VictorJuiz/thesis huggingface dataset:
Proneural Genes; Old Players with New Functions in Controlling Neocortical Neural Progenitor Cell Behaviour

The neocortex is a six-layered, mammalian-specific brain region that is the main subdomain of the cerebral cortex. Cerebral cortices differ in size and shape across species, and can be ‘smooth’ (lissencephalic) or highly folded (gyrencephalic) in small versus most larger mammals, respectively. For these complex cortical patterns to develop in a species-specific fashion, precise numbers of neurons with specific regional identities must be generated at their correct developmental times and in appropriate locations. Proneural genes encode basic-helix-loop-helix (bHLH) transcription factors (TFs) that are necessary and sufficient to promote neurogenesis and specify neuronal subtype identities. In the developing neocortex, three proneural genes are expressed, Neurog2, Neurog1 and Ascl1, but how these genes interact was poorly understood at the outset of my thesis project. My global hypothesis was that protein-protein interactions regulate proneural TF activity, including interactions between proneural TFs themselves, as well as interactions with other unknown factors. To test this hypothesis, I first showed that Neurog1 inhibits Neurog2 to slow down the pace of early neurogenesis, when deep-layer neurons are being born (Chapter 2). I then discovered that Neurog2 and Ascl1 expression defines four neural progenitor cell (NPC) pools in the neocortex; proneural negative, Neurog2+, Ascl1+, and double+, each with unique lineage biases, transcriptomes, epigenomes and gene regulatory networks (GRN) (Chapter 3). To test the requirement for double+ NPCs, I developed a novel split-cre ‘deleter’ approach, revealing an essential role as Notch ligand producing niche cells that preventing cortical folding in the lissencephalic mouse brain. Finally, I found that Neurog2 interacts with L3mbtl3, a potential link to recruit the gene silencing, polycomb repressive complexes (PRC) to the genome (Chapter 4). Strikingly, in L3mbtl3 knock-outs (KO), I observed a global decrease in cortical neurogenesis due to a derepression of transcriptional repressors, while L3mbtl3 overexpression also inhibited neurogenesis, but by interfering with mRNA processing of neurogenic genes. In conclusion, I have gained new insights into how proneural TF act together or with other proteins to precisely regulate the delicate process of cortical neurogenesis. My findings may impact the future design of proneural TF-based direct neuronal reprogramming strategies for regenerative medicine.

Advisor: Schuurmans, Carol
The Use of Dental Topographic Analysis in the Examination of Microsyopid (Mammalia, ?Primates) Evolution, Dietary Change, and Intraspecific Variation

Plesiadapiforms are possible stem primates that first appear shortly after the extinction of the dinosaurs. One family of plesiadapiform, the Microsyopidae, is known from several thousand specimens from the early Eocene (approx. 55-52 million years ago) of the Southern Bighorn Basin, Wyoming. This dissertation uses a suite of methods called dental topographic analysis (DTA) to quantify functional aspects of microsyopid teeth. It also introduces a new method to study diet using variation in the frequency of dental caries.First, using DTA, I show that three early species of microsyopids (Arctodontomys wilsoni, A. nuptus, Microsyops angustidens) deriving from before, during, and after a localized cooling event, underwent dietary change leading up to and during this climatic event, associated only in part with taxonomic turnover. This expands on previous research suggesting that this event played a role in faunal turnover. In the second study, I focus on intraspecific variation in diet. Previously, DTA has been primarily used to study diet in extinct taxa at the interspecific level. The later occurring Microsyops latidens is known from over 1,000 specimens, and thus gives us an opportunity to iii look at finer scale variation in dental morphology (and therefore diet) over time. Although they lived during a period when local climate likely fluctuated, results suggest that diet remained relatively stable, pointing to the plasticity of this taxon, although a single specimen from a poorly sampled interval is suggestive of one brief period of change. Finally, M. latidens is characterized by a high prevalence of caries. Caries frequency suggests that the diet of M. latidens may not have been as stable as the overall dental topographic data suggest. There is a period during which caries frequency is much higher than expected in comparison to extant taxa, pointing to a temporary increase in the consumption of sugary foods in M. latidens, possibly associated with the outlier specimen in the DTA analysis. This chapter provides a framework for assessing caries in other fossil taxa. Overall, this dissertation provides new insights into the complex diet of microsyopids, a group for which little previous ecological information was known.

Keywords: Dental
Microsyopids
Morphology
Plesiadapiforms
Topography
Advisor: Silcox, Mary T
A Comparison of the Product (Re)formulation Actions and Commitments of the Top Packaged Food and Beverage Companies in Canada

Canada’s packaged food supply is dominated by energy-dense products high in nutrients of public health concern, increasing obesity and non-communicable disease risk. Many packaged food and beverage companies voluntarily commit to improving the nutritional quality of their products. While monitoring is needed to hold companies accountable for these commitments and thereby prompt improvements, there has been little independent monitoring of their voluntary product (re)formulation efforts in Canada.This thesis aimed to conduct a comprehensive comparison of the product (re)formulation actions and commitments of the top 22 packaged food and beverage companies in Canada. In Study 1, a branded food database was used to compare the nutritional quality of products offered by these companies in 2017, overall and by food category, using multiple measures of nutritional quality. The nutritional quality of products offered by these companies differed significantly overall and by food category, with many products considered less healthy. Study 2 aimed to develop and apply a tool for quantifying the strength of companies’ voluntary recent actions and commitments to improve the nutritional quality of their products. Scores based on the Food Company Reformulation (FCR) tool were low, on average, suggesting that many of Canada’s leading food companies report limited or no action concerning product (re)formulation. Study 3 examined the relationship between the strength of companies’ voluntary product (re)formulation commitments and changes in the nutritional quality of their Canadian products, using companies’ FCR scores and branded food data collected in 2013 and 2017. While some companies improved the healthfulness of their products over this period, many companies’ product portfolios were unchanged or became less healthy from 2013-2017. Moreover, the products of companies reporting stronger voluntary product (re)formulation actions/commitments did not undergo greater improvement in nutritional quality over time, nor were their products significantly healthier. Overall, many of Canada’s leading food companies have not made meaningful improvements to the nutritional quality of their products in recent years; however, there is considerable variation between companies in terms of their product (re)formulation actions and commitments. These findings highlight a need for mandatory government interventions to help improve the healthfulness of Canada’s packaged food supply.

Advisor: L'Abbé, Mary R.
Feasibility of Using Transcranial Direct Current Stimulation to Improve Insight in Patients with Schizophrenia Spectrum Disorders

Impaired insight into illness is a common feature of schizophrenia that contributes to antipsychotic medication nonadherence and poor clinical outcomes. Currently, there are no established treatment options to improve insight in patients with schizophrenia. Common psychological interventions such as cognitive behavioural therapy and psychoeducation have shown limited effects on improving insight, indicating the need for alternative approaches. Here we explored the feasibility of using transcranial direct current stimulation (tDCS) to improve insight in patients with schizophrenia. First, we performed a systematic review and meta-analysis of randomized-sham controlled trials (RCT) to evaluate the clinical effects of tDCS in patients with schizophrenia. We showed that active compared to sham tDCS reduced the severity of auditory hallucinations and negative symptoms, but that the effects were more pronounced when ten or more sessions of tDCS were applied. Second, we examined the neuroimaging effects of tDCS on brain regions associated with impaired insight using task-based functional MRI and arterial spin labeling. We showed that bilateral tDCS to the parietal regions transiently modulated task-based brain activity and cerebral blood flow in the posterior parietal regions. Lastly, we examined the longitudinal relationship between impaired insight and antipsychotic medication nonadherence. We found that patients with impaired insight were more likely to show earlier nonadherence compared to patients with no or minimal impairment and that the rates of nonadherence in patients with impaired insight were significantly higher after 6 months of treatment initiation. Taken together, the results of this thesis work suggest that tDCS may be a feasible adjunctive treatment to improve insight in patients with schizophrenia. We also highlight the need to utilize intervention strategies early during treatment to improve or maintain insight and medication adherence in patients with schizophrenia.

Keywords: Illness awareness
Insight into illness
MRI
Neuroimaging
Schizophrenia
tDCS
Advisor: Gerretsen, Philip
Graff-Guerrero, Ariel
Design and Applications of Biomimetic Nanofibrillar Hydrogels

Networks of nanofibers are ubiquitous in biological systems: the cellular cytoskeleton is composed of actin fibers, microtubules, and intermediate filaments, while the extracellular matrix (ECM) is made up of collagen, elastin, and fibronectin fibers. The filamentous architecture in these systems impacts biological processes and imparts the ECM and cytoskeleton with unique nonlinear mechanical properties. Nanofibrillar hydrogels that recapitulate the structure and nonlinear mechanical properties of these biological nanofiber networks have tremendous potential for applications in tissue engineering and three-dimensional cell culture. My thesis is focused on using rod-shaped cellulose nanocrystal (CNCs) as building blocks for nanofibrillar hydrogels. I first present two approaches for preparing CNC-based hydrogels: (1) by grafting thermoresponsive gelling polymers to the CNC surface, or (2) by mixing aldehyde functionalized CNCs with a crosslinking polymer (gelatin). The second approach, CNCs crosslinked with gelatin, produced a biocompatible fibrillar hydrogel named EKGel that had a precisely tunable structure, as well as a scalable and simple synthesis. Furthermore, I demonstrated that, because of its filamentous architecture, EKGel recapitulates the unique nonlinear mechanical properties of biological nanofiber networks. After establishing its ability to recapitulate the structure and properties of biological nanofiber networks, I explored several potential applications of EKGel. For example, through a microextrusion 3D-printing approach, EKGel can be used to prepare patterned structurally anisotropic hydrogel sheets for tissue engineering. Additionally, by modulating the composition of EKGel I was able to mimic the dynamic structural changes that occur in the ECM during tissue fibrosis, making EKGel an excellent matrix for in-vitro studies of fibrotic disease. I also describe the application of EKGel for the culture of patient-derived breast tumor organoids and demonstrate that EKGel is an improved alternative to the current gold-standard, BME. Finally, I describe the incorporation of EKGel into a microfluidic tumor spheroids-on-a-chip platform for drug screening.

Keywords: Cancer
Cellulose
Fibers
Hydrogels
Organoids
Polymers
Advisor: Kumacheva, Eugenia
Making Difficult Decisions: An Activity-theory Informed Qualitative Study of Shared Decision-Making for Children with Medical Complexity

‘You are the expert when it comes to your child,’ is a common refrain heard by parents of children who frequently use healthcare. Parents are told that their ‘voice’ matters and that physicians want to work in partnership with parents to achieve the best for their children. At the same time, parents often express concern with being excluded from important discussions around the care of their child and feel that their concerns are not heard. The disparity between parental expectations and the reality of the healthcare experience, suggests that the willingness of physicians and parents to share the decision-making process may not be enough to ensure that a shared process unfolds. With a focus on children with medical complexity (CMC) who are frequent users of the healthcare system, this study aims to better understand the decision-making processes of those caring for CMC as a basis for developing solutions to improve the shared process. Taking a view of decision-making as a personal yet interconnected activity, we sought to understand the separate decision-making processes of the individual parties, parents of CMC, and the physicians treating CMC. With a better understanding of each party’s decision-making process, we then look at where the parent and physician decision-making processes have the potential to overlap and be shared. With the aim of developing an adaptable and practical model of shared decision-making (SDM) for CMC, we draw on findings from our studies on the individual processes of decision-making, build on existing models of shared decision-making and suggest a new model for SDM. The new model of SDM for CMC proposed as a result of this study reimagines shared decision-making as more than simply the exchange of information between the two parties. Our model considers how to best depict an SDM process that emphasizes the sharing of context within a limited scope, supports the family’s understanding, and is oriented towards achieving the family’s goal of coming to a decision with which they are comfortable.

Keywords: Child
Children with Medical Complexity
Parents
Pediatrics
Physician-Parent Communication
Shared Decision-Making
Advisor: Shachak, Aviv
Parkdale Infant Nutrition Security Targeted Evaluation Project (PINSTEP): Formative Research

Background: Socially and/or economically vulnerable women in Canada have lower rates of breastfeeding. Skilled lactation support is one key strategy for improving practices, but it is less accessible to vulnerable women. The Canada Prenatal Nutrition Program (CPNP) aims to support breastfeeding among vulnerable women, but investigation of the potential to integrate postnatal lactation support has not been explored. Objectives: Formative research was conducted with participants at one Toronto CPNP site with separately funded postnatal lactation support services to determine (1) maternal sociodemographic/psychosocial characteristics and their association with CPNP participation; (2) experiences with breastfeeding and the lactation support program (in-home lactation consultant visits, breast pumps); (3) utilization of the lactation support program, infant feeding practices, and associations between maternal sociodemographics and six-month breastfeeding practices. Methods: (1) retrospective chart review of registered clients from 2013-2016 (n=339); (2) focus groups and interviews with 46 clients; (3) prospective cohort study collecting infant feeding data to six months postpartum (n=199). Results: CPNP clients at this site demonstrated a variety of vulnerabilities (e.g. 80% were born outside of Canada, 65% had incomes below the Low-Income Cut-Off), with few differences in CPNP participation based on maternal characteristics. Qualitative participants reported that the lactation support program helped to mitigate some physical, practical, and self-efficacy breastfeeding challenges. The most valued elements were the in-home services delivered by skilled, non-judgmental providers. Seventy-five percent of prospective cohort study participants received at least one lactation consultant visit. All participants initiated breastfeeding, 84% continued for six months, and 16% exclusively breastfed for six months. In univariate analyses, food insecurity was associated with lower rates of any breastfeeding at six months (p=0.014) and ≤ high school education with lower exclusive breastfeeding for six months (p=0.034). Conclusions: Results indicate that this CPNP site serves vulnerable women, their lactation support program is well-accepted and utilized, and a high proportion of women continued breastfeeding to six months. Mixed methods implementation research is needed to evaluate the effectiveness and feasibility of delivering postnatal lactation support within other CPNP sites across Canada and further investigation of preceding and contextual barriers to breastfeeding, such as food insecurity, is required.

Keywords: breastfeeding
breastfeeding support
Canada Prenatal Nutrition Program
infant and child nutrition
infant feeding
Advisor: O'Connor, Deborah L
Sellen, Daniel W
Stimulated Emission Luminescent Solar Concentrators (SELSCs): A Modelling and Materials Study

A luminescent solar concentrator (LSC) consists of a slab of optical waveguiding material comprising a dispersion of fluorophore which absorbs, emits and conveys light to photovoltaic (PV) cells placed on the edges of the slab via total internal reflection. LSCs, however, suffer from a wide variety of losses, leading to poor solar efficiencies. Stimulated emission luminescent solar concentrators (SELSCs) have been proposed as a possible approach to substantially reduce escape cone losses. SELSCs consist of an LSC coupled to a seed laser which induces stimulated emission, increasing the probability of emission in the direction of the edge PV cell. The SELSC idea has seen scant research in literature. The objective of this thesis is to develop a scientific direction for the field by undertaking broad and in-depth investigations of SELSCs from a variety of perspectives. Further, the research herein is fundamental and has relevance for various similar applications including solar pumped lasers. First, we compare the performance of rectangular geometry based SELSC directly with LSC using an ideal 4-level system and show that under the right conditions stimulated emission can help outperform a conventional LSC. We also show that circular SELSC will always outperform rectangular slab SELSC. Furthermore, we demonstrate using calculus of variations that steady-state SELSC will always outperform pulsed SELSC. Second, detailed balance limits for the inversion of solar pumped devices, first reported by Roxlo and Yablonovitch, are revisited and amended. In particular, two previous inequalities are correctly amalgamated and reduced into a single inequality. With this revised detailed balance limit, a material model is proposed and detailed numerical calculations are carried out, thereby firmly establishing the bounds on performance. Finally, the luminescence of SiOx:Nd when annealed in forming gas is studied using a variety of characterization techniques to determine its potential as a suitable material for 1-sun inversion. The forming gas treatment greatly improved photoluminescence, and, while gain measurements were inconclusive, the detailed balance inequality indicates promise. In addition, insights are gained into the sensitization mechanism for SiOx:Nd films deposited using reactive sputtering. It appears to be either defect mediated or the silicon nanoclusters are also sensitized.

Advisor: Kherani, Nazir P.
Voice Your Values, a Tailored Advance Care Planning Intervention in Persons Living with Early Dementia: A Pilot Study

A palliative approach to care aims to meet the needs of patients and caregivers throughout the trajectory of a chronic disease, such as dementia, and can be delivered by clinicians who are not specialists in palliative care. Advance care planning (ACP) is an important component of the palliative approach. Timely ACP can improve outcomes for persons living with dementia (PLwD) and their care partners. Yet only a minority of PLwD participate in any ACP discussions. There remains a lack of evidence-based guidelines to inform clinical practice, specifically related to ACP for those living with early dementia. To address this gap, an intervention called Voice Your Values (VYV) was developed, that healthcare professionals can implement to identify and document the values and wishes of PLwD for their future care. The tailored VYV intervention was evaluated using a single group pre-test and post-test design to determine its feasibility, acceptability, and preliminary efficacy. A convenience sample of 21 dyads of PLwD and their trusted individuals, such as family and friends, was recruited from five geriatric clinics in Ontario. The VYV intervention was delivered to dyads over two sessions using a secure videoconferencing platform. The recruitment rate was lower (52%) than expected (60%); however, the retention rate was high at 94%, and 100% of the participants rated VYV as highly acceptable. The PLwD demonstrated improvement in ACP engagement (p=.00). The trusted individuals showed improvement in decision-making confidence (p=.01) and psychological distress (p=.02), but no improvement in dementia knowledge (p=.22). The video and sound quality were rated highly. All PLwD were able to articulate and document their values and wishes related to terminal and vegetative states. The VYV study experienced some difficulties with recruitment. As well, some intervention sessions took longer than expected to deliver, highlighting the need for ACP conversations and the high level of engagement from participants, but also raising concern about the practicality of such lengthy conversations in actual clinical settings with limited resources. That said, the study demonstrated a high retention rate, intervention fidelity, and acceptability. Future studies are needed to further refine the VYV intervention and establish its efficacy using randomization and larger sample sizes.

Keywords: Advance care planning
Aging
Dementia
Palliative approach
Pilot study
Primary care providers
Advisor: McGilton, Katherine