VictorJuiz/thesis huggingface dataset:
Innate Immune Transcription Activator Interferon Regulatory Factor-3 (IRF3) Contributes to Maladaptive Remodeling Post-myocardial Infarction
Keywords: Myocardial Infarction
Cardiac Remodeling
Interferon Regulatory Factor-3
Innate Immunity

Cardiovascular disease, and myocardial infarction (MI) in particular, remains a major burden in the developed world today. In fact, the remodeling process, which follows the initial ischemic episode of MI, is a major determinant of heart failure. Although several key mechanistic pathways involving cell growth and death have been identified, there is limited knowledge surrounding the role of the innate immune response as a positive or negative regulator of cardiac remodeling. Recent data strongly support a role for key regulatory components within the toll-like receptor (TLR) family as potent modulators of cardiac remodeling post-MI. It has been demonstrated that targeted gene knockdown of TLR4, as well as downstream adaptor proteins and kinases, significantly improve cardiac function and overall survival. While the well-known NF-κB transcriptional factor that is downstream to TLR4 signaling has been linked to remodeling, there has been no evidence thus far describing a role of the parallel interferon regulatory factor-3 (IRF3) signaling cascade in any facet of this process. Several key findings suggest that IRFs contribute to both cell growth and apoptosis, thus providing an appealing, and novel target for interrogation. In this thesis I describe how IRF3 contributes to maladaptive remodeling post-MI. In my first set of experiments, I demonstrate that IRF3 is acutely upregulated within the cardiomyocyte following MI and that this response contributes to excessive apoptosis post-MI. A targeted deletion of the IRF3 gene enhances cardiac function, decreases infarct size, and improves survival following MI. In the second set of experiments I demonstrate that IRF3 attenuates angiogenesis at the ischemic border zone by upregulating the expression of thrombospondins. I have shown that IRF3 deficiency, which liberates endogenous anti-angiogenic signals, promotes angiogenesis following ischemic injury. These data suggest that IRF3 is a potent regulator of cardiac remodeling and may be an effective therapeutic target to ameliorate maladaptive cardiac repair post-MI.
A Role for Bclaf1 in mRNA Processing and Skeletal Muscle Differentiation
Keywords: Bclaf1
myoblasts
pre-mRNA processing
skeletal muscle
yeast two-hybrid
apoptosis

Bcl-2 associated factor 1 (Bclaf1; previously known as Btf) is a nuclear protein that was originally identified as an interacting partner for the adenoviral anti-apoptotic Bcl-2 family member E1B-19K. Surprisingly, Bclaf1 does not share structural homology with the Bcl-2 family of proteins, but rather exhibits protein structure and subcellular distribution patterns reminiscent of proteins that regulate mRNA processing. In addition, Bclaf1 appears to be expressed at high levels in skeletal muscle and was recently shown to associate with emerin, a protein linked to muscular dystrophy. Despite these observations, roles for Bclaf1 in RNA processing and/or skeletal muscle differentiation remain to be elucidated. In an effort to identify new roles for Bclaf1 I conducted protein-protein interaction screens to identify candidate interacting proteins and pathways. I identified p32 and 9G8 as novel interacting partners for Bclaf1. Additional subsequent experiments demonstrated an interaction of Bclaf1 with tip associated protein (Tap) and association of Bclaf1 with ribonucleoprotein complexes. Given that all of these proteins have been linked to mRNA processing, a role for Bclaf1 in this pathway was investigated. Using several approaches, I demonstrated that Bclaf1 is able to associate with splicing complexes and mRNA species at various stages of processing. The function of Bclaf1 in the context of skeletal muscle differentiation was also explored using skeletal muscle cell lines and primary mouse myoblasts. Skeletal muscle differentiation led to a dramatic decrease in nuclear Bclaf1 steady-state protein, with the unexpected appearance of smaller Bclaf1 protein species that accumulated in the cytoplasm during differentiation due to cleavage by caspases. Furthermore, Bclaf1 depletion in a myoblast cell line led to increased myoblast fusion and myofiber dimensions during differentiation. Overall our findings indicate roles for Bclaf1 in the skeletal muscle differentiation program and in molecular events that regulate pre-mRNA splicing and related events.
Evolution and Ecology of Flyingfishes (Teleostei:Exocoetidae)
Keywords: phylogenetics
speciation
population genetics
habitat modeling
epipelagic
flyingfish

The flyingfishes (Teleostei: Exocoetidae) are a family of 53 epipelagic marine species distributed throughout tropical and subtropical surface waters. They form a key mid-trophic link between zooplankton and predators, and have evolved special adaptations to survive in the open ocean. However, little is known about their basic evolutionary history and ecology. Here, I apply a multidisciplinary approach to better understand the evolution and ecology of flyingfishes. I propose the first species-level phylogenetic hypothesis for the group, based on nuclear and mtDNA sequences, and show that the most speciose genus (Cheilopogon) is paraphyletic. Gliding evolved progressively from two- to four-wing strategies, and habitat preference is correlated with species range size. I also analyzed patterns of genetic diversity within the most abundant genus, Exocoetus, and found no evidence of cryptic species. Instead, I found that this genus likely consists of three genetically distinct species (in contrast to the five currently recognized) and two indistinct species that diverged very recently. Population genetic analysis of Exocoetus volitans (266 samples from 97 localities) indicates a single, circum-tropical population that is well connected; yet the Isthmus of Panama and an Equatorial barrier limit gene flow. Finally, I investigated species abundance, richness, diversity, and distributions within the eastern tropical Pacific Ocean (11,125 specimens). My results provide critical updates on species distributions and habitat preferences. Predictive modeling indicates that sea surface temperature is important for defining flyingfish habitat. This thesis addresses central issues concerning both evolution and ecology in the epipelagic zone, and highlights the need for better understanding remote marine regions and organisms.
Knowledge Sharing: An Empirical Study of the Role of Trust and Other Social-cognitive Factors in an Organizational Setting
Keywords: Knowledge Sharing
Trust
Knowledge Sharing Behavior
Homophily
Shared Perspective
Shared Language
Shared Vision
Tie Strength
Relationship Length
Social-Cognitive Factors
Trust as a Mediating Factor
Willingness to Share Knowledge
Willingness to Use Knowledge
Perceived Receipt of Useful Knowledge
Organizational Behavior
Professional Service Firm (PSF)
Knowledge Workers
Empirical Study

Effective knowledge sharing within project teams is critical to knowledge-intensive professional service firms. Prior research studies indicate a positive association between trust, social-cognitive factors, and effective knowledge sharing among co-workers. The conceptual framework proposed here builds on these studies, and draws from theoretical foundations from the organizational behavior, psychology, information studies, sociology, and management literature on organizational trust and knowledge sharing, and identifies the most significant factors found to influence organizational knowledge sharing directly and indirectly through trust. The study makes methodological contributions in the form of conceptualizations for knowledge sharing behavior, trust, and tie strength. Also, it provides a more nuanced and focused analysis, by factoring for knowledge type and co-worker working relationship. Data were collected from 275 knowledge workers (‘legal professionals’ and paralegals) engaged in shared legal project work, at one of Canada’s largest multijurisdictional law firms. The nature of their work required a significant reliance on co-workers, for both explicit and tacit knowledge. Multiple regression analysis, among other statistical techniques, was used to test the hypotheses and determine significant relationships. Of the factors examined in the study, the three found to have the strongest effect on respondents’ trust in their co-workers were shared vision, shared language, and tie strength. Furthermore, the two factors found to have the strongest effect on organizational knowledge sharing behavior were trust and shared vision. Overall trust was also found to have a mediating effect between shared vision and knowledge sharing behavior, and between shared language and knowledge sharing behavior. A significant implication for practitioners is that effective knowledge sharing among co-workers requires a nurturing manager to work on developing co-worker trust and shared vision. Furthermore, a manager wanting to promote trust between co-workers must nurture shared language and shared vision.
Individual Differences and the Learning of Two Grammatical Features with Turkish Learners of English
Keywords: Language teaching
instructed second language acquisition
English as a foreign language
individual learner differences

This study investigated relationships between individual learner differences and the learning of two English structures that differed in their grammatical difficulty. Using a quasi-experimental design, 66 secondary-level learners of English as a foreign language from three intact classes were provided with four hours of instruction on two L2 structures –one considered relatively easy to learn (i.e., past progressive) and the other relatively difficult to learn (i.e. passive construction). The participants were pretested on their knowledge of both structures and posttested immediately after the instruction. Learners’ progress was measured via written grammaticality judgment tests (GJT) and oral production tasks (OPT). The instruments to measure individual learner differences included a computerized language aptitude test, an L1 metalinguistic awareness test, a motivation questionnaire, a backward digit span test, and a learner retrospection questionnaire. The results revealed that aptitude and motivation were the two variables that significantly contributed to learners’ gains with respect to the ‘passive’ and that L1 metalinguistic awareness explained significant variation in learners’ gains regarding the ‘past progressive’. These relationships were observed with learners’ performance on the written but not oral measures. A detailed analysis of the aptitude test components revealed that the grammatical inferencing subtask was significantly related to L2 gains on the ‘passive’ – again only with respect to learners’ performance on the written GJT. The results also revealed that learners with different aptitude profiles (i.e., low, medium, high) benefited differently from instruction on the two target features. High aptitude learners performed better than low aptitude learners on the ‘passive’ as measured by the GJT posttest. With respect to the ‘past progressive’ only learners in the medium aptitude profile group improved significantly on the written GJT. These findings confirm that language aptitude holds a role in language learning but that there are other factors (i.e., motivation and L1 metalinguistic awareness) that also contribute to L2 progress. These results also provide evidence from a classroom-based study that the grammatical difficulty of what is to be learned is a factor in determining what cognitive abilities L2 learners rely on in their efforts to learn a new language.
Determining Lineage Fate, Survival and Proliferation of Differentiating Thymocytes: Interplay between Notch, TCR, PI3K and MAPK Pathways
Keywords: T cell development
Notch signaling

A common bipotent thymocyte precursor gives rise to both lineages of T cells, αβ and γδ. This thesis addresses how the interplay between intrinsic T cell receptor (TCR) signals and cell extrinsic signals provided by Notch and TCR ligands help to assign and support a final lineage fate decision. Emerging data supports a model in which differential TCR signaling capacity plays an instructional role in specifying lineage fate, particularly through induction of the ERK - early growth response gene (Egr) - inhibitor of DNA binding 3 (Id3) pathway. In particular, Id3 expression serves to regulate adoption of the γδ fate. Moreover, Id3 is both necessary and sufficient to enable γδ-lineage cells to differentiate independently of Notch signaling and become competent interferon (IFN)-γ-producing effectors. These findings identify Id3 as a central player that controls both adoption of the γδ fate and their maturation in the thymus. While loss of Notch signaling in γδTCR-expressing CD4-CD8- (DN)3 cells does not affect development, Notch signals are critical for pre-TCR-bearing cells to transition to the CD4+CD8+ (DP) stage of αβ T cell development. Notch signals affect the activation of the PI3K/Akt pathway, which is required for pTα/TCRβ (pre-TCR)-induced survival, differentiation and proliferation of developing αβ-lineage thymocytes. Here, I identify the key molecular players responsible for the interaction between the Notch and PI3K pathways at this critical developmental stage. Notch induction of Hes1 expression is necessary to repress the expression of the PI3K/Akt pathway inhibitor, PTEN, which in turn facilitates pre-TCR-induced differentiation. c-Myc, another critical target of Notch, is required for proliferation during β-selection. Lastly, I find that the majority of DN3 cells expressing both pre-TCR and γδTCR follow the signal strength model for lineage development, and commit and mature along the γδ-lineage. However, manipulation of signal strength, through γδTCR ligand availability or Id3 expression, can skew this development outcome. Taken together, the results from this thesis provide a detailed examination of the molecular mechanisms that are instrumental in determining lineage fate, survival, and proliferation of differentiating thymocytes. Central to these outcomes is the interplay between the Notch, TCR, PI3K, and MAPK signaling pathways.
Engineering Boronsubphthalocyanine for Organic Electronic Applications
Keywords: Organic Electronics
Subphthalocyanine
Photovoltaics
Light Emitting Diodes

Boronsubphthalocyanines (BsubPcs) are a class of organic semiconducting materials which are relatively underdeveloped in their synthetic methods and organic semiconducting applications. A comprehensive investigation of these materials is explored in a rigorous and strategic manner progressing through each stage of the materials development cycle: materials selection from computational screening, organic/organometallic synthesis of target materials using known methods or by the development of new synthetic methods, physical and chemical analysis of new materials, and device implementation in organic light emitting diodes and organic photovoltaic cells. The result is the formation of new compositions of BsubPc specifically engineered for application as organic semiconductors in devices. Specifically, phenoxy-boronsubphthalocyanine derivatives are investigated starting with a computational study of their molecular orbitals – a property that dictates their function (donor or acceptor behaviour) in organic electronic devices. The nature of the axial phenoxylate is found to vary the energy level of the frontier molecular orbitals minimally, by up to ~0.4 eV while the nature of the BsubPc periphery can shift the energy levels of the frontier molecular orbitals by >1 eV. The differential sensitivity of the axial phenoxylate and the BsubPc periphery becomes a key design element allowing controlled adjustments of the frontier molecular orbitals by peripheral modification and isolating the design physical chemical properties essential to device fabrication to the axial phenoxylate. Subsequently, an investigation into the solubility and sublimability of these materials is performed, which leads to their investigation in OLED and OPV devices. The success from the phenoxy-BsubPcs study has led to the exploration of new chemistry to expand the available axial nucleophiles beyond phenoxylates. Previously unattainable sulphur and nitrogen nucleophiles are synthesised using two methods (1) the condensation of Cl-BsubPc with phthalimides and (2) the activation of Cl-BsubPc using aluminum chloride to access thiols and anilines. The phthalimido-BsubPcs synthesized from this method are incorporated in OLEDs.
Kleinian Reparation: A Psychoanalytic Exploration of Residential School Apology in Canada
Keywords: Religion
United Church of Canada
History
Psychoanalysis
Canadian Government
Melanie Klein
Apology
Residential Schools

The work of mid-twentieth century psychoanalyst Melanie Klein stresses the importance of the phantasy world and its role within the human psyche. For Klein innate human destructive phantasies coexist with feelings of love, guilt, and reparation. Love and hate exist in tension with one another and one must cope with balancing these feelings. I will use the psychoanalytic concept of reparation as understood by Klein to explore the performance of apology and reparation. Reparation, for Klein, refers to the psychological need to make things good, that is to say, to mend and repair relationships with others. Using this concept this work will examine the United Church of Canada's 1986 and 1998 apologies to First Nations peoples for its involvement in the residential school system, as well as the Canadian government's “Statement of Reconciliation” and 2008 apology for residential schools. This work asks the question: are these apologies effective in their attempts to make amends for past injustices or are they examples of what Klein calls “manic reparation”, which works to conceal, hide, or preserve phantasies of aggression? Klein's theories will provide a new and evaluative theoretical lens to discuss apology. The academic study of apology currently seeks to find “categorical elements”, which are then used to decide if the apology is a “success.” But this approach is missing the important component of the implied reparative concept within an apology. An apology is not only a written text but also an act that can work to conceal or reveal the perpetrators’ view of their transgressions. Exploring the manifest and latent content of apologies will provide a richer insight into the apology process.
Modeling Evolution
Keywords: Evolution
Philosophy of Science

Evolution by natural selection began as a biological concept, but since Darwin it has been recognized to have broader application than biology. Applying evolutionary ideas beyond biology requires that the principles of evolution by natural selection be abstracted and generalized from the biological case. The received view of evolution by natural selection in biology is itself seriously flawed, which understandably renders the project of abstracting it and applying it elsewhere challenging. This thesis develops a generalized account of models of evolution by natural selection which is used to resolve various outstanding issues in the philosophy of biology. This also clarifies the methods and prospects of applying evolution by natural selection to non-biological domains. It does so by analyzing models of evolution both within biology and outside it, relying in particular on the contrast provided by models of firm competition in evolutionary economics. This analysis highlights those aspects of the classical view which must be abandoned or revised, and leads to the development of a neo-dynamical model of evolution, which is developed, explained, defended, and applied to problems in evolutionary biology and multi-level selection theory.
Development and Application of a Novel Method to Detect Mammalian Protein-protein Interactions
Keywords: Protein-protein interactions
Cancer
Alternative splicing

Understanding normal and cancer cell biology requires the development and application of systems biology approaches capable of probing the functional human proteome, and the protein-protein interactions (PPIs) within it. Such technologies will facilitate our understanding of how molecular events drive phenotypic outcomes, and how these processes are perturbed in disease conditions. In this thesis, I first describe the development of a mammalian, Gateway compatible, lentivirus-based protein-fragment complementation assay (magical-PCA), for the in vivo high-throughput identification of PPIs in mammalian cells. This technology provides a vast improvement over current PCA methodologies by allowing for pooled, proteome-scale mapping of PPIs in any mammalian cell line of interest, using any bait protein of interest. A proof-of-concept pooled genome-scale screen using the magical-PCA approach was performed using the human mitochondrial protein TOMM22 as a bait, providing evidence that this technology is amenable to proteome-wide screens. Moreover, the TOMM22 screens offered novel insight into links between TOMM22 and proteins involved in mitochondrial organization, apoptosis, and cell cycle dynamics. Second, I performed a pooled genome-scale magical-PCA screen with the oncoprotein BMI1, a component of the E3 ubiquitin ligase complex involved in histone H2A mono-ubiquitination and gene silencing, to identify novel BMI1 protein interactors. Consequently, I have uncovered a novel physical and functional association between BMI1 and components of the mammalian splicing machinery. I further discovered that BMI1 knockdown influenced the alternative splicing of a number of cellular pre-mRNAs in colon cancer cell lines, suggesting that the association between BMI1 and cellular splicing factors impinges on pre-mRNA processing. Importantly, BMI1 expression was shown to influence the alternative splicing of the SS18 oncoprotein towards an exon 8-excluded isoform, which was shown in this study to promote cell proliferation when assessed in an anchorage-independent growth assay. Together, these studies highlight the development of a new methodology for the detection and proteome-scale screening of mammalian PPIs. A proof-of-concept screen with human TOMM22 highlighted the utility of the approach, as I was able to detect both strong and weak or transient PPIs. Application of my screening methodology to BMI1 provided crucial insight into the function of this oncoprotein, and BMI1-driven tumorigenesis.