VictorJuiz/thesis huggingface dataset:
Protein-protein Interaction Network Alignment and Evolution

Network alignment is an emerging analysis method enabled by the rapid large-scale collection of protein-protein interaction data for many different species. As sequence alignment did for gene evolution, network alignment will hopefully provide new insights into network evolution and serve as a new bioinformatic tool for making biological inferences across species. Using new SH3 binding data from Saccharomyces cerevisiae, Caenorhabditis elegans, and Homo sapiens, I construct new interface-interaction networks and devise a new network alignment method for these networks. With appropriate parameterization, this method is highly successful at generating alignments that reflect known protein orthology information and contain high network topology overlap. However, close examination of the optimal parameterization reveals a heavy reliance on protein sequence similarity and fungibility of other data features, including network topology data, an observation that may also pertain to protein-protein interaction network alignment. Closer examination of interactomic data, along with established orthology data, reveals that protein-protein interaction conservation is quite low across multiple species, suggesting that the high network topology overlap achieved by contemporary network aligners is ill-advised if biological relevance of results is desired. Further consideration of gene duplication and protein binding sites reveal additional PPI evolution phenomena further reducing the network topology overlap expected in network alignments, casting doubt on the utility of network alignment metrics solely based on network topology. Instead, I suggest a new framework to think about protein-protein interaction network alignment focused on generating and validating small-scale inferences. I create a prototype alignment visualization and analysis tool to facilitate this approach, which will hopefully aid researchers in learning more about the mechanisms of network evolution and how network alignment can model them.

Keywords: evolution
interactomics
interface-interaction network
network alignment
protein-protein interaction
systems biology
Advisor: Bader, Gary D
Essays on the Peer-to-Peer Lending Business

Peer-to-peer (P2P) lending is a new way of originating loans where borrowers and lenders are directly matched via an online lending platform. From its inception in 2005, P2P platforms have been among the fastest growing segments in the financial services space. Transparency Market Research suggests that the opportunity in the global P2P market will be worth $897.85 billion by the year 2024, up from $26.16 billion in 2015. This work investigates the P2P lending market from both the platforms’ and investors’ perspectives. First, since P2P lending is a relatively new market, the fundamentals of the market keep changing over time. Therefore, treating all historical data equally may lead to a seriously misspecified model for the current market. This problem is referred to as concept drift in statistics and machine learning. Using a rich micro-level dataset from Prosper Marketplace, which is one of the largest online P2P lending platforms in the U.S., we show evidence that borrower and lender behavior is changing over time. Second, by leveraging certain machine learning techniques (naive Bayes classifier, ensemble modeling, and hidden Markov model) and structural modeling, we find evidence that Prosper Marketplace recognizes the concept drift problem when developing their model to assess borrowers’ risk and set interest rates. More specifically, we find that Prosper assigns different weights to data from different economic environments to train its model. In the counterfactual, we demonstrate that we can improve Prosper’s revenue by changing the way Prosper uses data. Third, we show that investors on Prosper Marketplace are more likely to invest in riskier loans during the end-of-week or end-of-month periods. The end-of-period effect is in line with the mental accounting theory. The end of a mental accounting period propels people to feel less connected with their present selves. This feeling of disconnection from their present selves makes people more likely to make riskier decisions since, even if the outcomes from those riskier investments turn out to be negative, they will soon enter a new mental accounting period and can easily blame their imperfect past selves for the wrong decisions.

Advisor: Ching, Andrew
Development and Evaluation of a Novel Instrument to Measure Severity of Intraoperative Events

Background Adverse events occur frequently in the operating rooms (OR) and often lead to morbidity, mortality, and increased healthcare costs. To better understand the nature, patterns, and impact of intraoperative events on patient outcomes, a reliable structured measurement of intraoperative events is essential. Methodology First, we performed a systematic review of published articles to synthesize evidence related to identification and detection of intraoperative events. Second, we performed a prospective cohort study of consecutive patients undergoing elective laparoscopic general surgery procedures to characterize intraoperative events using direct observation method. Third, we developed and evaluated a novel instrument to measure severity of intraoperative events and quality of associated rectification processes. Results In the systematic review, we found that frequencies of reported intraoperative events appeared to vary depending on the detection methods, with higher numbers reported when direct observations took place in the OR. When severity of intraoperative events was measured, most studies stratified it based on the seriousness of post-operative outcomes or the invasiveness of additional interventions required. Corrective processes to rectify intraoperative events were rarely assessed. In the prospective cohort study, we demonstrated that the surgical teams committed events frequently and encountered high amounts of auditory and cognitive distractions. Intraoperative events were classified as bleeding, mechanical, thermal, ischemic events and insufficient closure of anastomosis. We developed and evaluated a novel instrument to measure severity of intraoperative events on directly observed laparoscopic gastrointestinal operations called the SEVerity of intraoperative Events and REctifications (SEVERE). In its present format, the SEVERE index classifies events into five types and provides weighted item scores for severity and rectification of events. There is evidence of acceptable content validity and inter-rater reliability. It has yet to demonstrate evidence of criterion predictive validity. However, evidence of construct validity, specifically linking patient factors and procedure durations to SEVERE scores, exists. Conclusions We developed a novel instrument to measure severity of intraoperative events via direct observation method through a robust development phase and evaluated content and construct validity evidence. Once fully validated, the SEVERE index may prove to be a useful instrument in identifying patients at higher risk of developing post-operative complications.

Advisor: Jüni, Peter
Grantcharov, Teodor
The Application of Natural Abundance Carbon Isotope Ratio Analysis to Study Brain Fatty Acid Metabolism

Over the past two decades, an increasing amount of experimental evidence has linked altered brain n-3 polyunsaturated fatty acid (PUFA) metabolism to neurological and neuropsychiatric diseases. Observational studies have associated low dietary n-3 PUFA consumption with an increased risk of brain disease, implicating a potential role for diet in modulating brain fatty acid metabolism. Unfortunately, many of the currently available methods to investigate the role of diet on brain fatty acid metabolism are limited by their reliance on tracer compounds. The research carried out in this thesis explores the novel application of natural abundance carbon isotope ratio analysis to study brain fatty acid metabolism. Based differences in brain DHA carbon isotope ratios (13C/12C, referred to as δ13C signatures), we differentiated between incorporation of dietary preformed DHA, and that which had been synthesized from the precursor α-linolenic acid, as brain δ13CDHA signatures reflected the dietary source. We then showed that natural abundance carbon isotope ratio analysis can be used to measure brain DHA turnover. When the n-3 PUFA tissue stores of mice were isotopically equilibrated to a background diet and then switched to a diet where n-3 PUFA have a different δ13C signature, the corresponding changes in brain δ13CDHA signatures reflected the turnover of brain DHA. Estimated brain DHA half-lives were found to be consistent with previous estimates based on different methodologies. Lastly, we extended the application of natural abundance carbon isotope ratio analysis to measure the contribution of within brain lipogenesis to brain palmitate levels. Based on δ13C signatures of dietary sugars and palmitate, and the established brain δ13CPAM signature from mice equilibrated to these carbon sources, we estimate that nearly half of the brain palmitate was synthesized within the brain. Collectively, the research conducted in this thesis has generated convincing data to validate the application of natural abundance carbon isotope ratio analysis for the study of brain fatty acid metabolism.

Keywords: carbon isotope ratio analysis
Docosahexaenoic acid
fatty acid metabolism
Isotope ratio mass spectrometry
lipid metabolism
stable isotope
Advisor: Bazinet, Richard P
From DNA Topology to Pubertal Onset: Using Integrative Genomic Approaches to Study Transcriptional Regulation

Studying how cellular transcriptional programs are precisely controlled is essential for understanding development and disease. In this thesis, I first explore an essential aspect of transcriptional control: DNA topology. Topoisomerase II (TOP2) proteins regulate DNA topology by creating transient double-strand breaks. Topoisomerase II beta (TOP2B) facilitates gene transcription and is essential for postnatal development. However, the genome biology of TOP2B remains largely unknown. Through integrative analyses of the genome-wide binding profiles of TOP2B and many other transcriptional regulators, I discover that TOP2B associates with DNase I hypersensitive sites, tissue-specific TF binding, and evolutionarily conserved enhancers in the mouse genome. Particularly, TOP2B coincides with CTCF and cohesin, with a structural ordering at topologically associating domain (TAD) boundaries. I conclude that TOP2B is positioned to solve topological problems at critical cis-regulatory regions and its highly ordered binding is a prevalent feature of CTCF/cohesin sites flanking TAD boundaries. Next, we applied three gene expression profiling methods and integrative bioinformatics approaches to study the expression of genes associated with pubertal onset. Timing of pubertal onset varies in the general population and is associated with diverse later-life health outcomes. Studies of pubertal disorders and genome-wide association studies (GWAS) have identified hundreds of puberty-associated genes. However, their specific functions are not well characterized. To address this problem, I first showed that the expression of these puberty-associated genes is enhanced in multiple neuronal tissues using a human transcriptome dataset. We then used a sensitive qPCR platform to profile the mouse orthologs of these selected genes (n=179) in several mouse tissues during postnatal development in both sexes. To expand beyond the selected genes, we developed an automated 3’UTR-seq method to characterize changes of the transcriptome during postnatal development in mouse pituitary samples. My analyses have revealed abundant tissue-, age-, and sex-specific expression patterns of puberty-associated genes. These findings not only inform future functional studies but also provide valuable insights into the transcriptional regulation of the onset of puberty. Focusing on two distinct biological problems, my thesis explores the usage of integrative genomic approaches in studying transcriptional regulation.

Keywords: chromatin structure
DNA topology
genome-wide association studies
integrative genomics
next-generation sequencing
transcriptional regulation
Advisor: Wilson, Michael D.
Mediating for Immediacy: Text, Performance, and Dramaturgy in Multimedia Shakespeare Editions

This dissertation examines digital multimedia Shakespeare editions, a group of seven projects that combine a complete Shakespeare text (plays or poetry) with a complete performance recording (audio or video). I argue that these projects constitute a new form of edition, which uses performance to engage new users and to supplement users’ understanding of Shakespeare’s text. By placing text and performance as congruent and contiguous elements in a digital interface, these projects transpose performance into the experiential framework of reading, enabling users to set their own pace and direction, and to navigate between reading and spectating. Through its multimedial format, this emerging category also expands the responsibilities of the editor or editorial team, shifting their role from a focus on text to include dramaturgy, pedagogy, and digital design. While these projects do make Shakespeare’s works accessible in new ways, they also reinforce existing narratives, in particular the tendency to regard Shakespeare’s text as dense and alienating while viewing performance as transparent and engaging. The aim of this dissertation is to explore the intellectual and aesthetic frameworks underlying these projects, as well as to articulate some critiques and possibilities for future development. My goal is to propose a set of guidelines for an editorial apparatus that would govern an edition that comprises not only text, but also performance and digital design.

Keywords: Apps
Digital Humanities
Pedagogy
Performance
Shakespeare
Technology
Advisor: Lopez, Jeremy
Online Optimization for Demand Response

Electric power systems are shifting away from conventional fuel-burning generation and moving towards renewable energy generation. Flexibility from energy storage and demand response is needed to accommodate the variability of renewable power sources. A key challenge to demand response is the uncertainty of loads. In this thesis, we design online optimization-based algorithms for demand response. Using the performance-guaranteed frameworks we develop, we can utilize flexible loads for demand response in real-time while accounting for uncertainty. We first design online convex optimization algorithms for power setpoint tracking with flexible loads. We deal with different types of feedback from the loads: full and limited feedback and two intermediary feedback levels. This is done to account for different plausible communication scenarios. We apply our approaches to thermostatically controlled loads and charging electric vehicles. We then formulate a two-level method for the energy management of multi-energy buildings. A scheduling level and a tracking level are utilized to leverage the building's several sources of flexibility for providing ancillary services while satisfying its different energy requirements. Next, we establish a predictive online convex optimization framework in which estimates about future rounds are used to improve the performance of online convex optimization algorithms. We apply this framework for frequency regulation and curtailment, and observe performance improvement over standard algorithms. Thereafter, we extend the multi-armed bandit framework to an instance where the number of arms to play evolves according to a wide-sense stochastic process. We use this extension to curtail flexible loads' power consumption in response to random power imbalance due to renewables. Our approaches rely only on algebraic operations and projections onto a compact and convex sets. They thus are computationally efficient and can be scaled up to very large numbers of loads for real-time decision making.

Advisor: Taylor, Joshua A
Induced Abortion in Ontario

Induced abortion is one of the most commonly performed procedures among women of reproductive age. Most induced abortions occur in women experiencing unintended pregnancies, largely for non-medical reasons. To maximize a woman’s health and wellbeing, it is important to not only identify factors that heighten her need for induced abortion, but any negative consequences that may follow, including those directly related to the induced abortion procedure and the provider performing it. To address these points, three population-based studies were completed using data within Ontario’s publicly funded health care system, where induced abortion is legal and funded by the province’s health insurance plan. Project 1 investigated the intergenerational pattern of induced abortion between a mother and her teenage daughter. Project 2 examined the relation between induced abortion and the risk of venous thromboembolism soon after the procedure. Project 3 evaluated the surgical procedure volume of physicians who perform induced abortion and the associated risk of adverse outcomes following surgical induced abortion. Project 1 found that a teenage daughter is nearly twice as likely to have an induced abortion if her mother has had one. The greater the number of induced abortions a mother has had, the more likely her daughter is to have one as a teenager. Project 2 showed that up to 42 days after an induced abortion, a woman’s risk of having a diagnosed venous thromboembolism event is nearly double the risk of a woman without a recent pregnancy, although the risk is significantly lower than that after a livebirth. Project 3 observed that women whose surgical induced abortion is performed by a physician with a low procedure volume have an increased risk of experiencing an adverse event within 42 days after the procedure; however, adverse event rates vary widely between physicians, and are only partly explained by physician procedural volumes. This body of research may guide clinical, research and health policy efforts aimed to both reduce unintended pregnancy among young women, and improve the quality of care provided to women who receive abortion care.

Keywords: adverse event
induced abortion
intergeneration
teen pregnancy
termination of pregnancy
venous thromboembolism
Advisor: Ray, Joel G
Precursor Cell Migration In Electric Fields

Neural stem and progenitor cells (together termed neural precursors) (NPCs) are found in neurogenic regions of the adult brain. Their presence at injury sites has been shown to correlate with neural repair. NPCs are electrosensitive cells and undergo rapid and directed migration towards the cathode in vitro. The overall goal of this thesis is to investigate the use of electrical stimulation to promote precursor cell migration to improve healing. We first asked if NPC migration can be directed by electrical stimulation in vivo. We designed an electrode to direct NPC migration in vivo and transplanted NPCs on the corpus callosum in the mouse brain. We placed the cathode medial to the injection site and used biphasic monopolar electrical stimulation to promote NPC migration medially in stimulated brains compared to non-stimulated brains. We first observed that transplanted NPCs have a propensity to migrate laterally along the corpus callous, irrespective of stimulation. Interestingly, we found that this lateral migration correlated with the presence of an endogenous negative potential lateral to the injection site. With regard to an applied electric field, our stimulation paradigm following cell transplantation did provide a significant, albeit small, medial migration. Thus, we propose that endogenous electric fields are present in the brain and need to be over-ridden when directing cell migration in vivo. With a view towards understanding the potential for EF application to promote tissue repair in general, we asked whether directed migration in applied EFs is a general property of precursor cells. We examined the galvanotactic response of skin-derived precursor cells (SKPs). We demonstrate that unlike NPCs, SKPs undergo directed migration towards the anode in the presence of an EF in vitro in a substrate dependent manner. Further, SKP galvanotactic responsiveness is dependent on factors released from neighbouring cells. This research demonstrates the potential for electrical stimulation to serve as a tool to direct precursor cell migration in vivo and highlights the importance of considering the microenvironment for EF application.

Keywords: Electrical Stimulation
Galvanotaxis
Migration
Neural Stem and Progenitor Cells
Skin-Derived Precursor Cells
Advisor: Popovic, Milos R
Morshead, Cindi M
Cannabis Use and Cannabis Use Disorder: Burden of Disease in Canada, Trends in Utilization of Specialized Addiction Treatment Services in Ontario and Efficacy of Brief Interventions

Three broad topics related to the treatment of cannabis use and cannabis use disorder were examined. First, cannabis-attributable burden of disease in Canada in 2012 was quantified based on the burden of disease analyses, including comparative risk assessments. The cannabis-attributable burden of disease was substantial, most of it due to cannabis use disorder in the form of disability rather than mortality. Although the contributions of cannabis-attributable schizophrenia, lung cancer and road traffic injuries were comparatively minimal, lung cancer and road traffic injuries were the main contributors to cannabis-attributable mortality. Second, trends in treatment of problematic cannabis use were characterized through Ontario’s specialized addiction treatment system between 2010/11 and 2015/16. As cannabis use became less stigmatized and more accepted as normative behavior, clients in treatment for problematic cannabis use only decreased. At the same time, the frequency of cannabis use among all clients in treatment for problematic cannabis use increased. Taken together, treatment that was unnecessary from a clinical standpoint may have been reduced, but there may have been overall increases in severity. Third, the efficacy of brief interventions for cannabis use, compared with minimal control interventions, was reviewed based on participants recruited from health care settings in randomized trials. A systematic review and meta-analyses indicated an overall small number of studies on this topic. The available evidence indicated that brief interventions for cannabis use were not efficacious for improving cannabis-specific ASSIST scores and number of days of cannabis use. On the other hand, the evidence for other cannabis-specific outcomes was limited and mixed. Altogether, the three studies suggested continued monitoring of cannabis use disorder, continued public education of lower risk cannabis use, lack of evidence to scale up brief interventions for cannabis use, expansion of treatment options for cannabis use disorder and development of the evidence base for cannabis use.

Keywords: Addiction treatment
Brief interventions
Burden of disease
Canada
Cannabis
Marijuana
Advisor: Rehm, Jürgen