VictorJuiz/thesis huggingface dataset:
Mechanisms of Cholinergic Neuromodulation of Prefrontal Cortex in Health and Disease: A Combined Whole-Cell Electrophysiology and Multiphoton Calcium Imaging Approach
Keywords: Acetylcholine
Calcium imaging
Electrophysiology
Muscarinic
Nicotinic
Prefrontal cortex

The neuromodulation of the prefrontal cortex (PFC) by acetylcholine is essential for optimal executive function, where it exerts robust excitatory actions together with complex calcium ion signals via the nicotinic and muscarinic acetylcholine receptors. This thesis examines how cholinergic calcium fluxes regulate the ability of acetylcholine to excite prefrontal circuits and how these interactions are disrupted in rodent models of psychiatric and neurological illness. Using whole-cell electrophysiology together with multiphoton calcium imaging in slices of rodent PFC, I have found that cholinergic calcium mobilization can exert important regulatory control over cholinergic excitability: by enhancing sub-threshold cholinergic excitation and by constraining supra-threshold effects via the modulation of spike output. Importantly, these distinct interactions were disrupted in two separate models of neuropsychiatric disease with documented cognitive dysfunction. First, in pyramidal cells of prefrontal output layer 5, acetylcholine-induced calcium release was found to potentiate excitatory cholinergic currents via the electrogenic process of sodium/calcium exchange. This phenomenon was found to emerge in young adulthood, when executive function typically reaches maturity. What is more, this developmental consolidation of cholinergic signaling was abolished subsequent to the early stress of repeated maternal separation—a model of psychiatric vulnerability—where cholinergic responses retained an adolescent phenotype accompanied by a disruption in the expression of multiple developmentally-regulated genes associated with Gαq and calcium signaling. Second, in a well-characterized model of Alzheimer’s disease, I have found that layer 6 PFC pyramidal cells, which are known to be essential for peak attentional performance, are unable to sustain cholinergic excitation to the same extent as those of non-transgenic littermate controls as a result of the excessive activation of calcium-activated hyperpolarizing conductances. Further, I demonstrate that cholinergic excitation can be improved in the cortex of these mice by pharmacological blockade of SK channels, suggesting a novel target for the treatment of executive dysfunction. In sum, this thesis characterizes two distinct and potentially complementary mechanisms whereby calcium can shape cholinergic excitability in prefrontal circuits essential to executive function and how these interactions are disrupted in models of brain disease with documented cognitive dysfunction.
Socioeconomic Position, Modifiable Risk Factors and Coronary Heart Disease Incidence in Canada
Keywords: Heart Disease
Population Health Intervention Research
Simulation modelling
Social Determinants of Health

Coronary heart disease (CHD) is a leading cause of morbidity and mortality in Canada. Socioeconomic position (SEP; typically measured as education, occupation and/or income) is an important CHD risk factor, in addition to conventional risk factors (e.g. smoking, poor nutrition, physical inactivity, obesity, high blood pressure, diabetes or cholesterol). Evidence to inform which population health interventions will optimally reduce both the population level and social inequalities in CHD is urgently needed in Canada. The overall goal of this dissertation was to explore the relationship between SEP, modifiable risk factors and CHD incidence. The dissertation consists of four related manuscripts, each making a contribution to this area of research. The first manuscript assessed the potential use of mathematical simulation models to evaluate the impacts of population health interventions on social inequalities in CHD. This review served as a conceptual framework for this dissertation, highlighting a number of gaps in research evidence further explored in dissertation chapters. The second manuscript undertakes a causal mediation analysis to examine the direct and indirect pathways linking SEP and incident heart disease in a Canadian population-based cohort study. By assessing individual mediation pathways through modifiable CHD risk factors, the goal of this manuscript was to highlight potential targets for population health interventions that will result in the greatest reduction in social inequalities in CHD. In the third manuscript the ability of the Framingham CHD Risk Score prediction algorithm to predict future CHD incidence across SEP groups was assessed. The results from this study tested an important methodological assumption regarding the risk prediction tool used in the Population Health Model for Cardiovascular Disease (POHEM:CVD), to enable accurate simulation of CHD incidence by SEP group. Finally, the fourth manuscript assessed the validity of socioeconomic trends in modifiable CHD risk factors in Canada from 2001 to 2021 using POHEM:CVD. Combined, this body of work provides evidence regarding the potential benefit of targeting modifiable CHD risk factors on reducing population and social inequalities in CHD in Canada.
Point-of-Care Diagnostics for Lung Transplantation
Keywords: Biomarkers
Diagnostics
Lung Transplantation
Nanotechnology

Over the last few decades, lung transplantation (LTx) has become a well-established therapy for patients suffering from end-stage lung disease. Despite the many innovations that have occurred in recent years, the outcomes following LTx still lag behind those of other organ transplant procedures due to a lack of technologies that could monitor predictive biomarkers. Recently, several genomic and proteomic analytes have been identified that are prognostic of LTx outcome; however, traditional analytical methods are impractical for use in the transplant setting. Rapid analysis of molecular biomarkers reporting on the initial and long-term status of a donated organ would improve utilization rates and transplant outcomes. The work herein focuses on developing a novel class of chip-based sensors that would enable direct analysis of mRNAs and proteins that are correlated with the suitability of a lung for transplant. The biosensing approach utilized in these studies was performed using a simple and elegant electrochemical reporter system with metal electrodes of varying morphologies and sizes. By fabricating fractal circuit sensors (FraCS), we demonstrated the technological and biological validation required for a point-of-care (POC) diagnostic device to be used for gene quantitation in the transplant setting. This approach was applied to confirm the clinical validity of previously reported biomarkers (IL-6, IL-10, EGLN1, and ATP11B) and, importantly, was used to develop a FraCS prediction model (FPM), which was highly predictive (AUC 0.82) of primary graft dysfunction (PGD) in donor lungs. Using nanostructured microelectrodes (NMEs), a sensing platform was developed to detect two proteins implicated in chronic lung rejection: TGFβ1 and ET-1 – biomarkers involved in restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS). We highlight novel strategies used for the electrochemical detection of small (
Printed Educational Materials for Primary Care Physicians
Keywords: Evidence-based medicine
Knowledge translation
Primary care

In primary care settings, primary care physicians (PCPs) commonly have multiple brief visits, often with complex patients and have little time to review the multitude of clinical evidence available that may be relevant to their patients’ needs. This dissertation examines printed educational materials (PEMs) as a tool to facilitate the dissemination of clinical information for PCPs. I use the Technology Acceptance Model to study how the perceived ease of use and perceived usefulness of PEMs influences PCP attitude, intention, and use of PEMs. This dissertation is composed of three studies: 1) A systematic review of 40 studies of PEMs for PCPs to determine the effect of PEMs on patient and physician outcomes, 2) A focus group study to determine PCP preferences for the design and content of PEMs, and 3) The redesign and subsequent usability testing by PCPs of an existing PEM. The results of the systematic review demonstrate that PEMs do not have an effect on patient outcomes or physician cognition or behaviour outcomes. I also conclude that the included studies are limited by very poor intervention reporting. In the second paper, I highlight PCP preferences for PEMs, including that PEMs be relevant to their primary care patient population, short, concise, and specific in terms of their practice recommendations. I also present a list of these preferences for use by individuals who create PEMs. Lastly, in the third paper I redesigned an existing PEM using design principles and user preferences. I conducted a modified discrete choice experiment and usability testing to determine if the redesigned version is more usable and more often selected than the original. The redesigned PEM scored significantly higher on the System Usability Scale and was selected more often than the original version by PCPs across two settings: an opportunistic and a controlled setting. The opportunistic setting was at a large Canadian conference for family physicians in Quebec City, Canada. The controlled setting experiments were conducted as individual sessions at St. Michael’s Hospital in Toronto, Canada or at the participant’s clinic. This dissertation concludes that though PEMs are not found to be effective for changing patient or physician behaviour in their current state, there is an opportunity to optimize their design and potentially increase their effect on both physician and patient outcomes.
Lifting Problems, Cross-fiberedness, and Diffusive Properties on Elliptic Surfaces
Keywords: cryptography
elliptic surfaces
lifting

Given an elliptic curve E˜ over Fp the field of p elements, and given points P˜ and Q˜ in E˜(Fp) such that Q˜ = nP˜, the Elliptic Curve Discrete Logarithm Problem (ECDLP) is to find n. The difficulty of the ECDLP is the foundation for much of modern cryptographic security. S. Miri and V.K. Murty considered a lifting problem in which one asks to find lifts of points P ∈ E˜( Fp) to an appropriately chosen elliptic curve over Q. They saw that the ECDLP would be equivalent to this lifting problem if one could find lifts of E˜ with certain properties. We consider a variant of this lifting problem, which we see is unconjecturally equivalent to the ECDLP. Furthermore, we relate these ideas to a conjecture of B. Mazur which asserts that for any non-constant elliptic fibration {Et} t∈Q, the set { t ∈ Q : rk(Et( Q)) > 0} is finite or dense in R with respect to the real topology. Particularly interesting to us are elliptic surfaces considered by R. Munshi on which there is a second fibration by genus one curves such that the two fibrations interact in nice ways. On these surfaces, using the second fibration, non-torsion points are "diffused'' from one fiber Et to others, and hence positive rank fibers are "diffused'' through R, allowing one to conclude Mazur's conjecture for these families. We show that this process also "diffuses'' certain other properties of fibers. We see that, under certain conditions, the set of fibers having a list of properties motivated by our lifting problems is either finite or dense in R. Moreover, we study the dynamics of this process of diffusion, allowing us to bound the proportion of times our process produces fibers with the desired properties. We show that the probability that the diffusion process produces a lift with all of the (seemingly unrelated) properties is the product of each of the respective probabilities up to a controllable error bound. Hence we see that whether the output fiber of the diffusion process has these properties is "asymptotically independent.''
Dissociative Attachment and Reaction on Silicon
Keywords: density functional theory
dissociative attachment
reaction dynamics
scanning tunneling microscopy
silicon
surface science

Scanning tunneling microscopy (STM) and density functional theory (DFT) were used to study two types of reaction at a crystal surface: long-range migration and dissociative attachment. We developed the first dynamical model for the observation of long-range migration of ethylene across the rough Si(100) surface. Ab initio molecular dynamics revealed two requirements for this long-range migration: first the molecule must leave the surface through ‘ballistic’ motion, traveling out of range of its roughness, second it must ‘bounce’ like a skipping-stone to reach the observed distances. Additionally, comparable behavior was predicted for atomic chlorine following electron-induced dissociation of chlorophenyl at Cu(110). In a following chapter we examined the factors governing the choice of pathway in the dissociative attachment (DA) of H2 and HCl at Si(100). In a computational study, we correlated the location of the energy barrier along the minimum-energy pathway with the separation of chemisorbed products: an ‘early’ barrier for reaction at closely-separated silicon atoms and a ‘late’ barrier for more-widely separated silicons, suggesting a means of 'steering' the reaction by reagent translation or vibration. In the remainder of the thesis DA at Si(100) was examined for two families of molecules, a series of hydrogen halides and of primary alkyl alcohols. For the hydrogen halides we observed three patterns of DA, unaltered in their relative yields by temperature change. A detailed study of the molecular dynamics for hydrogen bromide linked the choice of pathway to the sequential approach to the surface of the light H followed by the heavy Br. The charge flow resulting from the attachment of H explained the preference for Br to react ‘Inter-Dimer’. For the family of alcohols, methanol, ethanol, 1-propanol, 1-butanol, and 1-pentanol, we again observed a dominant 'Inter-Dimer' reaction path, rather than the previously-accepted 'On-Dimer' mechanism. Neither theory nor experiment gave evidence of a significant alteration in energy-barrier along the series. This finding contrasted with the experimental and theoretical observations by previous workers in which the energy-barrier for DA at Si(100) increased with increasing alkyl chain length along a series of 1-bromoalkanes. The difference here is the absence of ‘chain-lifting’ during the alcohols’ reactions.
The Syrian Orthodox Christians in the Late Ottoman and Post-Ottoman Periods: Crisis and Revival
Keywords: Crisis
Late Ottoman
Post Ottoman
Revival
Syrian Orthodox;

Despite the protection afforded to the smaller minorities of the Ottoman Empire through the millet system (Chapter One), Syrian Orthodoxy witnessed weakness and depletion throughout the nineteenth century, caused by significant conversion to Western Christianity, particularly in Syria and in Iraq. In the meantime a separate Western Christian intrusion was unfolding among the Syrian Orthodox communities in India. The resulting problems prompted a first journey by a Syrian Orthodox patriarch to that part of the world. Patriarch Peter’s journey in 1874-1877 was a landmark event that first entailed a journey to England and audience with Queen Victoria. The hitherto little known involvement of the Anglican Church in this intrusion is uncovered in Chapter Three. The events following the 1895 violence in southeastern Anatolia became precursors to the genocidal Safyo of 1915, which resulted in the annihilation of nearly half the Syrian Orthodox in Anatolia and brought Syrian Orthodoxy to the verge of extinction (Chapter Four). The apathy of the victors of World War I towards the beleaguered survivors at the Paris Peace Conference of 1919-20 contrasted with the accommodation the exiled survivors found in the Arab lands to the south, where historical affinity was rekindled (Chapter Five). From the safety of this new environment, Syrian Orthodoxy, aided by the critical core of enlightened individuals, rose again drawing on venerable Syriac cultural tradition and an associated patriarchal standing that was characteristically free from social elitism and tribal sectarianism. Utilizing the quest for learning that was the mantra in the new nation states, the new leadership, despite meager resources, launched Syrian Orthodoxy on a course of revival and renaissance not witnessed since the days of Bar Hebraeus in the late thirteenth century (Chapter Six). In addition to conventional primary and secondary sources, this thesis relies substantially on hitherto untapped Syrian Orthodox archival material, which has shed new light on many important events. In particular, the analysis of nearly 5700 letters from ordinary people to the patriarch of the day (Chapter Two) has provided a subaltern view of society, as opposed to the elitist view which conventional history often offers.
The Role of Enamel Matrix Protein Amelotin on Biomineralization
Keywords: Amelotin
Biomineralization
Dental caries
Enamel
Matrix proteins

Dental caries is one of the most common chronic diseases of people worldwide. Despite recent advances in oral health care and restorative dentistry, the problem of dental caries and erosion remains unresolved due to the lack of knowledge of the natural biomineralization process of tooth tissues. Dental enamel plays a crucial role in preventing the tooth from destruction. However, if damaged or lost, it cannot be regenerated. Understanding the molecular mechanisms behind formation of enamel would not only make restoration of the tissue possible, but would also provide new insights for optimum design of calcium phosphate based biomaterials for dental and orthopedic applications. Amelotin (AMTN) is a recently discovered protein that is primarily expressed during the maturation stage of enamel formation and is localized at the cell-mineral interface on the surface enamel layer. In vivo studies using transgenic mice suggest a direct regulatory function for AMTN in enamel biomineralization. The aim of this PhD project was to test this hypothesis using different in vitro model systems of mineralization. I first showed that recombinant human (rh) AMTN accelerates hydroxyapatite mineralization in a dose-dependent manner when dissolved in the mineralization SBF buffer. Inactivation of a conserved SSEEL motif resulted in significant reduction in the mineralizing ability of the full-length molecule. I also evaluated the importance of phosphorylation in mineralization by testing a synthetic peptide containing a short sequence of AMTN including phosphorylated SSEEL in the crystallization assay and showed that it promoted mineralization albeit to a lesser degree than rh-AMTN. Detailed characterization of secretory enamel matrix in overexpressor mice showed rapid and uncontrolled mineralization. I also tested the mineralizing ability of AMTN in an established osteoblast cell line and demonstrated that AMTN transfected or introduced in the culture media in the recombinant form both accelerate the formation of mineralized nodules. AMTN molecules embedded in collagen gel matrix were also able to mineralize the collagen material in the SBF buffer within a few hours. The findings of this PhD project provide solid evidence that AMTN is a promoter of hydroxyapatite mineralization and likely a key player in the establishment of surface enamel layer.
Expression of Parkinson's disease and associated neurophenotypes in 22q11.2 deletion syndrome
Keywords: 22q11.2 deletion syndrome
Movement disorders
Parkinson's disease
Pharmacogenetics
Positron emission tomography
Schizophrenia

The etiology of Parkinson’s disease (PD) remains largely unknown with the exception of a few genetic mutations that affect a small proportion of patients. Case reports suggest that individuals with 22q11.2 deletion syndrome (22q11.2DS), a multisystem genomic disorder associated with hemizygous 22q11.2 deletions, may be at increased risk of early-onset PD. The aim of this thesis was to investigate 22q11.2 deletions as a risk factor for early-onset PD. The prevalence of PD was assessed in a well-characterized cohort of adults with 22q11.2DS. Neuropathological studies were performed in cases with available post-mortem tissue. Whole-genome sequencing was used to investigate the possible contribution of genome-wide rare coding mutations to disease penetrance in neuropathologically confirmed PD cases. Assessment of putative pre-diagnostic clinical and neuroimaging markers of PD in a subset of the older adults (30 to 54 years) provided evidence of an elevated prevalence of pre-morbid motor and olfactory deficits, and of nigrostriatal dopaminergic dysfunction assessed using 11C-dihydrotetrabenazine and positron emission tomography. The clinical context of early-onset PD in this adult cohort of individuals with 22q11.2DS was also investigated. Treatment response was excellent to the atypical antipsychotic, clozapine, a candidate for use in psychotic patients at risk of, or with, PD. Cognitive level and severe psychiatric disorders were mediators of baseline functional capacity in 22q11.2DS adults. Practical guidelines were developed from a review of the 22q11.2DS literature to help inform the management of 22q11.2DS-associated conditions, including PD. The results of these studies provided evidence that early-onset PD is associated with the 22q11.2 deletion with important implications for PD pathogenesis and for the clinical management of 22q11.2DS.