VictorJuiz/thesis huggingface dataset:
The Pathophysiology of R222Q Mutant Nav1.5 Channels

Mutations in the primary cardiac sodium channel (SCN5A) are associated with arrhythmias and cardiomyopathy, however the mechanisms underlying this phenotype, particularly cardiomyopathies remain unclear. To investigate R222Q-SCN5A associated arrhythmias and dilated cardiomyopathy (DCM), we used ventricular cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPSCs) from a patient heterozygous for an SCN5A mutation (c.665G>A/R222Q) with clustered regularly interspaced short palindromic repeat (CRISPR) corrected isogenic controls. Single cells and cell sheets largely failed to recapitulate the electric physiological changes previously associated with R222Q-Nav1.5 channels. The R222Q-SCN5A phenotype was unmasked using the electrically stimulated biowire platform to promote maturation. Biowires harbouring the R222Q-SCN5A mutation exhibited action potential (AP) abbreviation consistent with Ω-pore currents and contractile dysfunction associated with tissues dilation, reduced troponin T (TnT) expression and sarcomere disarray in the absence of fibrosis and changes to calcium handling. Collectively, these findings suggest that SCN5A plays an important structural role in CMs, which is disrupted by the R222Q mutation resulting in the tissue dilation and reduced myofibril density and organization and consequently contractile dysfunction.

Keywords: Arrhythmias
Dilated cardiomyopathy
Mutation
Nav1.5
SCN5A
Sodium channel
Advisor: Backx, Peter H
Developing the Future: Félix Nadar's Photographic Experiments

Writing in the 1880s, almost fifty years after photography’s introduction to the French public in 1839, Félix Nadar (né Gaspard-Félix Tournachon, 1820-1910) describes photography as “the most extraordinary in the constellation of inventions that have already made our still unfinished century [...] the greatest of the scientific centuries.” In Nadar’s formulation, as in the historiography of the nineteenth century more broadly, photography holds pride of place in a litany of new media and technologies that co-constituted the very notion of modern life and enshrined the ideal of progress. Progress, as Reinhart Koselleck reminds us, is a historically specific concept that describes a growing gap between historical experience and future expectation. Situating Nadar as part of a forward-looking culture of expectation, this dissertation examines the way Nadar positioned both photography, and his own celebrity, as historical figures key to the invention of the future. Drawing on archival research, close readings of Nadar’s images and texts, and theoretical approaches from media studies and the history of science and technology, I situate Nadar’s many photographic “firsts” as part of a larger history of technology employed to articulate the great possibility of the future. Nadar engaged with fields as diverse as aerostation and aviation, electricity, and instantaneous photography, among other innovations, and in so doing explored new idioms for the communication of technological futurity. Nadar’s experimental photography and his auto-archival practices, I argue, have also shaped how “Nadar” as a historical figure has come to be understood, for he approached his own legacy as an invention, in and of itself. Though the focus is on Nadar, this dissertation considers the ways in which nineteenth-century cultures of invention and media shaped photographers’ understanding of their own historical agency more broadly, and how photography participated in the visual culture of technology as a beacon of, and tool for, developing the future. My larger subject, therefore, is the role of visual and textual cultures of technology in the development of historical and future-oriented thinking across the nineteenth century.

Keywords: History of photography
History of technology
Media Studies
Advisor: Bear, Jordan
Franklin Book Programs (1952–1977): Imperialism, State and Knowledge Production

This thesis explores the role of the Franklin Book Programs (FBP) (1952–1977) in the print, publishing industry, textbook writing, and educational policies of the Middle East, with a specific focus on Iran. The Franklin Book Programs (FBP) was a private not-for-profit U.S. organization founded in 1952 during the Cold War and was subsidized by the United States’ government agencies as well as private corporations. The FBP initially intended to promote U.S. liberal values and also to create appropriate markets for U.S. books in ‘Third World’ countries (Robbins, 2007). However, from its initial objective of exporting U.S. culture to rival the influence of Soviet socialism, the FBP evolved into an international educational program publishing university textbooks, schoolbooks, and supplementary readings (Laugesen, 2012). As the FBP moved to become the most important organization of the Cold War with a global focus on the production of educational material, its activities broadened from the ones specifically related to translation to those related to the development of printing, publishing, book distribution, and bookselling institutions. Therefore, the FBP started to build and expand printing plants; it encouraged library development and more importantly undertook the training of teachers as textbook writers. Through archival study and historical analysis of the international role of the FBP (1952–1977) on the print and publishing industry and educational policies of the Middle East, this thesis examines the interrelation between imperialism, state, and knowledge production. Criticizing the prevalent understanding of imperialism as an economic system, this research explores and historicizes the ideological functioning of imperialism through its cultural and publication policies in the Middle East. Using a dialectical and historical materialism approach, my research shows that the print, the production, and the distribution of a wide range of liberal literacy, educational, and school texts throughout the Middle East was a continuation of U.S. anti-communist policies during the Cold War.

Keywords: Cold War
Franklin Book Programs
Imperialism
Iran
Middle East
Modernism
Advisor: Mojab, Shahrzad
Role of Ion Channels in Glioblastoma

Glioblastoma (GBM) accounts for the majority of astrocytic tumours and represents the most common primary brain cancer. Prognosis for patients is dismal even with aggressive treatment. Because of diffused GBM invasion throughout the brain, it is impossible for surgery to completely remove the tumour. Chemotherapeutic adjuvants are used in attempt to eradicate remnant GBM cells. Unfortunately, the standard clinically used drugs have limited therapeutic benefits. Thus, there is need to identify novel drug targets. Although ion channels contribute to a wide array of fundamental cellular functions, the role of ion channels in GBM is ill-defined. A better understanding of ion channels can potentially present new effective ways to treat GBM. In this thesis, I aimed to fill some of these knowledge gaps by investigating two exciting candidates: the transient receptor potential melastatin 7 (TRPM7), and the swelling induced chloride current (ICl,swell), both of which can potentially serve as cellular "sensors" for key GBM characteristics such as hypoxia and cell volume. In my first aim, I validated the involvement of TRPM7 in GBM cellular functions and the underlying signalling by employing a unique experimental approach. That is, I found that pharmacologically potentiating TRPM7 enhanced GBM motility. In my second aim, I evaluated the therapeutic potential of the specific TRPM7 antagonist waixenicin A. By employing both in vitro and in vivo approaches, I provided evidence suggesting that waixenicin A reduced GBM cellular functions. Lastly, in my third aim, I expanded my scope of study in order to gain a broader understanding of ion channels' roles in GBM by examining ICl,swell, a target that may complement TRPM7 in various physicochemical sensory roles. Here, I observed that inhibiting ICl,swell can also suppress GBM cellular functions. Overall, the objective of my thesis is to elucidate the ill-defined roles of TRPM7 and ICl,swell in GBM in order to identify potential targets for pursuit of further drug development.

Advisor: Sun, Hong-Shuo
Organizational Citizenship Behaviours: A Relational Perspective on the Critical Care Nursing Workforce to Patient Safety and Quality Care

One underrecognized essential component of highly reliable safety performance is the adaptive capacity and engagement of the front-line nursing workforce. Findings from a review of the literature revealed (a) conflicting evidence between studies creating a lack of consensus as to the nature and influence of nurses’ workplace behaviours on patient safety outcomes, (b) a gap in understanding nurses’ workplace behaviours in the context of high reliability settings, and (c) a lack of evidence on the Organizational Citizenship Behaviours (OCB) of nurses in critical care settings. Thus, this study explored the social functioning of relational work environments and workplace behaviours of Registered Nurses (RN) in critical care settings that promote safe patient outcomes and high quality care. This study was conducted using a sequential explanatory mixed methods design (Teddlie Tashakkori, 2009). The quantitative portion of the study included administration of a survey distributed to critical care nurses in Ontario with a response rate of 29.3% (N = 508) and administrative patient outcome data. The qualitative portion of the study included individual interviews with a random sample of seven nurses and six nurse leaders. Multivariable regression exploring linear, non-linear, multi-level, moderation, and mediation relationships was conducted and triangulated with qualitative findings. The study found that co-worker exchange relationships were the strongest relational work environment variable in predicting nurses’ workplace behaviours. Nurses frequently engaged in OCB for the benefit of co-workers and patients/families. At the individual-level, nurses’ OCB was associated with decreased self-reported medication errors ( = -0.07, p = 0.007), missed care ( = -0.16, p = 0.001), and increased nurse-perceived quality of care ( = 0.28, p = 0.01). Safety organizing behaviour (SOB) based on high reliability practices accounted for 57.3% of the total mediation effect between OCB and medication errors. Nurses’ organizational identification was influenced by the interprofessional teamwork climate ( = 0.23, p = 0.001) and SOB ( = 0.29, p = 0.001). Results from this study provide nurses, leaders, and researcher insights into the importance of the relational environment in critical care that contribute to highly reliable, safe, and high quality care through engagement in workplace behaviours.

Keywords: Critical Care
High Reliability Organizations
Leadership
Nursing
Organizational Behaviour
Patient Safety
Advisor: McGillis Hall, Linda
Workplace Control and Workplace Injustice

This dissertation examines how the internal life in contemporary workplaces might foster or undermine democratic values. It is an interdisciplinary work that combines normative political philosophy with empirical management and sociological studies of workplace control. The dissertation analyzes three major forms of workplace control: emotion, time, and knowledge. For each form of workplace control, I analyze the empirical details of how this control works in reality, and then analyze the empirical evidence concerning the positive and negative personal, social, and political consequences of such control. Building on the empirical analysis of workplace control, I ask why some forms of workplace control should be regarded as normatively problematic by engaging with the contemporary debates around distributive justice and democratic theory. Chapter 5 of the dissertation addresses the question of what personal and social goods a lower degree of workplace control can foster and whether the democratization of the workplace can lead to a lower degree of workplace control. Ultimately, the dissertation aims to present a coherent, comprehensive, and empirically solid picture of what modern forms of workplace control are and how they undermine important values of a free and fair democratic society.

Keywords: Democratic Theory
Social Justice
Workplace Control
Workplace Democracy
Workplace Injustice
Workplace Republicanism
Advisor: Carens, Joseph
Kohn, Margaret
Precise Temporal Regulation of Ribonucleoprotein Complexes during the Drosophila Maternal-to-Zygotic Transition

In early animal embryos, maternally loaded mRNAs and proteins regulate development prior to the handover of control to zygotically expressed gene products in a process known as the maternal-to-zygotic transition (MZT). RNA-binding proteins (RBPs) tightly regulate the translation, stability, and localization of maternal mRNAs through post-transcriptional regulatory mechanisms. For example, in the Drosophila melanogaster embryo, the Smaug (SMG) RBP forms ribonucleoprotein complexes with corepressors, Trailer hitch (TRAL), Maternal expression at 31B (ME31B) and Cup, as well as AGO1 and the CCR4-NOT deadenylase to regulate the translation and stability of hundreds of maternal mRNAs, and this regulation is required for proper development through the MZT. However, regulation of maternal proteins, including these RBPs is not well-studied. In this thesis, I show that the maternal proteome represents over half of the protein coding capacity of the Drosophila genome and that 2% of this proteome is rapidly degraded during the MZT. Cleared proteins include the post-transcriptional repressors Cup, TRAL, ME31B and SMG. While the ubiquitin-proteasome system is necessary for clearance of these repressors, distinct E3 ligase complexes target their degradation at distinct times: the C-terminal to Lis1 Homology (CTLH) complex targets Cup, TRAL and ME31B for degradation early in the MZT; the Skp/Cullin/F-box-containing (SCF) complex targets SMG at the end of the MZT. Deleting the C-terminal 233 amino acids of SMG abrogates interactions with F-box proteins and results in failure of the protein to degrade during the MZT. I map the regulatory elements of SMG protein degradation to conserved motifs within the C-terminus. Furthermore, I found that many of maternal mRNAs targeted for degradation by SMG are subsequently re-expressed zygotically. Unlike Cup, TRAL and ME31B, the deadenylase complex remains stably expressed in the embryo. Consequently, after zygotic genome activation, persistent SMG continues to function in complex with the CCR4-NOT deadenylase and downregulates zygotic re-expression of these mRNAs. Thus, timely clearance of SMG during the MZT permits an orderly gene expression program in the early embryo.

Keywords: CTLH complex
RNA-binding protein
SCF complex
ubiquitin ligase
Advisor: Lipshitz, Howard D
Evaluating the Feasibility of a Clinical Supervision Model for Evidence-supported Interventions for Children with Severe Disruptive Behaviour

The purpose of this dissertation was to enhance knowledge of the practice and role of staff supervision in supporting children’s mental health services and the implementation of evidence-supported interventions. This research examined the need, acceptability, and feasibility of implementing a model of clinical supervision to support the SNAP (Stop Now and Plan) evidence-supported interventions for children with disruptive behaviours and their families. Methods: In Paper 1, a descriptive cross-sectional survey of supervisors and practitioners (N = 54) established supervision in practice within Canadian SNAP evidence-supported interventions. In Paper 2, a multiple case study evaluated the acceptability, appropriateness, adoption, and feasibility of implementing an intervention-specific model of clinical supervision within SNAP sites (N = 3). In Paper 3, a feasibility study of implementing the SNAP model of clinical supervision in community sites (k = 6) over a six-month period examined the demand, acceptability, implementation, practicality, and effectiveness of the model on enhancing practitioner competence, and perceived support (N = 27). Results: Paper 1 showed that supervision was valued, however occurring variably across the SNAP affiliate sites. The results highlighted an opportunity to enhance the quality of supervision within the SNAP affiliate sites. Paper 2 demonstrated that the SNAP clinical supervision model could be adopted in practice with adjustments, was deemed acceptable and appropriate by SNAP supervisors, and was predominately feasible with real world circumstances taken into consideration. Paper 3 findings included a determination of partial demand for implementing the SNAP clinical supervision model, as well as the acceptability of the model, implementation benefits and challenges, challenges related to the practicality of implementing the model using existing resources, and the preliminary effectiveness of the model on enhancing practitioner competence. Conclusions: This dissertation contributes an understanding of the need for a structured model of supervision, as well as demonstrates how such a model incorporating theory and research can be specified and translated to practice. The studies demonstrate the feasibility of implementing the SNAP CS in community-based sites. The dissertation employed a systematic approach to researching supervision to present the first known Canadian study of implementing a model of clinical supervision in practice.

Keywords: Children's mental health
Clinical supervision
Evidence Supported Intervention
Implementation
Model
Stop Now and Plan (SNAP)
Advisor: Bogo, Marion
Modeling the Effects of Microbially-mediated Sulfate Reduction on Porewater S-isotope Ratios in Marine Sediments

Microbial sulfate reduction affects the balance between the burial and remineralization of organic carbon. We can trace the activity of microbial sulfate reduction with the concentration and isotope data of porewater sulfate and sulfide. This dissertation aims to improve the understanding of sulfur isotope measurements of marine porewater samples. Specifically, this dissertation is investigating (a) the isotope effects of disproportionation, (b) isotope fractionation due to microbially-mediated processes in the abyssal plain, and (c) effects of drilling-fluid contamination on the estimated rates and isotope fractionation of microbial sulfate reduction. Our understanding of the isotope effects of disproportionation comes mostly from laboratory cultures different from natural settings. This dissertation uses a modeling approach to investigate the constraints of such effects on the S-isotopes of sulfate and sulfide. The results show that with sulfate reduction and disproportionation co-occurring in marine sediments, the isotope effects of disproportionation are capped at about 16‰. Studies taking physical processes into account when studying microbially-mediated isotope fractionation in the abyssal plain are rare. This dissertation applies a reaction-transport model to the S-isotope data from the Eastern Equatorial Pacific (Site 1226, Ocean Drilling Program), with physical processes considered. Model results reveal sulfate reduction occurring at rates from 10^2fmol/cm^3/day near the seafloor to almost zero above the basement. The modeled microbially-mediated fractionation factor is between 1.058 and 1.062. This value is lower than the equilibrium value between sulfate and sulfide suggested by previous studies. The problem of drilling-fluid contamination to microbial studies is well-known but only qualitatively. Drilling fluid affects concentration and isotope data, which will lead to inaccurate estimations of the rates and isotope fractionation of microbial activities. This dissertation reviews porewater profiles of sites that have been drilled twice in the International Ocean Discovery Program. Concentration differences between independent drilling campaigns of the same locations suggest that porewater samples can contain 30% of drilling fluid. Here, reaction-transport models are used to reveal that drilling fluid leads to minor effects on the estimated sulfate reduction rates. However, its impact on the estimated isotope fractionation is significant. 30% contamination will cause an underestimation of the fractionation by more than 30‰.

Keywords: disproportionation
International Ocean Discovery Program (IODP)
porewater sulfate / sulfide
reaction transport model
sulfur isotopes
sulphur isotopes
Advisor: Wortmann, Ulrich G
The Development of Antisocial and Prosocial Lying in Children with and without Severe Conduct Problems

Lying is a typical part of childhood. However, for some children, such as those experiencing conduct problems, lying becomes problematic and atypical with increased age. Frequent and persistent antisocial lying is thought to be an early symptom of conduct problems. However, until the present thesis, it was unclear why children with conduct problems tell antisocial lies more than typical children. Furthermore, it was unknown whether and how often children with conduct problems tell prosocial lies (i.e., “white lies”), which are lies told to be polite or prevent hurting someone else’s feelings. This thesis outlines 3 studies (N = 316-387) examining antisocial and prosocial lie-telling among 6 to 12 year-old children with and without conduct problems. In Chapter 2, I found that while parents reported that the frequency of children’s antisocial lying increased alongside the severity of conduct problems, the frequency of their prosocial lying did not. Given that parent report methods may be unreliable due to social desirability bias or the inherent nature of lying being deceptive (i.e., parents may not catch their child lying), in Chapters 3 and 4 I examined prosocial and antisocial lying using behavioral measures. In Chapter 3, I used a disappointing gift paradigm to examine whether children would lie about liking a disappointing gift. Consistent with the parent-report results of Chapter 2, children with conduct problems were just as likely to tell a prosocial lie as typically developing children. In Chapter 4, I used a modified version of the temptation resistance paradigm to examine whether children will tell a lie to conceal a minor transgression (a form of antisocial lying). Again, consistent with the parent-report results of Chapter 2, children were more likely to tell an antisocial lie with increased conduct problems. However, theory of mind was shown to act as a protective factor against the relationship between increased antisocial lying and conduct problems. Together, my thesis suggests that children with and without conduct problems engage in different types of lying according to social context, and that socio-cognitive development may play a key role in the reduction of antisocial lying for children with conduct problems.

Keywords: antisocial lying
conduct problems
deception
executive functioning
prosocial lying
theory of mind
Advisor: Lee, Kang