell fate regulators. We perturbed the expression of putative ExEn repressor Nr5a2, and confirmed its ability to repress ExEn differentiation in ESCs. Moreover, we predicted and tested the ability of Sox17 to drive XEN cell conversion by activating autoregulatory and feedforward GRN motifs. We found that Sox17 autoregulates its expression by binding its own promoter, and further assembles feedforward loops activating Gata4, Gata6 and Sall4 to drive XEN cell fate. In our second study, we overexpressed Sox17 in epiblast stem cells (EpiSCs), and in contrast to ESCs, induced mesendoderm fate, a precursor of DE. We overlaid Sox17 promoter occupancy data onto RNA-seq time-series data following Sox17 overexpression in ESCs and EpiSCs, and drafted putative Sox17 GRN motifs. In ESCs, Sox17 regulates ExEn genes including Cyp26a1, Lgals2 and Muc13 whereas Sox17 activates primitive streak genes Lhx1, Fgf8 and T in EpiSCs, driving ExEn and mesendoderm fate, respectively. Additionally, we predicted Sox17 GRN motifs conserved in both ExEn and mesendoderm, regulating the expression of pan-endoderm genes including Foxa2, Foxq1, and Spink3. Together these data suggest that Sox17 activates conserved core GRN motifs as well as tissue-specific GRN motifs to drive cell fate.

Keywords: embryonic stem cells
endoderm
extraembryonic
gene regulatory network
Sox17
Advisor: Rossant, Janet
Stanford, William L
"With a Vow to Defend": Indigenous Direct Mobilization in Canada

Since 1969, Indigenous contentious mobilization has become a fixed feature of public life in Canada. Demonstrations, marches, blockades and occupations are important repertoires of action for Indigenous peoples pursuing historical redress, contemporary recognition, and redistribution of lands and resources. Moreover, institutionalized action channeled primarily through Indian Act band councils and associated peak advocacy organizations increasingly faces legitimacy challenges in Indigenous communities. Adopting theory from the comparative study of intergroup conflict, this dissertation explains the emergence of Indigenous contentious mobilization over the past forty years, and explores the dynamics of individual protest actions. I argue that Indigenous mobilization is best explained by models that emphasize norms and value rationality over interests and instrumental rationality. Historical change cannot be explained without reference to the changes to the complex of norms and institutions that govern Indigenous-Settler relations. Micro-level protest action follows a "calculus of right", wherein mobilization swells and declines with the perceived righteousness of contentious action, rather than material cost-benefit analysis.

Keywords: Canadian Politics
Conflict
Indigenous
Mobilization
Advisor: White, Graham
Cholinergic and Anatomical Dissociation of the Engagement and Disengagement of Spatial Attention in Rats

The spatial allocation of attention is a fundamental process that allows us to detect relevant behavioural stimuli, and involves both the engagement and disengagement of attention. The prefrontal (PFC) and posterior parietal (PPC) cortical regions have been identified as central nodes in a network for allocation of spatial attention. Additionally, these regions are modulated by the neurochemical acetylcholine. In this thesis, I investigated the neural underpinnings of engaging and disengaging spatial attention in rats, with a focus on the role of cholinergic input into the neocortex, including the PFC and the PPC. In the first experiment (Chapter 3), local field potentials in both the PFC and PPC, during the 5-choice serial reaction time task (5-CSRTT), were modulated by cholinergic cortical deafferentation. Specifically, successful target detection was associated with increased PFC-PPC coherence in the beta frequency during the preparatory pre-target period and with the increase in the PPC beta power. Both of these neural responses were attenuated after cholinergic deafferentation of the neocortex, which was also accompanied by a performance decrement. However, the 5CSRTT does not allow an independent examination of the attentional engagement and disengagement. Therefore, I created a cross-modal cued target detection (CTD) task to assess both the overt (Chapter 4) and covert (Chapter 5) orienting of attention. There was a decrement in the PPC beta power during the disengagement of attention and an associated attentional impairment in rats with cholinergic cortical deafferentation. Conversely, there was increased PFC beta power in both groups during the successful engagement of attention. Thus, the CTD experiments demonstrated that cholinergic innervation of the PFC was not critical for the engagement of attention, but was critical in the PPC for the attentional disengagement. In sum, I used behavioural, electrophysiological, and pharmacological methods to dissociate the neural underpinnings for the engagement and disengagement of attention.

Keywords: 192 IgG-saporin
Acetylcholine
Attention
Local field potentials
Orienting
Rat
Advisor: De Rosa, Eve
Affective Body Language Detection and Generation for Socially Assistive Robots

For socially assistive robots to be successfully integrated and accepted within society (especially by vulnerable populations such as the elderly), they need to be able to interpret human affective states (emotions, moods and attitudes) in order to respond appropriately during assistive human-robot interactions (HRI). Previous research has indicated that body language is a very important method of communicating affective states during natural human social interaction. This thesis focuses on developing, implementing and evaluating non-contact based autonomous affective body language recognition and classification systems that allow socially assistive robots to estimate a person's affect and respond appropriately during interactions. Both a novel static body language based recognition system and a novel dynamic body language based recognition system have been developed and implemented. The first system classifies body language using a categorical approach based on a person's accessibility (openness and rapport) towards a robot, while the second system uses a dimensional approach based on a person's valence (feeling of unpleasantness or pleasantness) and arousal (level of activity) levels. Both systems are implemented onto the human-like socially assistive robot Brian 2.1 and evaluated during one-on-one socially assistive HRI experiments. The results of experiments with young adults and elderly participants indicate that both systems accurately identify user affect. This thesis further investigates how individuals interact and perceive an affect-aware socially assistive robot, by designing Brian 2.1 to adapt its behaviours based on a user's degree of accessibility towards it throughout social HRI. Experiments indicate that participants were more accessible towards the accessibility-aware robot over a non-accessibility-aware robot, and perceived the former robot to be more socially intelligent. With this in mind, this work lastly investigates the development of an emotionally intelligent robot capable of effectively displaying its own affective body language during such interactions. Uniquely, body language based on movements and postures founded in human behaviour research are integrated onto Brian 2.1 in order for such a robot to be able to respond to a user's affective state using its own set of emotions. The importance of these body language displays are that they are designed and tested to be easily recognizable by non-expert users. A number of social HRI studies are conducted in this work and lay a foundational framework for developing socially assistive robots that can recognize and react to human affect while providing needed assistance.

Keywords: affect classification
affective body language
automated body language recognition
human-robot interaction
socially assistive robots
Advisor: Nejat, Goldie
Performance Analysis and Optimization of Wireless Heterogeneous Networks

Heterogeneity is becoming a key characteristic of future generations of wireless cellular networks. By deploying different low-power access points in addition to the traditional macro base-stations (BSs), various types of heterogeneous networks (HetNets) can be formed to improve the coverage and transmission rate. Through developing efficient algorithms, analyzing performance and optimizing systems design parameters, this thesis studies three representative HetNet architectures, namely shared relays, multi-tier HetNets, and distributed antenna systems (DAS). Relays utilize an in-band backhaul and have low deployment cost. The first part of the thesis studies a sectorized cellular system with relays and, in particular, focuses on a novel architecture in which each relay is shared by M adjacent cells. We develop a joint user scheduling, resource allocation and beamforming algorithm for shared relaying to maximize the proportionally fair utility, taking into account practical in-band backhaul constraints. The benefit of shared relaying in terms of rate and utility is shown in a system-level simulation. The use of shared wireless medium for the backhaul of relays induces half-duplex loss in relay system, which fundamentally limits the performance gain. Motivated by this fact, the second part of this thesis studies multi-tier HetNets with dedicated wired backhaul. Considering random deployment of BSs, we derive the closed-form mean proportionally fair utility of multi-tier HetNets in both downlink and uplink. The optimal user association and spectrum allocation schemes are obtained by optimizing this utility, and are validated with simulations. In a multi-tier HetNet, BSs typically transmit independently. The third part of the thesis studies a DAS in which distributed antennas are connected via wired backhaul to the central controller and can cooperatively transmit to users. This thesis analyzes the downlink spectral efficiency of DAS where antennas are randomly deployed. We show that for a regular DAS with fixed cell boundaries, selective transmission outperforms blanket transmission in most cases, and the cell-edge spectral efficiency under blanked transmission is upper bounded by a constant. Accounting for random user distribution, the user-centric DAS layout, where no explicit cell boundaries exist, is also analyzed, which is shown to outperform the regular DAS from a network perspective.

Advisor: Yu, Wei
On Philosophical Problems in the Foundations of Chaos Theory

This dissertation examines several philosophical issues in the foundations of chaos theory and fractal geometry. In Chapter 1, I argue that our epistemological and ontological investigations would be better served by looking at the particular successes and failures of individual chaotic models, rather than focussing on broad questions of approximate truth. The rest of the dissertation can then be seen as a set of attempts to put this program into practice. In Chapter 2 I consider the prospects for instrumental fractal models of non-fractal physical objects. Although philosophers have contended that such models must always be inferior to non-fractal models, I argue that in some cases fractal models can be vastly epistemologically superior to their non-fractal rivals. In Chapter 3 I take up questions of ontology, and consider the prospects for the existence of fractals in physical space. Although philosophers have argued that physical fractals are an impossibility, I argue that classical mechanics and chaotic models could entail the existence of interesting fractal regions of space. In Chapter 4 I consider two definitions of observational equivalence for chaotic models, and ague that they fail to meet acceptability criteria.

Keywords: chaos theory
epistemology
fractals
observational equivalence
philosophy of physics
scientific realism
Advisor: Berkovitz, Joseph
When Least Expected: Stories of Love, Commitment, Loss and Survival - The Experience and Coping Strategies of Spouses of People with an Early-onset Dementia

Abstract Understanding the needs of families and in particular spouses of people with early-onset dementia (e.g., those who develop a dementia under the age of 65), has become increasingly recognized as an area of importance by the healthcare community because of the negative biopsychosocial consequences to patients and families. However, there is a dearth of research about the experiences of younger spousal caregivers. The goal of this qualitative, grounded theory study was to understand the experiences of spouses of people who have frontotemporal dementia and early-onset Alzheimer's disease, throughout the disease trajectory. I conducted semi-structured interviews with 30 participants; 17 had partners with frontotemporal dementia and 13 had partners with early-onset Alzheimer's disease. Spouses were recruited with the intention of capturing various stages of the caregiving career. The participants ranged all the way from spouses of people who were newly diagnosed, to individuals who had already been placed in long term care. Three themes emerged from the data analyses initially: (1) issues related to life-stage, (2) disease invisibility and (3) living with continuous uncertainty. These themes led to a fourth theme of caregivers feeling like they were falling through the cracks of the healthcare and social support systems since there are no appropriate services/policies set up for younger people affected by dementia. Finally, a core theme of surviving chronic crises emerged as spouses described how they coped with the continuous challenges related to their partner's dementia. Spouses live through series of crises that they need to constantly manage, leading to a feeling that they are barely surviving. The most common coping strategies that spouses employed through the illness trajectory included: advocacy, reframing, self-care and spirituality. Over the caregiving trajectory, spouses adapted to the impact of having a partner with early-onset dementia. The applicability of the findings is that they point to the timing, to the types of clinical interventions and to policy initiatives.

Keywords: caregiving
dementia care
early-onset dementia
frontotemporal dementia
grounded theory
spouses
Advisor: McDonald, Lynn