VictorJuiz/thesis huggingface dataset:
An Investigation of Lipid Transport between the Endoplasmic Reticulum, Peroxisomes and Lipid Droplets

The interplay between peroxisomes and the endoplasmic reticulum (ER) and lipid droplets (LDs), is suggested to be important for peroxisome maintenance and metabolic functions. It is hypothesized that peroxisomes receive lipids from these two organelles as a source of lipids for growth and proliferation and substrates for metabolic activities. However, how lipids are exchanged between these organelles is poorly understood. Using RNA interference analysis, I have demonstrated that depletion of a peroxisome membrane protein ACBD5 decreased LDs size upon oleic acid loading. Consistently, induction of LD growth and proliferation by oleic acid in patient fibroblasts lacking peroxisomes were impaired, suggesting a role of peroxisomes in LD maintenance. Oxysterol binding protein (OSBP)-related proteins (ORPs), were implicated in the transport of lipids at ER-peroxisome contact sites. Using the peroxisome membrane expansion assay and overexpression subcellular localization studies, I had shown that ORP6 is a potential cholesterol transporter at ER-peroxisome contact sites.

Keywords: Intracellular lipid transfer
Lipid droplet
Membrane contact sites
Oxysterol binding proteins
Peroxisome
Advisor: Kim, Peter K
Pathogenesis of Integrin αIIb-mediated Fetal and Neonatal Alloimmune Thrombocytopenia: The Effect of Maternal Antibodies on Hematopoietic Stem Cells

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disorder caused by maternal immune responses to fetal platelet antigens, particularly αIIbβ3 integrin. Interestingly, although αIIb and β3 have similar genetic polymorphic frequencies, the reported incidence of αIIb-mediated FNAIT is at least 20 times less than β3-mediated FNAIT, the mechanism of which is unknown. Since hematopoietic stem cells (HSCs) express αIIb, I tested whether HSCs are affected in αIIb-mediated FNAIT. A mouse model was established in which fetal death was more frequently observed compared to the β3-mediated FNAIT model. Maternal anti-αIIb antibodies bound fetal HSCs in vivo, and impaired HSC migration was observed in embryonic day (E) 14.5 fetuses and post natal day one (PND1) neonates. I found that the liver may be a site of macrophage-mediated clearance at E14.5, prior to complete splenic development. PND1 HSC distribution was also irregular: significantly decreased in bone marrow and blood and significantly increased in lung and spleen.

Keywords: alloimmune
hematopoietic stem cells
human platelet antigen
thrombocytopenia
αIIbβ3 integrin
Advisor: Ni, Heyu
Connectivity Coarse Filter Approach for Marine Protected Area Network Design

Human use of the ocean is impacting biodiversity sustainability. To mitigate human pressure, governments have committed to protecting 10% of their oceans/coasts as Marine Protected Areas (MPAs). Determining the most effective placement of MPAs for conserving biodiversity should be done at a network scale such that MPA networks are placed to provide the greatest protection for multiple species. I propose a methodology to determine priority conservation areas for distinct species assemblages, located at different depths, to determine MPA network placement, using the Pacific Ocean in Canada as a case study. I found dispersal ability had a larger impact on MPA network configuration for species spending a long time as larvae compared to species spending a short time as larvae, and that climate change is likely to shift priority-area locations. The methodology proposed for MPA design relies on limited data and can be applied to other regions and ecosystems.

Keywords: Biophysical Model
Climate Change
Marine Protected Area
Marxan
Pelagic Larval Duration
Spatial Ecology
Advisor: Fortin, Marie-Josée
Krkošek, Martin
Characterization and Measurement Circuit Design for a Novel Low Noise and High Sensitivity MEMS Capacitive Accelerometer

A novel MEMS capacitive accelerometer was characterized and tested using a specifically designed low noise measurement circuit. The accelerometer architecture results in a low noise, highly sensitive single-axis device. Numerical simulations were conducted on the mechanical and electrical properties of the accelerometer and then verified experimentally. The accelerometer has a -3 dB bandwidth of 150 Hz, single-sided measurement range of 12 g and an estimated noise floor of 0.83 μg/√Hz which gives it a dynamic range of 121.5 dB. The core of the measurement circuit uses a transimpedance amplifier gain stage and a precision diode rectifier to demodulate the signal from the carrier wave. It has a noise floor of approximately 0.7 μV/√Hz and a range of ±10 V and was used to experimentally measure an accelerometer noise floor of 0.94 μg/√Hz.

Keywords: Accelerometer
Capacitive
Circuit
MEMS
Noise
Advisor: Ben-Mrad, Ridha
Evaluation of a Motor Imagery Electroencephalography Brain-computer Interface as an Access Technology for Children

Brain-computer interfaces (BCIs) have been proposed as an access technology for children with severe motor impairments. This study created an electroencephalography (EEG) pediatric BCI driven by motor imagery (MI) and evaluated its performance when controlled by 11 typically developing children aged 9-14 years. The online BCI demonstrated a limited ability to classify left versus right hand MI using spatial features (average 52±9%). Average classification in a retrospective analysis of a MI task versus rest, reached 70±3% indicating the potential for successful BCI control. Small or absent event-related desynchronization in participant-specific topographic representations of MI activity suggest that pediatric brains may not produce MI-related EEG patterns comparable to those of adults. EEG signal features known to be robustly discriminatory and effective in adults may not be appropriate for the pediatric population. Future pediatric MI-BCI studies should recruit larger cohorts of children and youth to test the generalizability of the present findings.

Keywords: Access technology
Brain-computer interface
Electroencephalography
Motor imagery
Pediatric
Advisor: Chau, Tom
Variations in Silviculture Practices Alters the Composition and Degradation of Soil Organic Matter in the Snowden Demonstration Forest, British Columbia

Forest management practices such as clear-cutting may result in the loss of soil carbon (C) potentially accelerating global warming from enhanced soil priming. Green tree retention (GTR) is an emerging silviculture treatment that retains forest cover and is suggested to be a better alternative. However, molecular-level analysis of soil organic matter (SOM) of GTR is lacking. Two different GTR practices and clear-cutting were evaluated at the Snowden Demonstration Forest. SOM biomarkers were analysed with gas chromatography-mass spectrometry (GC-MS) complimented with solid-state 13C nuclear magnetic resonance (NMR). Results suggests that harvesting of forest biomass resulted in significant differences in the composition of SOM (specifically lignin-derived inputs) compared to the uncut treatment 13 years post-harvest. Additionally, degradation of bulk soil (alkyl/O-alkyl ratio) was a result of lignin oxidation by fungi. Analysis of SOM with forest management practices employed in the logging industry will assist with the development of sustainable forest management practices.

Keywords: Forest harvesting
Gas chromatography-mass spectrometry
Nuclear magnetic resonance
Pacific Northwest
Sequential biomarker analysis
Soil organic matter
Advisor: Simpson, Myrna J
Multifaceted Control of Pancreatic Development by Mesenchymal Regulators of Hedgehog Signaling

Pancreatic development is coordinated by signaling pathways through dynamic epithelial-mesenchymal interactions that remain poorly understood. My work investigates epithelial-mesenchymal cross-talk underlying digestive organ development and reveals the existence of organ-specific mesenchymal niche signals as well as the specific downregulation of Hedgehog signaling in the pancreatic mesenchyme. Signaling activation via loss of Hedgehog negative regulators Sufu and/or Spop in the mesenchyme, but not the epithelium, severely inhibits pancreatic growth and endocrine differentiation through shifting mesenchymal identity towards a more gastrointestinal fate. Despite required downregulation by Sufu and Spop, mesenchymal Hedgehog signaling is still required as inactivation leads to malformations resembling the congenital disorder, annular pancreas. Altogether, my work demonstrates that the fine tuning of mesenchymal Hedgehog signaling by negative regulators, Sufu and Spop, is critical for proper pancreatic development and the establishment of organ-specific mesenchymal niches.

Advisor: Kim, Tae-Hee
UDP-glucose: glycoprotein glucosyltransferase 1 (UGGT1) substrate characterization

UDP-glucose: glycoprotein glucosyltransferase 1 (UGGT1) plays a quality control role in the ER by recognizing misfolded glycoproteins and glucosylating their Man9 N-glycans. To study the substrate specificity of UGGT1 and to produce an acceptor substrate for co-crystallization with UGGT1, I have purified Man9-glycosylated forms of bovine RiboB, RiboS, and S-protein. I have also produced variants of these proteins with the single N-glycan at Asn34 re-located to other sites. Using circular dichroism, I have established that RiboB is more thermostable than S-protein and RiboS. Accordingly, S-protein and RiboS are readily glucosylated and bound by human UGGT1. The Man9 form of the S-proteinN34Q/Y76N variant bound to UGGT1 with a KD of 76 μM. This substrate is a candidate for co-crystallization with UGGT1. The methods described here can also be used to study other UGGT1 substrates and will facilitate work aimed at understanding how UGGT1 recognizes its misfolded glycoprotein substrates.

Advisor: Rini, James M
The Role of Mdivi-1 in Colorectal Cancer

Cancer initiating cells (CICs) are known for their ability to self-renew while simultaneously giving rise to the tumor bulk. Attention has been given to their unique metabolic mechanisms to ensure their survival. Mitochondrial fission, regulated by dynamin-related protein 1 (DRP1), is upregulated in many cancers, and is required for the CIC fraction to maintain their stemness. Inhibiting DRP1 activity with pharmacological agent mitochondrial division inhibitor 1 (mdivi-1) results in decreased cell growth, viability, and importantly, tumorsphere formation. We hypothesize that colon cancer initiating cells (CCICs) are more dependent on DRP1 than non-colon cancer initiating cells (non-CCICs), and treatment of cultures with mdivi-1 will reduce proliferation and survival due to decreased DRP1 function. We find CCICs to express lower activated DRP1, yet their rate of proliferation decreased at a higher rate to the non-CCICs, while having a less viable population. We provide support that mdivi-1 treatment can compromise CCIC activity.

Advisor: O'Brien, Catherine A
The role of trophic interactions in shaping species persistence and coexistence outcomes

What maintains species diversity? While trophic interactions are hypothesized to promote species diversity, there are few empirical tests of how trophic interactions influence rare species persistence and coexistence. Here, I ask how fitness in rare plant species is indirectly influenced by the surrounding community via pollinator interactions. I found that the surrounding community can increase rare species fitness, but only when neighbouring species have a similar pollinator niche. This suggests that the effect of the surrounding community on rare species fitness depends on the overlap in trophic partners (mutualists, antagonists), and by promoting rare species fitness and persistence, trophic interactions can facilitate rare species establishment, invasion, and potentially coexistence in communities. I test these questions in an on-going experiment asking how herbivory influences plant species coexistence. Together, these results suggest that trophic interactions play a critical role in maintaining species diversity via rare species persistence, invasion and coexistence in communities.

Keywords: coexistence
community ecology
herbivory
persistence
pollination
population ecology
Advisor: Gilbert, Benjamin
Modulation of Wnt and Notch Signalling Pathways for Sensory Hair Cell Regeneration in the Mammalian Auditory Organ

I investigated the temporal pattern and underlying mechanisms of the transient regenerative response to canonical Wnt activation in the neonatal mouse cochlea. Ectopic Wnt activation in vitro in typically quiescent embryonic day (E) 13.5 and postnatal day (P) 0 cochleae promoted prosensory and supporting cell proliferation, respectively; however, this effect was no longer observed at P5. This age-dependent decline in proliferative capacity occurred despite similar levels of β-catenin accumulation in cochleae following transient exposure to the Wnt activator at all three developmental stages, suggesting that barriers to Wnt-mediated regeneration lie downstream of β-catenin stabilization and might be related to a lack of key transcription factors or limited access to downstream target genes. Furthermore, maintaining Wnt activation in early neonatal stages promoted changes in the expression of specific Wnt and Notch pathway genes and extended the window for hair cell induction in response to Notch signalling inhibition.

Keywords: Development
Hearing
Mouse cochlea
Notch
Regeneration
Wnt
Advisor: Dabdoub, Alain
An Examination of Interaction Dynamics During Sibling Conflict using Dynamic Structural Equation Modelling

Micro-processes of sibling interactions are associated with important aspects of child development (Dirks et al., 2015; Gass, Jenkins Dunn., 2007; Pike, Coldwell Dunn., 2005; Stocker, Burwell Briggs., 2002) underscoring their value for developmental research. Using a novel statistical framework, dynamic structural equation modeling (DSEM), interaction processes such as reciprocity and intrapersonal and interpersonal flexibility were examined during a 5-minute conflict resolution task on a sequential basis. Successful interactions among siblings require a certain degree of behavioural flexibility. In this study, siblings engaged in a “tit-for-tat” interaction dynamic, whereby they matched one another’s behaviour from one moment to another. Siblings who demonstrate more flexibility were more constructive in their approach to conflict resolution. However, this behaviour was moderated by the dyadic composition, because as the power differentials increases between siblings (i.e., increasing age disparities between siblings), the more dominant partner (older sibling) behaved less flexibly towards their younger sibling.

Keywords: Conflict Resolution
Interaction Processes
Sibling Dynamics
Sibling Interaction
Advisor: Jenkins, Jennifer
Perceptions of end-of-life communication in older adults with advanced heart failure and their family caregivers

In advanced heart failure, end-of-life communication can be integral to one’s understanding of illness and preparation for the end-of-life. In older adults with heart failure, end-of-life communication is challenged by an uncertain illness trajectory, the risk of mortality, and the presence of multimorbidity and frailty, which all underscore the need for earlier communication. In this qualitative study of older adults with advanced heart failure and their caregivers, most participants had a limited understanding of illness and did not understand the consequences of serious illness. In this context, four challenges of end-of-life communication were identified: trivializing illness, positivity in late-life, discomfort in having end-of-life discussions, and reluctance to engage despite need. The findings highlight the need to address understanding of illness for patients and caregivers to perceive the need to discuss end-of-life care and emphasize the importance of engaging in end-of-life communication as an iterative process earlier in advanced illness.

Keywords: end-of-life care
end-of-life communication
geriatrics
heart failure
older adults
qualitative
Advisor: Kuluski, Kerry
The adherens junction protein α-catenin regulates tissue growth

α-catenin is a mechanosensory adherens junction (AJ) component linking E-cadherin to F-actin. In addition to adhesion, α-catenin regulates tissue growth. Mammalian studies identified α-catenin as a tumour suppressor, but the underlying mechanisms remain unclear. I investigated α-catenin’s role in growth regulation in Drosophila wings and found that the Hippo and JNK pathways are activated downstream of α-catenin downregulation or overexpression. α-catenin’s growth and adhesion functions can be uncoupled: high levels are required for growth regulation, whereas minimal levels suffice for adhesion and epithelial integrity. α-catenin recruits Jub, a negative regulator of Hippo signaling, to the AJs through its N-region. Although the mechanosensory M-region of α-catenin is dispensable for wing growth and adhesion, I found that the M1-domain suppresses Jub junctional recruitment and growth. This work shows that α- catenin acts as an AJ protein to restrict tissue growth at least in part through modulating the recruitment of Jub to AJs.

Advisor: Tepass, Ulrich
Teacher Presence Pedagogy, a thematic interview discussion about online learning

This paper examines drivers of online instruction methods, through thematic open-ended interviews with 10 graduate-level faculty, active in online and blended learning courses in a major Canadian public university. The research forms a bounded case study of ten instructors who teach online courses using a web-based environment, PeppeR. The research question motivating this study is: How do online instructors describe the processes and activities they try to nurture in online courses, and what sort of decisions and methods do they use? Educators are conscientious about being stakeholders, giving concrete examples, and offering suggestions that are meaningful. Findings highlight detailed responses from educators which emphasize design and organization, facilitating discourse, and direct instruction in a computer-mediated environment. Ideas around effective online teaching presence echo in the pedagogy of stakeholders in an environment of engaged learners and faculty.

Keywords: Asynchronous discussion
Community of Inquiry
Knowledge building
Online learning
Teacher presence
Advisor: Brett, Clare
Hewitt, Jim
Rescuing Dopamine Transporter Deficiency Syndrome

The dopamine transporter (DAT) is a membrane protein essential to dopamine homeostasis. Abnormal dopamine homeostasis is implicated in multiple conditions including the newly discovered dopamine transporter deficiency syndrome (DTDS). DTDS is an autosomal-recessive disorder caused by mutations that impair DAT maturation. Bupropion and ibogaine can rescue DTDS DAT mutants. We therefore examine the structure-activity relationships responsible, in hopes of discovering more efficacious and potent compounds. An SAR-based screen of bupropion and ibogaine analogs demonstrated necessity for a secondary amine and single halogen substitution on bupropion along with a flexible heterocyclic ring, chair-like substituent and hydroxyl substitution on ibogaine. Lead candidates noribogaine and PAL594 were able to rescue mature DAT. We also report that there is no link between DAT inhibition and chaperoning, suggesting that chaperoning is mediated allosterically. Future studies should aim to validate the presence of the putative DAT allosteric site, computer-assisted drug discovery and a mouse model.

Keywords: bupropion
dopamine
dopmaine transporter
Dopmaine transporter deficiency syndrome
noribogaine
structure activity relationship
Advisor: Salahpour, Ali
Epithelial Cells Exhibit Dynamic Filopodia During Zebrafish Epiboly

Initially, the zebrafish embryo consists of a cell mass (blastoderm) atop a large yolk cell. During gastrulation, epiboly is the process whereby the blastoderm thins and spreads downwards to enclose the yolk. The blastoderm comprises an outer epithelium, the enveloping layer (EVL), and inner deep cells (DCs). The EVL stretches during epiboly, while the DCs undergo cell rearrangements. I observed cellular protrusions between EVL and DCs and investigated their potential role in facilitating epiboly. I classified the protrusions as filopodia by using actin markers and examined their spatio-temporal dynamics by live imaging. Filopodia were found throughout the EVL and in the largest number during early epiboly at the animal pole, where DC rearrangements are greatest. In functional studies, expression of a constitutively active actin bundling protein resulted in increased EVL filopodial length and delayed epiboly. These results suggest that EVL filopodia may function during early epiboly to promote DC rearrangements.

Keywords: Cell Protrusions
Epiboly
Filopodia
Gastrulation
Zebrafish
Advisor: Bruce, Ashley E.E.
Design and Optimization of Nanoparticulate Permeability-Modifiers for pH-independent Drug Release and Alcohol-resistant Dosage Forms

Most drugs on the market are either weakly basic or weakly acidic. Their pH-dependent solubility may result in undesired drug release kinetics of modified-release dosage forms (MRDFs) due to the food and/or drug-induced effect on gastrointestinal pH. Moreover, co-ingestion of alcohol with MRDFs of opioids has posed a high risk of dose dumping and drug toxicity. This thesis thus aims to design nanoparticulate permeability modifiers to mitigate these problems. For pH-independent drug release, a pH-responsive starch-based terpolymer nanoparticle (TPN) system incorporated in ethylcellulose (EC) developed by our group was optimized using a central composite design (CCD). The incorporation of TPNs in EC was able to modulate local pH within the matrix to increase permeability and solubility of basic drugs. Alcohol-insoluble and non-swellable nanoparticle compositions were designed using CCD to compensate for the high solubility of ethylcellulose coating in alcohol and exhibited improved processability compared to the current alcohol-resistant coating technology.

Keywords: Alcohol resistance
Coated dosage forms
Ethylcellulose
pH-responsive nanoparticles
Pore formers
Terpolymer
Advisor: Wu, Xiao Yu S.
Individual Differences in Autobiographical Memory and Their Relationship to Cognitive Aging

Individuals differ in how they remember the past: some recall the gist of an event, whereas others re-experience specific details. While memory decline is a hallmark of cognitive aging, trait-level individual differences in memory abilities have received little consideration in aging research. Given the functional decline that accompanies memory deficits, one might expect that strong native episodic memory is protective—but we hypothesized that individuals with lower episodic memory abilities would report less age-related functional decline. We reasoned that those who have relied on congenitally strong episodic memory throughout life must newly adjust to age-related memory decline, whereas those with lower episodic memory abilities enter aging prepared with compensatory strategies. We tested a large sample of older adults online and found, as predicted, that lower self-reported episodic memory abilities were associated with less age-related functional decline. These findings emphasize the importance of considering individual differences when studying cognitive aging trajectories.

Keywords: aging
autobiographical memory
individual differences
Advisor: Levine, Brian