VictorJuiz/thesis huggingface dataset:
Binding, Activation and Cellular Actions of Teneurin C-terminal Associated Peptide (TCAP)-1 with its Putative Receptor, Latrophilin-1 (ADGRL1), in Immortalized Cell Lines

Teneurins are multifunctional type II transmembrane proteins that bind the Adhesion G-protein coupled receptor subfamily L/Latrophilin (ADGRL) in the only intermolecular synaptic adhesion unit conserved between invertebrates and vertebrates. However, the specific interaction between teneurin and ADGRL is not well understood. The distal extracellular region of teneurin possesses a potentially cleavable bioactive peptide termed the ‘teneurin C-terminal associated peptide’ (TCAP). A synthetic version of TCAP-1 is highly active in cells, causing increased expression of cytoskeletal components and actin re-arrangement. Yet the mechanism by which TCAP-1 induces these effects remains unclear. HCT116 cells over-expressing ADGRL1 have increased uptake of TCAP-1 compared to wild-type cells. ADGRL1 expression causes increased adhesion between cells and reduces their expression of f-actin. TCAP-1 treatment induces f-actin polymerization and modulation of cellular morphology only in ADGRL1-expressing cells. These data are the first to establish TCAP-1 as an endogenous ADGRL1 ligand, and further elucidate its mode of action.

Keywords: Latrophilin
Peptides
Receptor-ligand interaction
TCAP
Teneurin
Advisor: Lovejoy, David A
Wnt/ β-catenin: A Novel Candidate Pathway for Bone Repair in Neurofibromatosis Type 1

Skeletal abnormalities occur in half of the individuals with neurofibromatosis type-1 (NF1), the most difficult to manage is congenital pseudarthrosis of tibia (CPT). High levels of β-catenin result in a phenotype similar to CPT in mice fractures. β -catenin in CPT samples was up-regulated, therefore we hypothesized that Wnt/ β-catenin pathway partially mediates the effect of NF1 mutation on bone by altering the differentiation of MSCs into osteoblasts. Conditional knock-out Nf1 mice were crossed with conditional β-catenin over-expressing and knock-out models. Adenovirus expressing Cre recombinase was injected at the fracture site to activate the conditional alleles. Fracture healing was evaluated by radiological, histological and biomechanical tests. Nf1 deficient tibial fractures were associated with higher cellular β-catenin levels and delayed healing, exhibiting a fibro-cartilaginous phenotype with abundant undifferentiated MSCs. Down-regulating and stabilizing β-catenin, improved and exacerbated Nf1 deficient fracture healing respectively. These data indicate that the level of β-catenin in NF1 patients and Nf1 deficient fractures is abnormally elevated, and this level inhibits osteoblastogenesis and bone repair. Since pharmacologic agents to inhibit β-catenin are under developemt, this data also suggests a novel therapeutic approach to improve bone healing in patients with NF1.

Keywords: CPT
Fracture repair
Neurofibromatosis
NF1
Pseudarthrosis
tibia
Advisor: Alman, Benjamin A
Integrin Activation and Focal Adhesion Kinase in the Survival and Regeneration of Injured Adult Rat CNS Neurons

The retina develops as an outpouching of the diencephalon, and retinal ganglion cells (RGCs) are central nervous system (CNS) neurons whose axons form the optic nerve and extend into the brain. The retina provides an excellent model to study diseases affecting both RGCs and other CNS neurons. Integrin attachment to the extra-cellular matrix (ECM) provides developmental, survival, differentiation and axon extension cues to RGCs which are suspected to be dependent on focal adhesion kinase (FAK) activation. Damage to the optic nerve induces RGC apoptosis and release matrix metallo-proteinases (MMPs) to degrade the ECM and arrest pro-survival signals. This work demonstrates that MMP activation and reduced FAK activity occur early in the apoptotic process and that by respectively reducing and increasing their activity we are able to rescue significant amounts of RGCs, and increase the number of regenerating axons following optic nerve transection.

Keywords: Apoptosis
CNS
focal adhesion kinase
integrins
Retina
Advisor: Koeberle, Paulo D
Agur, Anne
Characterizing Novel PPAR Agonists Derived from Cashew Nut Shell Liquid for the Treatment of Metabolic Disease

The peroxisome proliferator-activated receptors (PPARα,γ,β) are important druggable targets to treat patients with type 2 diabetes and dyslipidemia. However, current PPAR agonists lead to serious adverse effects, including edema, cardiovascular disease, weight gain, and bone fractures. We hypothesized that PPAR agonists with properties similar to their endogenous ligands may be therapeutically desirable for treatment of metabolic disease while limiting the adverse effects. Using in vitro models, we found that a number of LDT compounds derived from cashew nut shell liquid acted on the PPAR receptors. Specifically, we identified LDT409 that showed partial agonistic activity and equal binding affinities to PPARα and PPARγ receptors with reduced affinity for PPARβ. Using diet-induced obese mice, we determined that LDT409 was protective from high fat diet-induced weight gain, fatty liver disease, and insulin resistance without increasing markers of edema, bone loss, and heart failure. Together, these studies suggest that LDT compounds will be efficacious to treat metabolic disease and may have fewer adverse effects compared to traditional PPAR agonists.

Keywords: CNSL
diabetes
DIO
dyslipidemia
fatty acids
PPAR
Advisor: Cummins, Carolyn L.
Engineering the Refugee Crisis- Governmentality through humanitarianism in the evolving context of Turkey

This study explores the dynamics of forced migration and refugee management in the context of Turkey through an examination of the evolving legal framework between 2013 and 2016. Weaving together a policy discourse analysis with the narratives of refugees in Turkey and their agency, I seek to challenge conventional discourses of victimhood and the use of humanitarian rhetoric to further political interests and manage flows using a critique of governmentality through humanitarianism. Particular attention is paid to the shift from an open door policy to the implementation of the New Law on Foreigners and Temporary International Protection, the provision of works permits and the Turkey-EU deal. This paper compares and contrasts the differing experiences of non-Syrian asylum-seekers and Syrians under guest status. In addition, I contemplate the discourse of crisis and management and interrogate the rhetoric of vulnerability and humanitarianism in the context of the migration-foreign policy nexus and Turkey-EU relations.

Keywords: Govermentality
Humanitarianism
Migration management
Turkey
Advisor: Tavakoli, Mohamad
Harnessing Neuronal-glial Interactions to Prevent Postanesthetic Cognitive Deficit

General anesthetics trigger memory deficits that persist long after the anesthetics have been eliminated, by increasing an extrasynaptic GABAA receptor-mediated tonic inhibitory current in the hippocampus. This increase in tonic current contributes to cognitive deficits associated with postoperative delirium, a debilitating disorder that affects 20% of elderly patients undergoing surgery. The Îą2-adrenergic receptor (Îą2R) agonist dexmedetomidine (DEX) reduces postoperative delirium in ICU patients. The mechanisms involved are unknown. Interestingly, DEX modulates astrocyte function to protect neurons in other injury models. This thesis explores the mechanism of DEX-neuroprotection from anesthetic-induced increase in tonic current, using a cell culture model. My studies show that DEX stimulates astrocytic Îą2Rs to release neuroprotective factors, possibly including BDNF and EGF, which act on hippocampal neurons to prevent the anesthetic-induced increase in tonic current. These results present a potential mechanism by which DEX reduces anesthetic-induced cognitive deficits and identifies alternative drugs that may treat postoperative delirium.

Keywords: Astrocytes
Dexmedetomidine
Electrohpysiology
General Anethetics
Postoperative Cognitive Disorders
Treatment mechanisms
Advisor: Orser, Beverley A
Growth in Infants Receiving Modified Fat Breast Milk for the Treatment of Chylothorax following Cardiothoracic Surgery

Background: In infants diagnosed with chylothorax, breast milk provision is often discontinued and a medium chain triglyceride (MCT) formula is prescribed. Alternatively, modified fat breast milk (MFBM) can be used as treatment, however its impact on growth is unclear. Objective: To assess growth in cardiac infants receiving nutrient enriched MFBM for chylothorax treatment. Methods: In this open-label trial, infants were randomized in to one of two interventions: Target Fortification, where MFBM protein concentration was measured prior to fortification (n=3); or Higher Initial Concentration, where MFBM was fortified to a higher initial energy and nutrient level (n=2). For this thesis, analysis of the two MFBM interventions were combined. Growth was compared to infants receiving the standard MCT formula treatment (n=7). Results: No differences were found in the change of weight-for-age, length-for-age, head circumference-for-age and weight-for-length z-scores between the groups. Conclusion: Further MFBM subject recruitment is required to determine how the different nutrient enrichment methods impact growth.

Keywords: Breast Milk
Chylothorax
Growth
Infant
Advisor: O'Connor, Deborah L
Modeling and Proof of Concept of a Passive Irrigation Controller for Efficient Water Use in Low-Income Areas

Irrigation has been shown to contribute to the alleviation of poverty around the globe. However, its success is limited by water scarcity. Human Centered Design (HCD) principles were employed to address agriculture's involvement in global water scarcity from an engineering standpoint, particularly in low-income areas. An irrigation controller was developed in partnership with a low-income community in Nicaragua to regulate soil water potential (SWP). Ground research and interviews inspired the adaptation of passive technology using locally available materials such as PVC fittings. A prototype was constructed and presented to the community for feedback. A semi-empirical model of the controller was developed and experimentally verified to enable sizing of the components and evaluation of the system capabilities. The controller model was coupled to an environmental model to predict the performance. The model results show the controller has a potential water savings of up to 69%.

Keywords: Agriculture
Human Centered Design
Irrigation Control
Soil Water Potential
Advisor: Bilton, Amy M
Chronic Neurovascular Dysfunction in a Preclinical Model of Repeated Mild Traumatic Brain Injury

Outcomes associated with repeated mild traumatic brain injury (mTBI) are considerably worse than those of a single mTBI. Despite higher prevalence relative to moderate injuries, the repeated mTBIâ s pathological progression has been understudied. For moderate-to-severe TBI, metabolic mismatch has been identified as a key component in pathological progression, and hence amenable to therapeutic targeting. Here, I present a mouse model of repeated mTBI induced via three controlled cortical impacts delivered at three day intervals for purpose of probing the aspects of the neurovascular coupling in chronic repeated mTBI in Thy1-ChR2 mice. Resting cerebral blood flow and cerebrovascular reactivity were investigated via arterial spin labelling MRI, and intracranial electrophysiological measurements of evoked neuronal responses to optogenetic photostimulation were performed. Immunohistochemistry revealed alterations in vascular organization and astrocyte reactivity. This work provided the first insights into the neurophysiological alterations post repeated mTBI and enables new understanding of the associated cerebrovascular deficits.

Advisor: Stefanovic, Bojana
Investigating the interaction of AKAPs with PLN to mediate phosphorylation processes

A common characteristic of cardiomyopathy is dysregulated Ca2+-cycling. During Ca2+-cycling, Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) reuptakes Ca2+ into the sarcoplasmic reticulum (SR). SERCA is inhibited by Phospholamban (PLN). PLN inhibition is reversed through phosphorylation of Ser16 by protein kinase-A (PKA) when anchored to A-kinase anchoring proteins (AKAPs). Previous studies identified 3 human PLN-mutants –R9C, R14Del, and L39stop– causing cardiomyopathy. We were interested in the mechanisms by which wild-type PLN (PLN-WT) and PLN-mutants are phosphorylated through AKAPs-PLN-PKA interactions. Using publically-available RNA-seq and proteomic data we identified muscle AKAP (mAKAP) to be expressed in the heart. Immunofluorescent data showed mAKAP to be expressed in the SR and co-localizing with PLN. Immunoprecipitation in co-transfected HEKs showed pull-down of mAKAP and PLN-WT/mutants. We showed PLN-mutants exhibit altered protein phosphorylation and mAKAP-PLN interactions. In conclusion, we determined a possible link between mAKAP and PLN for the regulation of PLN phosphorylation by PKA.

Keywords: A-kinase associated protein (AKAP)
cardiomyocyte
cardiomyopathy
heart
phospholamban (PLN)
protein kinase A (PKA)
Advisor: Gramolini, Anthony
Inkjet Printed Optoelectronic Devices

This thesis describes the development of efficient, printable infrared detectors using colloidal quantum dot solids. The realization of such devices, that exploit the benefits of solution- processable materials, has so far been hinderered by the complex chemical processing needed to assemble these semiconductor-nanocrystal films. Recent advances in quantum dot processing have simplified processing and produced quality inks that can be deposited in a single step to make high-performance devices. However, reliance on aggressive solvents that damage dot surfaces prevents their use in inkjet-printing. Here I develop a protocol that achieves uniform and smooth quantum dot films via inkjet-printing. I then demonstrate, for the first time, high sensitivity inkjet- printed photodiodes that are tunable from the near to short wavelength infrared. The resulting devices exhibit detectivities of 1.4x1012 Jones, on par with commercial IR detectors. This new, CMOS-compatible process opens the door to the realization of multiwavelength hyperspectral sensors as novel integrated systems.

Keywords: Infrared
Inkjet
IR
Photodetector
Printing
Quantum Dots
Advisor: Sargent, Edward
Motivating Smokers to Quit Through a Computer-based Conversational System

Cigarette smoking contributes to one in every five deaths annually in the United States according to the Centre for Disease Control and Prevention (CDC). The majority of cigarette smokers are unmotivated to quit, meaning that they don’t plan to attempt to quit or seek help in quitting within the next six months. Motivational Interviewing (MI) is an effective counselling style for eliciting behaviour change. This thesis presents an Artificial Intelligent (AI) conversational system that uses MI to engage smokers in a conversation about smoking, with the goal of moving them towards a decision to quit. A total of 221 subjects were recruited online to participate in two studies. The first study engages 121 subjects in a conversation to improve the system’s Natural Language Under- standing (NLU) abilities. The second study engages 100 subjects in a conversation and measures the effectiveness of the system in increasing their motivation to quit. The result of the two studies shows potential for the conversational system to help an unmotivated smoker to move towards the decision to quit.

Advisor: Rose, Jonathan
Selby, Peter
Hyperpolarized 129Xe MRI of Embryonic Stem Cell-derived Alveolar-like Macrophages in Rat Lungs: Proof-of-concept Study Using Superparamagnetic Iron-Oxide Nanoparticles

The purpose of this work was to investigate the effect of SPION-labeled alveolar-like macrophages on hyperpolarized 129Xe MRI signal in vivo by measuring the change in T2* at two different time points after instillation. MRI was performed in 6 healthy mechanically ventilated rats prior to the instillation of 4 million SPION-labeled ALMs and repeated 5 minutes and one hour following instillation. T2* changes were measured and compared to rats receiving 4 million unlabeled ALMs. Regions of signal loss were observed immediately after instillation of unlabeled and SPION-labeled ALMs but only persisted one hour after the instillation of SPION-labeled ALMs. One hour after the instillation of SPION-labeled ALMs the T2* decreased by 54.0 ± 7.0 %, compared to a full recovery after unlabeled ALMs. Histology confirmed that the location of SPIONs in the airways of each rat were co-localized to the regions of signal loss observed with MRI.

Advisor: Santyr, Giles E
Methylmercury Cycling at the Aquatic-terrestrial Interface in a High Arctic Freshwater Continuum

Methylmercury (MeHg) is a global toxin which bioaccumulates and biomagnifies through food webs. To discern how MeHg enters Arctic food webs, it is important to understand spatial and seasonal cycling of MeHg at the terrestrial-aquatic interface, processes which are sensitive to climate change. This research determined hotspots of MeHg production and degradation in a High Arctic freshwater continuum, and how these processes varied between ice-on and ice-off conditions. Different compartments of the Skeleton Continuum of Lake Hazen, Nunavut were sampled to capture variation in MeHg production and degradation. Examining interconnectedness of the landscape revealed that production hotspots occur in multiple compartments (lake/pond sediments, pore water), yet downstream degradation hotspots and storage (lake water, wetland soils) prevent MeHg from entering the downstream system. Additionally, high MeHg concentrations found in the springtime (water column, snow) solidify the theory that spring freshet is an important source of MeHg to freshwater systems.

Keywords: Arctic
Contaminants
Freshwater
Methylmercury
Seasonality
Advisor: Lehnherr, Igor
Scaling Blockchain Applications with Pub/Sub

The world of distributed ledger technology(DLT) has been getting signicant attention. Many new applications want to utilize the trustless model and the high consistency guarantees this technology grants. This thesis aims to identify the needs of various business use cases and explores how DLT technology can be adapted to suit these applications. We recognize existing initiatives to adopt certain DLTs with some applications, however, there still exists gaps between these initiatives and production grade solutions. We provide a list of applications that can utilize the features of DLT technology and propose an encompassing structure to facilitate the needs of these applications. Specically, we focus on a DLT-based publish and subscribe system for a subset of the interested applications. We provide the design and rationale behind the technology selection and analyze the relationship between DLT technology and Pub/Sub.

Keywords: Blockchain
Pub/Sub
Advisor: Jacobsen, Hans-Arno
An Integrated Model For Thermal Analysis of an Aircraft Landing Gear Bogie Pivot Pin

While operating on rough runways, commercial aircraft landing gear may experience overheating issues on the bogie pivot pin. This thesis is an integrated model that generates the landing gear dynamic behaviour and predicts the temperature of the pin. The integrated model consists of four individual components. Built in MATLAB Simulink, the dynamic model outputs the pin rotation angle and the dynamic loading with a given input runway profile and aircraft characteristics. The structural stress model is an ABAQUS finite element analysis model that determines the contact pressure distribution on the pin contact surface at any given dynamic loading. The dynamic variables and the pressure distribution are collected and used in the heat generation model to calculate the frictional heat generation and distribution. Finally, the heat conduction model in ABAQUS performs thermal analysis to obtain the operational temperature of the bogie pivot pin.

Keywords: Finite Element Analysis
Landing Gear
Thermal Modelling
Advisor: Liu, Hugh H.T.
Steeves, Craig A.
Clinical Decision Support Systems for Opioid Prescribing for Chronic Non-cancer Pain in Primary Care Settings

This thesis sought to provide an understanding of the potential benefits and possible limitations of clinical decision support systems (CDSS) for opioid prescribing for chronic non-cancer pain (CNCP) in primary care settings. Findings from the scoping review and the exploratory qualitative study indicated few potential benefits and significant limitations. There were few studies and, although some reported that the CDSS led to more appropriate prescribing, they used lower quality designs. None of the studies examined patient outcomes or assessed for unintended consequences. Many had conflicts of interest. Developers did not appear to be using evidence when designing a CDSS. Investigators did not follow guidance for the evaluation of complex interventions. The research also demonstrated barriers to implementation for a specific CDSS we evaluated, including increased work, an interrupted workflow and poor buy-in. Therefore, more research is needed before widespread implementation of CDSSs for opioid prescribing for CNCP in primary care settings.

Keywords: Chronic pain
Clinical decision support systems
Complex interventions
Knowledge translation
Opioids
Primary care
Advisor: Sullivan, Frank
An Electrochemical Study on the Effect of Pb on Ni, Cr and Ni-22Cr in Caustic Conditions at 75°C and 230°C Relevant to Steam Generator Tubing Materials

Mechanistic understanding on the corrosive effect of Pb on Ni-Fe-Cr alloys used for nuclear power plant steam generator tubing is uncertain. The purpose of this research was to determine the specific impact of Pb on Ni, Cr and Ni-22Cr in highly alkaline conditions at moderately high temperatures. By utilizing electrochemical techniques, the study analyzed the plating and stripping of Pb on the different metal/alloy substrates. The Pb based equilibrium potential and the limiting current density for Pb plating were determined to be a function of the pH of the environment. Depending on the metal, different degrees of Pb plating may also occur. Pb stripping seems to happen more efficiently on Ni followed by Ni-22Cr then Cr, and this may have implications on activation effects.

Keywords: chromium
corrosion
lead
nickel
nuclear power plant
steam generator tubing
Advisor: Newman, Roger C
Measuring the Construct of Clinical Utility in the Context of Genetic Testing: A Scoping Review

Understanding how clinical utility is measured across a range of clinical scenarios can provide strategies for operationalizing this construct, in turn supporting more consistent and robust evaluations of genetic tests. The current scoping review explored the range of outcomes used to measure the value of genetic testing in the literature, spanning 2015-2017. The search strategy and data analysis were guided by the Fryback and Thornbury (F-T) Hierarchical Model of Efficacy. In total, 194 peer-reviewed evaluative studies that used experimental or observational designs were included in this review. Findings herein suggest that additional clinical areas, more robust study designs and novel strategies for measuring the construct of clinical utility are warranted. Additionally, the results suggest refinements to the meaning and content of the domains embedded in the F-T framework. These results can inform future systematic reviews, research design in genetic test evaluative studies and reflections on the concept of clinical utility.

Keywords: Clinical Utility
Scoping Review
Advisor: Hayeems, Robin