VictorJuiz/thesis huggingface dataset:
Digital Signal Processing for the Canadian Hydrogen Intensity Mapping Experiment

This thesis presents the design, development, operation, and performance of digital signal processing systems for the Canadian Hydrogen Intensity Mapping Experiment (CHIME) and its Pathfinder. CHIME is designed to investigate the behaviour of Dark Energy in order to constrain its physical mechanism; it will do so by examining the geometry of the recent universe using as a `standard ruler' the imprint of the Baryon Acoustic Oscillation (BAO) feature in the 21 cm emission of neutral Hydrogen. In order to construct the complete set of visibilities for CHIME's 2048 inputs and 400\,MHz of bandwidth, the FX correlator's X-Engine must be capable of ingesting 6 Tib/s of data and completing 8.4×1014 complex multiply-and-accumulate operations per second; these requirements make CHIME's X-Engine by far the largest currently in operation. Using mass-produced Graphics Processing Units (GPUs), commercial off-the-shelf computer hardware, and a sealed-loop liquid-cooling system, the CHIME correlator X-Engine achieves high performance and exceptional efficiency. This thesis presents a detailed description of the X-Engine hardware design and a thorough evaluation of its performance, with additional commentary on aspects of the design and deployment which may warrant additional consideration by those planning similar systems. The substantial computational power available in the correlator system provided an opportunity for pre-integration excision of transient Radio-Frequency Interference (RFI). A number of RFI mitigation techniques were examined, including Median Absolute Deviation and Spectral Kurtosis measures; the latter was implemented on CHIME and the Pathfinder, and results from tests of the RFI detection system are presented. The CHIME Pathfinder, in addition to acting as a test-bed for hardware and analysis techniques, produced an archive of visibility data spanning three years; from this, maps were produced covering the entire northern sky for 609 sidereal days. This thesis details the data processing pipeline which was employed to generate these maps as well as analysis of the resulting data products with regards to their overall variability and the properties of known point-like sources.

Keywords: CHIME
Correlators
Radio Astronomy
Radio Instrumentation
RFI Mitigation
Advisor: Vanderlinde, Keith
Within-Host Fine-Scale Evolutionary Dynamics of Infectious Bacterial Populations

Bacteria have a remarkable ability to adapt to numerous challenges in their environment and this evolutionary potential of bacterial pathogens has dire negative impact on human health. Understanding the fine-scale evolutionary dynamics of bacterial populations over the course of infections will help improve therapeutic strategies. In cystic fibrosis (CF) patients, lung infections caused by opportunistic pathogens such as Pseudomonas aeruginosa, Burkholderia multivorans, and Burkholderia dolosa are associated with high rates of mortality. In this thesis, I present a high-resolution view of the evolutionary dynamics of these three individual bacterial populations longitudinally sampled from CF patients. First, I analyzed the genomes of 233 P. aeruginosa isolates collected over the course of one year. This work revealed the expansion of two sub-lineages. I identified various mutations in these sub-lineages occurring in loci previously known to be associated with virulence and antibiotic resistance. Next, I investigated 111 B. multivorans isolates collected from a CF patient over the course of an early incident, chronic infection spanning one year, and after lung-transplantation. I employed a genome wide association study approach to find genetic variants associated with resistance to three antibiotic families. I observed that variants associated with resistance to β-lactam antibiotics were overrepresented in recombinogenic regions. Lastly, I examined whether the fine-scale evolutionary dynamics of B. dolosa, the most abundant bacteria in the lungs of the studied patient, was associated with shifts in the host’s clinical status from clinical stability to pulmonary exacerbation. Preliminary results do not suggest a correlation between the evolution of B. dolosa with the onset of a pulmonary exacerbation. Throughout these studies, I found unprecedented depth of genotypic diversity as these CF pathogens evolve in short time scales and strong signals of parallel evolution. Overall, this thesis reveals the power of deep, longitudinal sampling and the importance of using high-resolution approaches to study within-host evolution of bacterial pathogens as they undergo rapid, extensive changes that lower-resolution studies would not capture. This work provides an in-depth view of patient specific bacterial population dynamics, which is a step towards developing therapeutic strategies in which treatment may be tailored specifically to each CF patient.

Advisor: Guttman, David S
Persistent Hypermetabolism after Severe Burn Injury: Effects of Hepatic Stress and Regeneration

Burn injury represents one of the most severe forms of trauma. Persistent hypermetabolism and inflammatory response are common in major burned patients, contributing to morbidity and mortality. The underlying mechanisms are largely unknown and therefore novel and effective treatments are lacking. Liver is the fundamental mediator of post-burn immunologic and metabolic derangement and significant hepatomegaly is universally present and associated with the persistent hypermetabolism and inflammatory response in severely burned patients. We sought to understand if such a hepatomegaly is the consequence of 1) increased hepatic fat infiltration due to intensified lipolysis in white adipose tissue (WAT) and inter-organ cross-talk between liver and WAT, or 2)aberrant liver regeneration induced by stress response and liver damage which carries on hypermetabolic and pro-inflammatory signaling, contributing to persistent hypermetabolism and inflammatory response after major burn injury. Rodent models of burn plus LPS administration, high fat diet (HFD) plus burn, and 30% TBSA burn of Sox9-cre/ERT2:ROSA26-EYFP mice were used for the studies. In the rat model of burn plus LPS, we demonstrated 1) increased ER stress, inflammasome activation, apoptosis and lipolysis in WAT,contributing to liver steatosis (Chapter 2);2) hepatic ER stress and inflammasome activation, contributing to liver damage and organ dysfunction(Chapter 3). In the mouse model of HFD plus burn, we showed that hepatic fat infiltration and meta-flammation augment the liver damage and metabolic dysfunction post-burn(Chapter 4). We lineage-traced the facultative liver progenitor cells after burn injury and demonstrated that liver regeneration by this group of cells peaked around 2 weeks post-burn. Significant activation of multiple inflammatory and metabolic signaling pathways was indicated by transcriptomic analysis and verified by further analysis in the liver stem cells and their progeny post-burn as compared with both sham and self-renewal mature hepatocytes. Concomitant down-regulation of LXR signaling in the liver stem cells post-burn implicated the therapeutic potential of LXR agonist in ameliorating pro-inflammatory response and restoring lipid homeostasis after major burn injury (Chapter 5). In conclusion, severe burn injury leads to hepatic stress response, liver damage and steatosis, stimulating liver regeneration from facultative stem cells which contributes to persistent hypermetabolism and pro-inflammatory response.

Keywords: ER stress
liver
metabolism
mitochondria
stem cell
unfolded protein response
Advisor: Jeschke, Marc G
Localization of Heat Shock Proteins HSPA6 (Hsp70B′), HSPA1A (Hsp70-1) and HSPA8 (Hsc70) in Cultured Human Neuronal Cells

Heat shock proteins (Hsps) are protein repair agents that detect and refold misfolded proteins and prevent their aggregation. Accumulation of protein aggregates is a key feature of neurodegenerative diseases. Treatments that showed beneficial effects in current animal models of neurodegenerative diseases have repeatedly failed in human clinical trials. A better understanding of the proteostasis machinery in human cells is required to design more effective therapeutic compounds. HSPA6 (Hsp70B′) is a stress-inducible member of the HSPA (Hsp70) multigene family that is absent in rat and mouse genomes and has been little studied compared to inducible HSPA1A (Hsp70-1), or constitutively expressed HSPA8 (Hsc70). HSPAs are involved in refolding proteins that misfold due to stress or disease. Binding to DNAJ (Hsp40) inhibits aggregation of misfolded proteins until they can be refolded by HSPA, but this machine cannot dissociate aggregated proteins. Recent studies have identified a disaggregase function performed by the mammalian HSPH (Hsp110) family in co-operation with HSPA/DNAJ in vitro. To advance knowledge of the mammalian disaggregation/refolding machine, this thesis investigates localization of HSPA6, HSPA1A, and HSPA8 with other components of the machine following stress in differentiated human neuronal SH-SY5Y cells. Unique targeting of HSPA6 to nuclear perispeckles and differential localization with disaggregation/refolding machine components at the nucleolus compared to HSPA1A or HSPA8 is observed following thermal stress. siRNA knockdown demonstrates that HSPA6 is protective in the neuronal stress response. MG132 proteotoxicity induces HSPA6 which targets the periphery of cytoplasmic protein aggregates with components of the disaggregation/refolding machine and thus may be involved in the response of differentiated neuronal cells to protein aggregation. Constitutively expressed HSPA8 exhibits similar intracellular targeting as inducible HSPA1A and may act as a rapid stress responder in neuronal cells, circumventing the time lag required to upregulate HSPA1A. In cancer cells, elevated levels of Hsps contribute to their ability to resist cell death. The chemotherapeutic agent cisplatin induces components of the disaggregation/refolding machine. Knockdown of HSPA family members enhances the killing effect of cisplatin on human neuroblastoma cells.

Keywords: Differentiated SH-SY5Y human neuronal cells
Heat shock protein
HSPA1A (Hsp70-1)
HSPA6 (Hsp70B′)
HSPA8 (Hsc70)
Mammalian protein disaggregation/refolding machine
Advisor: Brown, Ian R
Reconstructing the Evolutionary History of Tumours

Tumours are composed of multiple subpopulations, each of which has its own genotype and phenotype. These genotypes are related to each other in an evolutionary tree, where the root of the tree is the germline genome. Subpopulation genotypes are therefore typically characterized in terms of their somatic mutations. These mutations are responsible for the tumour's properties . Finding the genotype of these different subpopulations can help study cancer biology and provide more accurate predictions of patient outcomes. Determining the genotype of these subpopulations from a limited number of sequenced bulk tumour samples is the subclonal reconstruction problem. As the number of subpopulations present is not known, and the subpopulations are related to each other in a tree, using non-parametric, tree-structured clustering algorithms is a natural approach to solve this problem. I present three advances in subclonal reconstruction. In the first I present an algorithm that expands the set of mutations available for subclonal reconstruction by modeling the interaction between two types of mutations, Single Nucleotide Variants (SNVs) and Copy Number Alterations (CNAs). CNAs affect the observed evidence of SNVs in a way that depends on their evolutionary relationship. Thus, to perform subclonal reconstruction on CNA-affected SNVs, the reconstruction must include both types of mutations. I develop the method PhyloWGS and demonstrate accurate subclonal reconstruction in the face of SNV/CNA interactions. The choice of non-parametric prior used affects subclonal inference. Different priors favour different trees and have different technical attributes. I compare the treeCRP prior against the Tree Structured Stick Breaking (TSSB) prior. This is the first use of the treeCRP prior in subclonal reconstruction. I found that the treeCRP had better mixing and lower computational cost compared to the TSSB but generated less accurate subclonal reconstructions. When performing subclonal reconstruction multiple trees can fit the observed data equally well. Incorporating pairwise haplotypes in subclonal reconstruction reduces this ambiguity. These haplotypes are inferred on the basis of reads that span the loci of two mutations. I incorporate pairwise haplotypes in subclonal reconstruction with a new algorithm called PhyloSpan. I demonstrate more accurate subclonal reconstruction with reduced ambiguity using PhyloSpan.

Advisor: Morris, Quaid
Frey, Brendan J
Post-translational Regulatory Mechanisms Acting on KLF4 Mediate Pluripotency Exit in Naïve Mouse Embryonic Stem Cells

Pluripotent embryonic stem (ES) cells have the potential to self-renew and differentiate to generate all adult tissues. Pluripotency is regulated by an interconnected network of transcription factors including OCT4, SOX2, NANOG and KLF4. This transcriptional network is integrated with extracellular signaling pathways regulating pluripotency and differentiation. Mouse ES cells can be maintained in a state known as naïve pluripotency by culture in leukemia inhibitory factor (LIF) and two signaling pathway inhibitors (LIF/2i). A previous study observed that a reduction in Klf4 transcript, due to LIF withdrawal, was the first change in pluripotency gene expression during differentiation. Based on this finding I hypothesized that removal of KLF4 protein from transcriptional network would be required for exit from pluripotency. To investigate this I examined the levels of pluripotency associated transcription factors in the nucleus of ES cells as they exit the pluripotent state. This investigation revealed that a reduction in KLF4 protein levels did not occur immediately following the reduction in Klf4 transcription; instead I identified nuclear export of KLF4 protein was required for the reduction in Klf4 transcription and pluripotency exit. Next, I investigated Klf4 gene and protein regulation and found that LIF/2i maintains Klf4 expression through both transcriptional and post-translational mechanisms. Specifically, KLF4 protein is highly stable in LIF/2i and this stability is maintained by physical interaction with active transcriptional complexes which ensure nuclear anchoring of the KLF4 protein. Surprisingly, KLF4 protein stability is so high (t½ >24 hr) that protein levels change by

Keywords: Early embryogenesis
Embryonic stem cells
KLF4
Nuclear export
Pluripotency exit and differentiation
Post translational regulation
Advisor: Mitchell, Jennifer A
Modeling Invasive Processes at the Tumor-Stroma Interface in Vitro Using Gels for Live Analysis of Compartmentalized Environments (GLAnCE)

Engineered tumor tissues carry promise as tools for making unique biological discoveries, as well as for identifying therapeutic opportunities to tackle cancer. This is because, in a field where 2D tissue culture may be exhausting its potential for further discoveries, 3D tumor tissue grown in vitro represents an intermediate step between these simplistic cultures and the exponentially more complex tissues in vivo. As such, it is necessary for in vitro tumor models to capture sufficient complexity, in order to deliver novel insights that are otherwise unattainable; this means incorporating multiple cell types into tissues with 3D geometries that are recapitulative of specific, disease-relevant, in vivo tissue structures. In this work, the interface between tumor tissue and its surrounding stromal space is generated in vitro, as a site of particular significance for tumor growth. This tumor- stroma interface/edge represents an architecturally unstable site, where cancer cells invade adjacent spaces whilst stromal cells infiltrate the tumor mass; both these processes are associated with increased disease aggressiveness and poor prognosis. We here explore the parameters of this cellular exchange in vitro, which is highly dynamic in terms of spatial heterogeneity and over time. By developing a novel culture platform to visualize and quantify tumor expansion, a spatial stratification is made between the phenotypes, and differentiation states, of cancer cells at the invasive edge versus the bulk of the tumor tissue. Expansion of the stromal tissue compartment in the form of fibroblast infiltration is further assessed by correlating infiltration efficiency to fibroblast differentiation status, a relationship which is then explored by altering the infiltrative phenotype. The work presented here demonstrates how complex in vitro tumor tissues can recapitulate the evolving dynamics of a disease-relevant tissue site, thereby giving access to novel mechanistic insights. It further suggests that the parameters of cellular movement within a tissue space are highly informative and can be leveraged to generate more applicable tumor and tissue models and functional readouts, not only for asking biological questions closer to in vivo physiology, but also to assess the impact of phenotype-altering culture treatments, as a first step towards the identification of compounds with therapeutic benefit.

Keywords: cancer-associated fibroblast
compartmentalized culture
fibroblast activation
in vitro co-culture
tumor invasion
tumor-stroma interface
Advisor: McGuigan, Alison P
Random Sorting Networks, the Directed Landscape, and Random Polynomials

The first part of this thesis concerns random sorting networks. A sorting network is a shortest path from 12···n to n···21 in the Cayley graph of the symmetric group Sn generated by adjacent transpositions. We prove that in a uniform random n-element sorting network σn, all particle trajectories are close to sine curves with high probability. We also find the weak limit of the time-t permutation matrix measures of sign. As a corollary, we show that if Sn is embedded into Rn via the map τ→(τ(1),τ(2),...τ(n)), then with high probability, σn is close to a great circle on a particular (n-2)-dimensional sphere. These results prove conjectures of Angel, Holroyd, Romik, and Vir'ag. To prove these results, we first find a local limit and prove that local speeds follow an arcsine distribution. The second part of this thesis concerns last passage percolation. The conjectured limit of last passage percolation is a scale-invariant, independent, stationary-increment process with respect to metric composition. We prove this for Brownian last passage percolation. We construct the Airy sheet and characterize it in terms of the Airy line ensemble. We also show that last passage geodesics converge to random Hölder-2/3- continuous functions. To prove these results, we develop a new probabilistic framework for understanding the Airy line ensemble. The third part of this thesis concerns random polynomials. Let Gn = ∑ni=0 ξipi, where the ξi are i.i.d. non-degenerate complex random variables, and {pi} is a sequence of orthonormal polynomials with respect to a regular measure τ supported on a compact set K. We show that the zero measure of Gn converges weakly almost surely to the equilibrium measure of K if and only if Elog(1 + |ξ0|) < ∞, and that the zero measure of Gn converges weakly in probability to the equilibrium measure of K if and only if P(|ξ0| > en) = o(n-1). Our methods also work for more general sequences of asymptotically minimal polynomials in Lp(τ), where p ∈ (0, ∞].

Keywords: directed landscape
KPZ universality class
last passage percolation
random polynomials
random sorting networks
Young tableau
Advisor: Virag, Balint
Dynamicity in Speech Perception

Human listeners dynamically adjust their perceptual category boundaries and cue weights following brief exposure to idiosyncratic speech (Norris et al., 2003; Idemaru and Holt, 2011). This dissertation presents five experiments, each exploring a different facet of when and how listeners recalibrate. The first three experiments use the classical perceptual learning paradigm, where listeners are exposed to speech exhibiting an idiosyncratic pattern, such as an atypically high VOT boundary between /t/ and /d/, and then tested on whether they adjusted their boundary according to that training. Experiment 1 used weaker evidence to train listeners on the pattern than previous studies, by using word-initial targets in training. Experiment 2 exposed listeners to a more complex pattern than previous studies, by using a second-order (i.e. context-dependent) idiosyncrasy. In both experiments, listeners succeeded at learning. Experiment 3 tested whether listeners make use of phonological category knowledge in learning these patterns. There was no evidence of learning. However, some methodological weaknesses made it difficult to conclude that listeners could not learn this type of pattern; further work is needed to assess this. The last two experiments looked at cue reweighting -- reliance on different acoustic cues to the same contrast. Experiment 4 tested the effects of noise on cue weighting. It confirmed previous work showing that noise affects cue weighting, and expanded beyond previous work in showing that different types of noise affect cue weighting differently. Noise especially suppressed reliance on cues incongruent in periodicity with the noise type, suggesting listeners may be sensitive to spectral characteristics of background noise in adaptive cue reweighting. Experiment 5 was the first test of unsupervised learning of cue reweighting based on exposure. Listeners were exposed to a contrast varying on along two acoustic dimensions where one was a more reliable cue than the other. The results suggested that listeners learned to reweight perceptual cues based on their exposure, supporting the hypothesis that listeners implicitly learn multi-dimensional statistical distributions in speech. Together, these experiments provide new data and contribute novel methodologies to further our understanding of the dynamic nature of adaptation in human speech perception.

Keywords: implicit learning
phonetics
psycholinguistics
speech perception
Advisor: Schertz, Jessamyn