VictorJuiz/thesis huggingface dataset:
Spatial Information Modulates the Neurocognitive Dynamics of Episodic Autobiographical Memory Retrieval
Keywords: Autobiographical Memory
Cognitive Neuroscience
Neural Oscillations
Parietal Lobe
Spatial Cognition
Transcranial Magnetic Stimulation

Episodic autobiographical memory (EAM) enables reliving past experiences, recalling the sensory information associated with that event. Spatial information is thought to play an early and important role in EAM, contributing to the dynamics of retrieval. Using a combination of behavioural, neuroimaging, and neurostimulation approaches, this dissertation aimed to examine the temporal dynamics of EAM and the role spatial information plays in its retrieval. Chapter 2 demonstrated a temporal precedence for spatial information at the behavioural level, but importantly found high individual variability in early recall of spatial information. Further, individual differences in spatial aspects of EAM were reflected in hippocampal and precuneus grey matter volumes. Chapter 3 examined the temporal dynamics of EAM at the neural level using magnetoencephalography (MEG). While cueing individuals with familiar locations altered the dynamics of retrieval, it did not confer an early neural advantage. Together with the findings from Chapter 2, these results indicate that early spatial information alters the dynamics of EAM retrieval, but does not play a ubiquitous or automatic role in EAM. This study also found that spatial perspective during EAM retrieval was associated with a well-established neural component of episodic memory recollection. Transcranial magnetic stimulation (TMS) administered to the precuneus disrupted this association, demonstrating that this region is crucially involved in neural processing of spatial perspective during EAM. In Chapter 4, I assessed how regions representing spatial information, such as the precuneus and medial temporal lobe (MTL), interact dynamically during EAM retrieval. Using MEG to measure oscillatory activity, this study found that theta (3-7 Hz) and high gamma (65-85 Hz) oscillations underlie MTL-parietal communication, demonstrating the importance of coupling between theta and gamma oscillations in EAM. TMS to the precuneus disrupted this oscillatory activity, suggesting that this region plays a causal role in network-wide theta and gamma oscillatory activity. Together, these studies elucidate the behavioural and neural dynamics of EAM retrieval, as well as spatial contributions to EAM. Future research is needed to further clarify the key contributions of specific regions and the dynamic activity underlying widespread neural communication during EAM.
Colloidal Quantum Dots for Solar Energy Conversion
Keywords: Energy conversion
Nanocrystals
Solar cells
Surface chemistry

Increasing global energy demand requires the development of clean energy sources that will help reduce the consumption of fossil fuels. Solar energy, the most abundant renewable source, is converted to electricity using photovoltaic devices. The photovoltaics market has witnessed rapid growth in the past decade, and today many photovoltaic strategies aim at low-cost, solution-processed manufacture. Colloidal quantum dots (CQDs), an emerging semiconductor material, have attracted attention in view of their spectral tunability. The bandgap of CQDs is readily tuned to harvest infrared solar energy. This could enable both full-spectrum devices and also tandem solar cells that can be integrated with wider-bandgap semiconductors. Unfortunately, a high density of surface-associated trap states, low carrier mobilities, and an inhomogeneous energy landscape have previously limited CQD photovoltaic performance. I introduce three strategies to address these problems. Through new materials processing approaches, I succeeded in increasing charge extraction, reducing bandtail states, and lowering the barrier to carrier hopping in CQD solids. The benefits from enhanced charge extraction were demonstrated in a double-sided junction architecture enabled by the engineering of an electron-accepting layer. This architecture resulted in an increase in the width of the carrier depletion region and a resultant decrease in recombination. I elucidated the effect of bandtail states on carrier transport and designed a solution-phase ligand-exchange method to create CQD inks that can be deposited as an active layer in a single step. The resulting CQD films exhibited a flattened energy landscape that increased the carrier diffusion length and contributed to solar cells having certified solar power conversion efficiencies of 11.3%. I then explored the translation of this strategy to small-bandgap infrared CQDs. Through management of surface ligands, I improved CQD passivation while reducing CQD fusion. I conclude with a new strategy for the design of a hybrid material system that combined CQDs with epitaxially-grown inorganic metal halide perovskites. The matrix-passivated CQD films showcased a two-fold increase in carrier mobility and superior thermal stability compared to pristine CQDs. This work provides promising pathways to achieve more fully the potential of CQD solids, and to showcase these advances in improved performance for CQD solar cells.
Investigation of Cell Growth and Differentiation Pathways in Neuroblastoma
Keywords: Cancer
Differentiation
ERRy
KLF5
Neuroblastoma

Neuroblastoma (NB) is a pediatric malignancy of the sympathetic nervous system and is derived from neural crest stem cells (NCSC). Over half of all patients present with metastatic disease with less than 50% surviving, despite aggressive multi-modal treatments including retinoic acid (RA) differentiation therapy. In my thesis studies, I used two approaches to identify novel genes and pathways involved in NB cell growth and differentiation. First, I identified genes that are differentially expressed between NCSCs and differentiated cells resident to the embryonic rat dorsal root ganglia (DRG), and prioritized those that correlated with patient outcome for further study. The expression of Kruppel-Like Factor 5 (KLF5) is increased in differentiated cells of the DRG and high expression of KLF5 correlates with favorable prognosis in NB patients. KLF5 was expressed in a panel of NB cell lines, was post-translationally modified selectively in cells with amplification of the MYCN oncogene, modified KLF5 protein forms were found in the nucleus and shRNA-mediated knockdown of KLF5 expression reduced apoptosis and increased proliferation in these cells. The second part of my thesis used an in-silico approach to identify small molecules that induced a gene expression profile similar to RA. I identified 4-hydroxytamoxifen (4HT), the active metabolite of the breast cancer therapeutic, tamoxifen, and demonstrated that it reduced NB cell growth and induced apoptosis in NB cell lines. 4HT also reduced NB xenograft tumour growth and increased survival relative to vehicle control. I further demonstrate that 4HT inhibits the transcriptional activity of the estrogen related receptor gamma (ERR) and shRNA mediated knockdown of ERR reduces NB cell growth in vitro. 4HT also induces the expression of cholesterol biosynthesis pathway enzymes, cellular cholesterol, and combination with the cholesterol biosynthesis inhibitor, fluvastatin, further reduces NB cell growth in vitro, identifying novel drug combinations for the treatment of NB.
Respiratory Function and Swallowing Impairment in the Spinal Cord Injury Population
Keywords: Dysphagia
Respiratory-Swallow Coordination
Spinal Cord Injury

Respiratory-swallow coordination is imperative to prevent aspiration of foreign material into the airway. Swallowing events typically occur during the expiratory phase of respiration; this is thought to facilitate laryngeal vestibule closure to prevent entry of material into the airway, and promote post-swallow clearance of any material that has penetrated into the laryngeal vestibule. By contrast, inspiration immediately post-swallow presents as a risk for aspiration. Individuals with respiratory impairment, such as those who have sustained a spinal cord injury, may experience changes in respiratory-swallow coordination, affecting their safety during oral intake. The focus of this dissertation was to explore the relationship between swallowing and respiration in the spinal cord injury (SCI) population. This was investigated in three phases: 1) a systematic review of current literature describing swallowing impairment and the efficacy of behavioural interventions in the SCI population; 2) a prospective study evaluating respiratory-swallow coordination in healthy young adults across a range of different liquid consistencies; and 3) a prospective study evaluating respiratory-swallow coordination in the SCI during a drinking task with 5 different liquid consistencies. Considered altogether, this work was able to provide novel contributions to the field of dysphagia research. This dissertation revealed a gap in knowledge about swallowing pathophysiology in the spinal cord injury population, with a need for high quality studies assessing the effectiveness of behavioural interventions in this population. The work of this dissertation was able to confirm stable respiratory-swallow relationships for healthy young adults across five liquid consistencies and provide reference data for respiratory phase pattern and pause duration. Finally, this dissertation provided evidence of changes in swallowing efficiency and respiratory-swallow coordination in the SCI population. These results demonstrate a need for further evaluation of the swallowing and respiratory subsystems in this population to establish clinical guidelines for assessment and intervention.
Unsupervised Multi-Scale Analysis for the Identification of Placental Subtypes of Human Preeclampsia and Fetal Growth Restriction
Keywords: fetal growth restriction
gene expression
histopathology
placenta
preeclampsia
subtypes

Preeclampsia (PE) and fetal growth restriction (FGR) are two of the most common pathologies of pregnancy, both thought to be primarily driven by placental dysfunction. Despite decades of research into the underlying etiologies of these disorders, as well as potential biomarkers and treatments, no single discovery has been found to be applicable to the entire clinical spectrum of PE or FGR patients, likely due to the existence of multiple disease subtypes. Therefore, the main goal of this thesis was to investigate if the application of unsupervised clustering techniques to placental gene expression data could elucidate transcriptional subtypes of PE and FGR with increased clinical and histopathological homogeneity. Clustering of three overlapping large microarray datasets revealed 3-5 molecular clusters, depending on the study. However, three subtypes of PE placentas were consistently identified within clusters 1-3, and, eventually, each co-clustered with a group of placentas from normotensive suspected FGR pregnancies. Within cluster 1, PE and suspected FGR samples demonstrated less severe clinical outcomes, molecular similarity to healthy term controls, and either no placental lesions or mild histopathology, suggesting a dominant non-placental source of the disease. Cluster 2 PE and FGR placentas revealed overwhelming evidence of “canonical” maternal vascular malperfusion features and increased placental expression of hypoxia and hormone activity genes. Cluster 3 PE and FGR samples displayed signs of an “immunological” pathology, with a transcriptional signature of immune response, apoptosis, and cytokine activity, and histological lesions affiliated with allograft rejection, such as massive perivillous fibrin deposition. In the largest microarray dataset (N=330), two additional clusters were discovered. Cluster 4 samples were preterm controls with histological chorioamnionitis, while cluster 5 was associated with confined placental mosaicism, but no clinical or histological cohesion. Furthermore, specific differences in the expression of three genes by qPCR were found to be sufficient for separating placentas into transcriptional clusters 1-4, which will allow future studies to focus on the identification of subtype-specific biomarkers and therapeutics for PE/FGR without having to first cluster microarray data. Matched maternal samples will also be necessary to comprehend the development of hypertension in some patients but not others with similar placental profiles.
Understanding biomolecular control of collagen mineralization and application to scaffold design for the regeneration of hard-soft tissue interfaces
Keywords: biomineralization
collagen
periodontium
scaffold
tissue interface

In vertebrates, collagen biomineralization is important to the structure and function of hard tissues, such as bones and teeth. This process is finely controlled, determining not only what tissues mineralize but also the phase and orientation of the incipient crystals. Currently, the molecular factors which direct collagen mineralization in vivo are poorly understood. A particularly elegant example of control over mineralization occurs at the tooth root. Here, collagen fibrils of the periodontal ligament become mineralized over only ~200 nm. This sharp interface between hard and soft tissues is an excellent environment in which to investigate the molecular control of collagen biomineralization. Elucidating the factors controlling biomineralization will contribute to the development of better treatments for periodontitis, a highly prevalent disease which results in tooth loss. We developed an in vitro model of collagen biomineralization using remineralizing sections of mouse periodontium. We show that extracellular matrix proteins retained within fixed tissue sections are sufficient to direct remineralization with a high degree of fidelity. Naturally mineralizing tissues remineralize leaving the ligament unmineralized. Modification of ECM components by enzymatic or chemical means results in a reduction in the rate of mineralization in the naturally mineralizing tissues. This suggests that the promotion of mineralization is more important to the spatial control of mineralization than inhibition. Drawing inspiration from our in vitro model we developed a trilayered collagen scaffold which incorporates individual tissue-specific compartments for the regeneration of the periodontium. SEM and TEM analysis shows that bone and cementum compartments contain biomimetic mineralized collagen. Layers are intrinsically connected with no need for adhesives. This represents the first of a generation of multiphasic scaffolds for periodontal regeneration which are designed to have control over mineralization. This work contributes to our understanding of collagen biomineralization. Understanding the mechanisms of which not only contributes to the development of better scaffolds for tissue regeneration but has the potential to contribute to the development of treatments for mineralization related diseases such as osteoporosis and heart valve calcification.
Characterization and Control of Leukemia Stem Cells in Acute Myeloid Leukemia
Keywords: Acute myeloid leukemia
cancer stem cell
gene regulatory network
Leukemia stem cell
Predictive model
statistical regression

The overall goal of this thesis is to explore the potential application of leukemia stem cell (LSC) properties for improving the treatment and management of adults with acute myeloid leukemia (AML), solidifying the clinical relevance of functional stem cell frequency estimates from xenotransplantation assays to human disease, and gaining insight into the gene regulatory logic underlying blood stem cells. Conventional risk stratification schemes in AML do not account for the leukemia initiating capacity of LSC within patient samples even though mounting evidence indicates its importance in the etiology and pathogenesis of AML. This may be attributed, at least in part, to insufficient data in support of the definitive relevance of xenografts (the gold standard assay for detecting LSC) to human disease. Instead, clinical schemes have focused on an ever-increasing number of genomic lesions for sorting patients into incrementally refined risk categories as newer technologies and larger study cohorts enable higher resolution and more complete capture of the continuum of genomic variation. Here, the derivation of the LSC17 gene expression score resulted in the first LSC-based diagnostic tool that complements and refines current risk assessment schemes, setting the stage for enhancing the overall accuracy of prognostic and predictive models in the clinic. The backbone of AML treatment has largely remained unchanged since the 1970s, and is curative for
Nanoparticle Guided Dentin Micro-tissue Engineering: Characterizing Fluid Dynamics for Delivery and Tissue Mechanical Response
Keywords: Dentin
Fluid dynamics
Mechanical integrity
Micro-tissue engineering
Nanoparticle
Root canal treatment

Disease process and iatrogenic procedures compromised the mechanical integrity of remaining dentin, which in turn increased the susceptibility of endodontically treated teeth to vertical root fracture. Cracks and fracture of endodontically treated teeth diminished the treatment predictability. Micro-tissue engineering principles are applied to design tissues with improved mechanical and biological characteristics. Chitosan nanoparticles (CSnp) are bioactive biopolymers, when applied to dentin displayed antimicrobial and enhanced toughness characteristics. Crosslinking CSnp with dentin collagen provides additional stabilization towards efficient mechanical load-transfer and resistance to matrix degradation. However, effective transport of nanoparticles into root canal remains to be a challenge owing to the complex canal morphology and non-uniform stresses generated with the syringe-based delivery method. The objectives of this study were: (1) to characterize the stability of the nanoparticle dispersion and surface ultra-structure of micro-tissue engineered dentin, (2) to evaluate the fluid-dynamics and delivery efficacy associated with a novel strategy based on activated microbubbles to deliver nanoparticles into root canal, and (3) to examine the effect of micro-tissue engineering with crosslinked-CSnp on the mechanical characteristics of root dentin. CSnp dispersion of 1mg/ml concentration was selected based on the nanoparticle aggregation kinetics. This concentration sustained the stability with optimal charge density and dispersity. Crosslinking CSnp on dentin resulted in a denser/homogeneous coating with altered hardness and elastic modulus on dentin surfaces. Ultrasonically activated microbubbles induced fluid-dynamics with high velocity and inertial stress through intensified cavitational bubble dynamics but formed a coating of CSnp mixed with dentin smear layer on canal wall. Manually agitated microbubbles generated uniformly high viscous stress with increased particle flux facilitating homogeneous coating of CSnp on root canal dentin. Micro-tissue engineered root canal dentin with crosslinked-CSnp and water-soluble chitosan resulted in decreased strain distribution enhancing the stability of root under physiologically loads. There was an increase in the sustained load at fracture in specimens treated with photodynamically-crosslinked-CSnp. The findings from this study emphasized the advantage of manually activated microbubbles to deliver CSnp in root canal and the impact of micro-tissue engineering with crosslinking CSnp on dentin to enhance the mechanical characteristics of root. These outcomes have potential application in clinical practice.
An Exploratory Case Study of Nursing Intellectual Capital and Hospital Performance
Keywords: case study
hospital performance
nursing intellectual capital

Nursing intellectual capital has emerged as a concept articulating the nature and significance of nursing knowledge inputs, or resources. While considerable literature has examined intellectual capital and its relationship to improved business performance, less is known about nursing intellectual capital and performance. Therefore, the purpose of this study was to explore the elements that comprise nursing intellectual capital, the conditions that help to develop it, and whether nursing intellectual capital is related to hospital performance. An exploratory case study was conducted in a large, academic hospital in Toronto, Canada, with the knowledge-based view of the firm serving as a theoretical lens. Two clinical programs, differentiable by performance metrics, were selected and served as the embedded units of analysis. Three sources of data – including administrative documents, archival records and key informant interviews – were collected at the program and organization levels. Twenty-one (21) key informant interviews were conducted, comprised of clinicians (n=8) and administrators (n=13), and data were qualitatively analyzed using the Framework Method approach to thematic analysis. Findings suggest that there is ambiguity regarding nursing intellectual capital, as well as overlap between nursing and other interprofessional knowledge resources. Participants spoke about a range of resources that were then classified at the individual and collective levels, manifesting as explicit and implicit in nature. Seven contextual factors were identified regarding the development of nursing intellectual capital, including: infrastructure, leadership, the influence of nursing in the organization, financial support, organizational culture, workload and time, and individual-level factors. All participants agreed generally that nursing intellectual capital related to hospital performance, and some highlighted nursing’s contribution to patient care; however, results were limited in explaining the relationship. Challenges in linking nursing intellectual capital to performance were likely owing to the limited translation of the case study’s balanced scorecard, as well as overlap between nursing intellectual capital and the balanced scorecard as organizing frameworks. This is the first study to explore the nature and potential relationship of nursing intellectual capital to hospital performance. Findings provide insight into the conceptualization, measurement, and management of nursing knowledge resources. Implications for leadership, theory development and future research are discussed.