VictorJuiz/thesis huggingface dataset:
Characterizing the Molecular Mechanisms Involved in the Formation of Multidrug-tolerant Persister Cells in Streptococcus mutans

Bacterial populations contain a small fraction of specialized dormant cells known as persisters that ensure survival from killing by all antibiotics currently in use. These multidrug-tolerant persisters are phenotypic variants that withstand cell death from antibiotics due to inactive cellular processes that most conventional antibiotics target, and are capable of reverting to normal growing cells upon the removal of antibiotics. Thus, persisters are a major contributor in resiliency of chronic microbial infections towards antibiotic therapy. Streptococcus mutans utilizes quorum-sensing for coordinating and regulating bacterial behaviors and adaptive responses at a population-wide level. Previous work has shown that this cariogenic pathogen utilizes its CSP-ComDE quorum-sensing system to direct its stress response for survival. Our objectives were to investigate the nonheritable persister phenotype in S. mutans, and to identify the molecular mechanisms by which it forms these multidrug-tolerant persisters. Persister formation in S. mutans was found to be regulated by multiple mechanisms, including two toxin-antitoxin systems, genes involved in transcription/replication, sugar metabolism, cell wall synthesis, and energy metabolism. Furthermore, we identified that the inducible CSP ‘alarmone’, the peptide pheromone responsible for communicating stress and triggering adaptive responses in the population, is important for the induction of persister formation. We demonstrated that this inducible mechanism is regulated by a CSP-inducible gene encoding a transcriptional repressor that is responsible for regulating DNA damage tolerance and identified novel persister genes that contribute to the formation of quorum-sensing-induced persister cells.

Keywords: Antibiotic tolerance
Persister cells
Streptococcus mutans
Advisor: Lévesque, Céline M
Simultaneous White Noise Models and Optimal Recovery of Functional Data

We consider i.i.d. realizations of a Gaussian process on [0,1] satisfying prescribed regularity conditions. The data consist of discrete samplings of these realizations in i.i.d. Gaussian noise and the goal is estimation of the underlying trajectories. Further, we want our estimates to enjoy expected L2 errors, conditioned on the realized trajectories, which attain optimal rates. Under general conditions on both design and process, an asymptotic equivalence, in Le Cam's sense, is established between an experiment which simultaneously describes these realizations and a collection of white noise models. The risk properties of our estimation goal may then be studied in an idealized setting and benchmarks established for practically implementable procedures. In this context, the white noise models are projected onto a basis satisfying general conditions in relation to the covariance kernel of the process which generated the data. This reduces the problem of initial interest to that of recovering a collection of normal means in euclidean norm, the means of interest having Gaussian structure. A variant of Stein estimation is applied for recovery of these means and a key inequality derived showing that the corresponding risks, conditioned on the underlying means, can be made arbitrarily close to those that an oracle with knowledge of the process would attain. This establishes various notions of optimality for our recovery procedure. Finally, guarantees are derived for practically implementable variants and empirical performance is illustrated through simulated and real data examples.

Advisor: Yao, Fang
Symptoms And Function During The Early Recovery Period Following Orthotopic Liver Transplantation Surgery

Background: Following OLT surgery, studies have focused more on long-term patient-reported outcomes, and less on those amenable to earlier intervention. The few early recovery period studies documented pain, mood changes, fatigue and functional limitations, but did not explore fully the relationships between these symptoms and function. This study examined the relationships of pain, mood, fatigue and fatigue impact and function in the early postoperative period, and explored the relationship between patients’ function and the fatigue and fatigue impact of primary caregivers. Method: A prospective, descriptive correlational repeated-measures design was used to collect data at baseline postoperatively, then at 4, 8 and 12 weeks upon discharge using the Brief Pain Inventory-Short Form, Profile of Mood States-Short Form, Modified Fatigue Impact Scale and the Human Activity Profile (HAP). Data for caregiver fatigue and fatigue impact were also collected. Results: Patients (N = 58) were on average 54 (10.4) years old, mostly male (66%), married (77%) and 65% had untreatable viral, alcohol-induced or autoimmune liver disease. The 23 primary caregivers were on average 56.5(7.85) years old, female (71%) and life partners of patients (88%). Linear regression analysis found no significant association between pain, mood, fatigue and function. Fatigue impact explained 11% of the variance in the patients’ HAP adjusted activity scores (AAS; p = .11). No significant association was found between the fatigue and fatigue impact of caregivers and the function of patients. Throughout follow-up, patients reported their worst pain upon movement in the moderate range. At 12 weeks, 22% reported moderate to severe pain upon movement, 28% reported moderate to extreme fatigue levels, and 21% reported fatigue impact often or almost always. Baseline HAP-AAS scores were low, but improved throughout follow up. At 12 weeks, patients’ mean HAP-AAS scores suggested functional impairment. Caregiver fatigue and fatigue impact scores were in the moderate range at baseline, and in the mild range by 12 weeks. Conclusion: Future interventional studies are needed pre- and postoperatively, to minimize fatigue impact and evaluate the outcomes of these interventions on the postoperative function. More caregivers are also required to determine their fatigue and fatigue impact during the early recovery period, to support them during the early recovery period.

Keywords: caregivers
function
liver
orthotopic
symptoms
transplantation
Advisor: McGillion, Michael H
Policy Networks and Paradigm Change in Ontario Forest Policy, 1988-2014

This dissertation was developed from documentary research, analyses of public hearing transcripts, and a case study examining 25 years of forest policy change in Ontario from 1988 to 2014. The ideas and actions of the actors in the policy network, and the political, social, and economic structures in which they operated, are investigated using the Dialectical Model of Policy Networks. The relationships among the key policy actors are traced through significant events and legislation: the Timber Management Class Environmental Assessment (1988-1994), the Crown Forest Sustainability Act (1994), the Living Legacy-Ontario Forest Accord (1998), The Endangered Species Act (2007), the Far North Act (2010), and the Ontario Forest Tenure Modernization Act (2011.) The results of the analyses indicate that Ontario’s forest policy evolved over the study period. The policy focus was on timber supply for the forest industry in 1988. This gave way in 1994 to sustainable forest management, which also served environmental and social values. By 2007 the ecological values of forest policy began to predominate. The analyses reveal that as the ENGOs in the forest policy network gained strength, their ideas and their successful political advocacy drove ecological changes. In contrast, the network influence of the Ontario Ministry of Natural Resources was weakened by ongoing budget cuts and confusion about its mandate. The forest industry lost its historical power in the network due to the economic crisis and downsizing of the industry and by tactics that caused further estrangement from the government. Professional foresters lost their prominence in the network as decisions about forests became associated with political rather than technical and scientific values. Aboriginal Peoples were unable to break into the network for purposes of furthering their treaty and Aboriginal rights and to obtain economic benefits for their remote communities. Questions are raised about the persistence of the new ecological forest policy network and the acceptance of the network of further reform. The result, however, of these shifts in network dynamics is that Ontario forest policy has experienced a paradigm change.

Keywords: Environmental policy
Forest Policy
Forestry
Natural Resources
Policy networks
Public Policy
Advisor: Smith, Tat
Strategies for Dynamically Scheduling Inspections for Condition-based Maintenance

Over the past several decades, many advances have been made in optimizing the maintenance practices of capital assets. Condition-based maintenance strategies in particular analyse real data and system measurements to facilitate evidence-based asset management. In traditional condition-based maintenance practices, regular inspections are considered a given requirement. Most measurements, however confirm that the machine in question is in good working order and that no maintenance is necessary. The central thesis of this dissertation is that under some circumstances, non-periodic inspection scheduling can result in significant savings by eliminating superfluous inspections, increasing the inspection rate as the asset ages, resulting in better use of the remaining life of the asset. The cost and time of inspections are incorporated into our decision policy that produces an inspect-or-replace result jointly with an optimal time for the next inspection. We use a Weibull proportional hazards model to compute the system reliability, combining the age of the system along with the condition monitoring data. Through our case studies, we compare our models against a periodic inspection policy, and the classical age policy. We study some preconditions for our model, under which our model performs better than classical age and periodic models. We further develop the model to allow for amortized payment of the initial installation cost. Using the amortized model, we integrate maintenance decisions with economic decisions, resulting in a more realistic model. We find that the amortized model provides costs savings above and beyond our first model. In our final model, we introduce failure costs and repair times that are dependent on the age and state of the system at failure. By adding this component, we reflect the reality of varying types of failure, and the variability of the resulting repair time. Our numerical results indicate that allowing the cost and repair time to be a function of the age and state of the system at failure produces better results than the model with fixed cost and repair time. By these three models, this dissertation demonstrates the significant cost saving that can be made with appropriate strategies to optimally schedule inspections, without sacrificing system reliability.

Keywords: Condition-based maintenance
inpsections
maintenance
reliability
Advisor: Jardine, Andrew K
Banjevic, Dragan
Plasmonic and Catalytic Properties of Shape-Controlled Metal Nanoparticles and their Assemblies

This work explores the effect of the shape of metal nanoscale building blocks on the structural, optical, and plasmonic properties of their assemblies, as well as on the catalytic performance and hydrogen interactions of individual nanoparticles with specific shapes. In Chapter 3, I describe the linear self-assembly of bifunctional metal nanoparticles in the presence of monofunctional nanoscale chain stoppers. Chain stoppers with controlled reactivity were synthesized allowing control over the morphology of the self-assembled structures. Analysis of the degree of polymerization of linear nanostructures provided information about self-assembly kinetics, side reactions, and the distribution of species in the reaction. This work facilitated testing of theoretical models developed for molecular polymerization and fabrication of linear nanoparticle assemblies with controllable properties. In Chapter 4, I developed linear solution-based self-assembly of cubic metal nanoparticles, examined the morphology of the nanocube chains and their optical characteristics. In comparison with chains of nanospheres with similar dimensions, compositions, and surface chemistry, predominant face-to-face assembly of nanocubes leads to a larger volume of plasmonic hot spots, uniform electromagnetic field enhancement in the gaps between nanocubes, and a new coupling mode for nanocube chains, associated with Fabry−Perot structure. In Chapter 5, I investigated plasmon-mediated enhancement of the catalysis by palladium-based nanoparticles with different shapes and composition, bearing surface plasmon resonance in visible range. The photocatalytic activity of palladium-based nanoparticles depended more on their shape than internal structure. These findings pave the way for the design of palladium nanocatalysts with enhanced performance acting under visible light illumination. In Chapter 6, I developed a facile scaled-up synthesis of monodisperse palladium nanoparticles with various shapes, stabilized with a mesoporous silica shell. Hydrogen-nanoparticle interactions were studied using temperature programmed desorption. These findings help elucidate the nature of hydrogen interactions with topologically different palladium nanoparticles.

Keywords: catalysis
nanoparticles
plasmonics
self-assembly
Advisor: Kumacheva, Eugenia
Delineating the Molecular Mechanisms of KIF7 in Vertebrate Hedgehog Signal Transduction

The Hedgehog (Hh) signalling pathway plays important roles in embryonic development and for adult tissue homeostasis and regeneration of multi-cellular organisms. Mutations in components of this pathway often result in human developmental disorders and cancer. The primary cilium, a microtubule based extension from the cell surface is required for Hh signalling in vertebrates. Hh ligand binding to the Patched (Ptch1) receptor leads to the ciliary accumulation and activation of the seven transmembrane protein Smoothened (Smo) and changes the localization of several pathway components within primary cilia subdomains. How Smo activation affects the localization of effector proteins in cilia and how this relates to the activation of target genes is unclear. Genetic and biochemical analysis revealed that the kinesin family protein 7 (Kif7) trafficks to the primary cilia upon pathway activation and fulfills dual positive and negative roles during mouse Hh signalling. Through proteomic and biochemical analysis, we aim to better understand the molecular mechanisms underlying the functions of Kif7 in vertebrate Hedgehog signalling. Using a mass spectrometry-based proteomic approach, we identified Liprin-1 (PPFIA1) and the PP2A phosphatase as Kif7-interacting proteins, and showed that these proteins regulate Kif7 phosphorylation and its activity. We further identified DYRK2 as a protein kinase that phosphorylates Kif7. Overall, our study identified phosphorylation as a post-translational modification that dictates Kif7 localization within primary cilia and its control of Gli transcriptional activity. Lastly, through biochemical assays we examined the relationship between SuFu and Kif7, two key regulators of the Hh pathway. Collectively, these studies highlight the importance of Kif7 in vertebrate Hh signalling.

Keywords: Hedgehog signalling
Kif7
Advisor: Angers, Stephane
An Existential Perspective on the Role of Human Agency in the Retraining of Immigrant Skilled Workers in Canada

This qualitative study explored the career re-development of immigrant professionals in Canada by centering the investigation on their Canadian retraining journey. The goal of this study was to provide a deeper understanding of the transition issues, retraining decision-making process, retraining experiences and outcomes, and coping strategies of the immigrant professionals to uncover the role of human agency in dealing with the existential givens of their Canadian career re-development. Twenty participants, 11 females and 9 males between the ages of 30 and 50, were interviewed for this study. The participants held at least a bachelor’s degree and had at least 3 years of work experience prior to their migration. They received Canadian retraining and had at least 1 year of post-retraining Canadian work experience. Semi-structured interviews were completed and the interview transcripts were analyzed using grounded theory qualitative analysis approach. Similar to previous research findings, the immigrant professionals in this study had intact career identities and meaning prior to their migration. Many participants were confident about transitioning into their original professional field in Canada with some participants having expected to pursue Canadian retraining. The participants, however, experienced systemic career transition barriers in Canada, such as language and acculturation barriers, discrimination, isolation, and non-recognition of their foreign credentials and work experience by Canadian employers. They completed Canadian retraining to cope with these barriers and pursue their career goals. Almost all of the participants shared that their retraining facilitated their career re-development and many were either undergoing or planned on pursuing additional retraining to improve their future career prospects. Throughout their career re-development process, focusing on their long-term career goals (which provided them with meaning), acceptance and openness, and social supports provided them the perseverance to utilize their human agency. The participants accessed their human agency to revise their meaning-making, create a plan of action, and take action with the intention of pursuing their long-term goals. This career re-development process is summarized in the model proposed by this study, the Existential and Human Agency Model of Career Re-development. The implications of the findings of this study for policy, professional resources, and immigrant professionals are discussed. Suggestions for future research directions are provided.

Keywords: Canadian retraining
career transition
existential theory
human agency
immigrant career
immigrant retraining
Advisor: Chen, Charles P
Discourses and Realities of Online Higher Education: A History of [Discourses of] Online Education in Canada’s Open University

My dissertation research aims to develop a comprehensive account for the current state of online higher education beyond the common social and educational expectations about the adoption of online education. Online education, according to dominant discourses in higher education, is commonly expected to (a) enhance educational accessibility to university education and (b) improve the quality of university instruction. And, this expectation further produces an imperative for its rapid adoption across all higher education institutions. However, my research fundamentally challenges these two rhetorical discourses, by providing an in-depth description of the disjunction between such discourses and the realities of praxis. Drawing on key concepts from Michel Foucault and Mikhail Bakhtin, I trace the historical development of these two discourses as two institutional principles of openness and innovation in an open university. The complex relationships between the institutional discourses and peoples’ practices, mediated by multiple factors are carefully addressed. My analysis reveals that multiple understandings of openness and innovation co-exist within the university, and members take different pedagogical approaches to online education according to their own understanding of those two principles. As a result, openness and innovation often conflict with each other at the operational level, and the conflict is also visible within the ongoing struggles between instructors and learning designers, with regard to the adoption of a particular form of online pedagogical practices. In summary, my findings demonstrate how the adoption of online education may introduce new problems and potentially oppressive power relationships among stakeholders in higher education, unlike the rhetorical claims that simply promote online education as a revolutionary solution for diverse social and educational problems. This disjunction continues to increase and is intensified by the existing instructional theory-practice gap in the academic field of online higher education. I urge that researchers and educators in online higher education as a united group, to make a collective effort to better understand and resolve the ongoing conflicts among the stakeholders and ultimately better serve our online students.

Keywords: Discourse Analysis
Distance Education
Foucault
Higher Education
Online Education
Open University
Advisor: Brett, Clare M
Relationship Between Ectopic HOXB4 Expression and Self-renewal in Normal and Leukemic Hematopoietic Cells

Lifelong production of mature blood cells is mediated by long-term hematopoietic stem cells (LT-HSCs) which are capable of regenerating themselves through a process termed self-renewal. Importantly, it is the ability of LT-HSCs to sustain self-renewal that distinguishes them from other hematopoietic cells and enables them to long-term reconstitute all of the blood cells in recipient mice. Exogenous HOXB4 expression in primary bone marrow (BM) cells is currently understood to enhance the self-renewal of LT-HSCs and thus induce their expansion. However, the apparent expansion of LT-HSCs induced by HOXB4 may also be accounted for by alternative mechanisms that hinge on the acquisition of stem cell-like properties in non-LT-HSCs. In evaluating the effect of HOXB4 overexpression in purified cells further down the hematopoietic hierarchy, I found that HOXB4-transduced individual short-term HSCs (ST-HSCs) were capable of generating sustained primary grafts comprising only a subset of hematopoietic lineages. Lineage-restricted patterns of reconstitution were also observed when reconstituted BM from multilineage-engrafted primary recipients were limit diluted into secondary recipients. My results support a model in which multilineage reconstitution mediated by ectopic HOXB4 expression is maintained, in part or possibly exclusively, by lineage-restricted progenitor cells that have newly acquired the ability to sustain self-renewal by virtue of enforced HOXB4 expression. To determine if this endowment of sustained self-renewal potential represents a reprogramming phenomenon, I’ve also undertaken an investigation into the effect of withdrawing ectopic HOXB4 expression on long-term engraftment. My results reveal a dependency on continued HOXB4 expression for sustained self-renewal capacity suggesting active HOXB4 protein production is required for the permanence of the grafts generated by lineage-restricted progenitor cells. Finally, long-term follow-up of HOXB4-transduced cells uncovered a large number of leukemias developing in experimental animals. My work highlights the negative consequence of cells acquiring sustained self-renewal potential, and paves the way for future investigation into the importance of maintaining this self-renewal program in cancer development.

Keywords: Hematopoietic Stem Cells
HOXB4
Leukemia
Lineage-Restricted Progenitors
Retroviral Overexpression
Self-Renewal
Advisor: Iscove, Norman N