title: Spatiotemporal patterns of proteins associated with GABA synthesis and transport in the developing auditory brainstem

contributor:
Gillespie, Deda
Goldreich, Dan
Nurse, Colin
Neuroscience

subject: development synapse refinement inhibition immunohistochemistry brainstem neuroscience

abstract:
During an early developmental period, some glycinergic synapses in the brainstem and spinal cord release predominately GABA, which activates GABAA receptors on the postsynaptic membrane. The function of this early GABAergic transmission is unknown but presumed to contribute to synapse maturation. Classically, the enzyme glutamic acid decarboxylase (GAD), which synthesizes GABA from glutamate, has been considered the sole source of GABA in neurons. GABAergic neurons typically express one or both of the two known isoforms of this enzyme, GAD65 and GAD67. However, co-transmitting synapses in the midbrain were recently reported to acquire GABA through other means – GABA transporters (GAT1 and GAT3) and/or aldehyde dehydrogenase (ALDH1A1).
To determine the source of GABA in immature glycinergic neurons of the auditory brainstem, we immunostained for GADs, GATs, and ALDH1A1, co-staining with markers for glial cell and synaptic terminals to verify cellular and subcellular location.
GAD65 was expressed in synaptic terminals whereas GAD67 was localized to neuronal cell bodies, proximal dendrites, and presumabed synaptic terminals. However, during the peak period of GABA transmission in the first postnatal week, expression levels of both GAD65 and GAD67 were surprisingly low. Although GAT1 and GAT3 expression levels coincided with the peak period of GABA transmission, neither GAT was localized to neuronal cell bodies. In contrast, ALDH1A1 was expressed during the first postnatal week and was localized to neuronal cell bodies. These results suggest that immature glycinergic neurons of the auditory brainstem may not acquire GABA through classical GABA synthesis or GABA reuptake, but perhaps are able to synthesis GABA through the putrescine degradation pathway mediated by ALDH1A1.

abstract: Thesis

abstract: Master of Science (MSc)

abstract:
Evolutionarily older parts of the mammalian brain, such as the brainstem, typically play little role in higher-order functions, but contain regulatory centers that are critically important for keeping the organism alive. As conventional wisdom has been that brainstem centers require fast inhibitory communication (mediated by the neurotransmitter glycine) to carry out their critical functions, an ongoing mystery lies in why many immature inhibitory neurons in the developing brainstem use the relatively slow inhibitory neurotransmitter, GABA. We and others have speculated that inhibitory neural circuits of the brainstem require GABA for maturation and/or refinement.

As a first step in addressing this question in the auditory brainstem, we looked for the cellular and molecular sources of GABA by performing antibody stains for various proteins known to be involved in GABA synthesis and transport. Our results suggest, somewhat surprisingly, that GABA in the immature brainstem likely arises from non-classical sources.


title: TP5: A POTENTIAL THERAPEUTIC DRUG FOR PARKINSON’S DISEASE

title: INVESTIGATING THE THERAPEUTIC EFFECTS OF TRUNCATED PEPTIDE 5, A CDK5/P25 INHIBITOR, IN AN IN VITRO AND IN VIVO MODEL OF PARKINSON’S DISEASE

contributor:
Mishra, Ram
Neuroscience

subject:
Neuroscience
Parkinson's Disease

abstract:
Parkinson’s Disease is a chronic progressive neurodegenerative disease that
affects approximately 2000 out of 100 000 people over the age of 80. This disease is
typically characterized by impaired motor function, as well as cognitive and autonomic
dysfunction as the pathology worsens. The two main hallmarks typically associated with
PD are the dopaminergic loss in the nigrostriatal pathway and the presence of Lewy
bodies. However, a cellular dysfunction has been commonly found in neurodegenerative
diseases, known as the hyperactivation of the Cdk5/p25 complex. This complex is an
essential target to focus on the protection of neurons and prevent the pathology of PD to
worsen as treatments are currently only temporary in symptom relief. Truncated Peptide 5
(TP5) is a Cdk5/p25 inhibitor that has demonstrated potential therapeutic effects in
neurodegenerative disease models such as Alzheimer’s Disease. Paraquat is an herbicide
that has implicated Parkinson’s Disease symptoms in those who have been exposed to
this toxin. The purpose of this study was to explore TP5’s therapeutic effects to determine
if TP5 has the potential drug to treat towards PD. TP5 was tested in vitro and in vivo
models that are exposed to paraquat to induce Parkinson’s Disease like phenotypes and
biochemical features. A truncated fragment of TP5, known as Peptide A, was also further
explored to determine potential therapeutic effects like TP5. TP5 has shown its ability to
protect differentiated SH-SY5Y cells and the dopaminergic morphology and behaviour of
C. elegans when exposed to paraquat. These results further support that TP5 has
neuroprotective effects against models of Parkinson’s Disease. TP5 was also able to
regulate the physiological mechanism of Cdk5, such as neurite outgrowth, to further understand its relationship with Cdk5 activity. Lastly, TP5 restored dopaminergic
morphology against worms exposed to paraquat. These results suggest TP5 influences the
pathology of PD, in both neuroprotective and neurorestorative manner, to confirm that
TP5’s potential as a therapeutic drug for Parkinson’s Disease.

abstract: Thesis

abstract: Master of Science (MSc)


title: The role of hemocytes in formation of the cardiac extracellular matrix

contributor:
Jacobs, Roger
Biology

subject:
Extracellular matrix
Hemocytes
Drosophila
Heart

abstract: Cardiovascular disease is a leading cause of death worldwide. Changes in the cardiac extracellular matrix (ECM) are associated with cardiac pathologies such as cardiomyopathy and cardiac hypertrophy. The ECM is a dynamic scaffold of proteoglycans, fibrous proteins, and glycoproteins that sheathes and protects many organs and tissues, including the heart, by attenuating mechanical stress. Misregulation of ECM proteins triggers changes in matrix stiffness, which can lead to age-associated and congenital heart defects. ECM rigidity is also important to the migration of cells, such as hemocytes, the invertebrate blood cells. In the embryo, hemocytes also perform fibroblast functions, through the deposition of the ECM proteins Collagen and Laminin. Hemocytes are hypothesized to be critical for ECM assembly, and by extension, for heart development. The consequences of impaired hemocyte function in the embryo and during larval growth are unknown and are the focus of this research. Using Drosophila melanogaster as a model, I used genetic tools to manipulate hemocyte survival and motility to assess their role in ECM organization and structure around the heart. Concerted gene knockdown and confocal microscopy techniques were employed to evaluate the effects of altered hemocyte abundance and motility on hemocyte behaviour and resulting changes to the ECM. Here I provide evidence to support a role for hemocytes in the turnover of a vital ECM protein, the Type IV Collagen Viking. I also developed a novel protocol to photobleach and observe fluorescence recovery in intact, living larvae using confocal microscopy. Recovery of fluorescence of GFP tagged ECM is a measure of the rate of ECM protein turnover during development or growth. This novel technique has allowed for assessment of recovery of Viking-GFP after photobleaching in vivo, as a measue of Viking protein turnover at the cardiac ECM.  This new technique can be employed to determine the turnover of other major ECM proteins. Combining hemocyte impairment with photobleaching provides the opportunity to observe innate protein turnover at the ECM in real time, both in normal and hemocyte-deprived matrices. Recovery of Viking-GFP fluorescence was also observed in hemocyte-deprived conditions. My findings reveal gradual recovery of Viking-GFP at the cardiac ECM in controls, and potentially slower recovery in hemocyte-impaired conditions. These observations suggest a role of hemocytes in ECM protein turnover. This work will help reveal the role of hemocytes in organizing the cardiac ECM and provides a novel technique for the in vivo assessment of ECM protein turnover. Ultimately, this research sheds light on how hemocyte function affects overall structure of the cardiac ECM and contributes to an enhanced understanding of how changes in this ECM influence predisposition to and progress of cardiac disease.

abstract: Thesis

abstract: Master of Science (MSc)


title: The Impact of FAM84B Expression on Breast Cancer Tumorigenesis and Tamoxifen Resistance

contributor:
Tang, Damu
Medical Sciences

subject:
FAM84B
Breast Cancer
Tamoxifen Resistance
HRASLS

abstract: Breast cancer (BC) is the second most common malignancy in the world and it accounts for 15% of female deaths due to cancer every year. The development of these tumours is regulated by the activities of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Tamoxifen (TAM) is frequently used to treat patients with ER+ BC; however, a recurring problem is the development of resistance and the mechanisms leading up to this event remain unclear. FAM84B is reported to be associated with the development of various cancers such as esophageal squamous cell carcinoma and prostate cancer. The function of the protein is unknown; however, insight towards its mechanism of action has been made through the discovery of its structural similarities with the H-Ras-like suppressor (HRASLS) subfamily of enzymes. We hypothesize that FAM84B upregulation enhances BC tumorigenesis and facilitates the development of TAM resistance in this disease. We observed that both overexpression and knockdown of FAM84B had little effects on cell proliferation; however, the latter reduced the ability of MCF7 cells to form isolated colonies. We performed similar analyses using a FAM84B mutant with deletion of its HRASLS domain and we observed that MCF7 cells expressing this protein showed higher rates of cell proliferation and increased ability to form isolated colonies compared to cells with baseline expression of wild-type FAM84B. These results suggest that FAM84B regulates BC cell proliferation through a complex manner. An analysis of patient-derived BC tissue revealed that FAM84B expression was associated with BC at early stages than later stages, which suggests a possible role of the protein in directing events associated with the early developmental stages of the disease. Additional analyses demonstrated that overexpression and knockdown of FAM84B had little impact on TAM-derived cytotoxicity of MCF7 cells. We observed higher expression of FAM84B in TAM-resistant MCF7 cells in comparison to TAM-sensitive cells, while TAM-resistant and TAM-sensitive xenograft tumours showed similar levels of FAM84B expression. This suggests that the contributions of FAM84B in BC tumorigenesis and resistance to TAM are complex; alternatively, FAM84B may not play a major role in either events. Future studies will be needed to clarify the effects of FAM84B on BC tumorigenesis and progression.

abstract: Dissertation

abstract: Master of Science (MSc)

abstract: Breast cancer (BC) is the second most common malignancy in the world and it accounts for 15% of female deaths due to cancer every year. Although hormonal therapy with tamoxifen (TAM) is a commonly used treatment for the disease, a recurring problem is that tumours eventually develop resistance to the drug. We are interested in investigating the role of FAM84B in BC tumorigenesis and the development of TAM resistance in these tumours. FAM84B has been shown to have higher expression in esophageal squamous cell carcinoma than in normal tissue and the protein was associated with increased tumour growth. Similar studies in prostate cancer have shown that FAM84B is associated with progression of the disease. The results of our analyses suggest that FAM84B may have a possible role in promoting events associated with enhancing the viability of MCF7 cells, leading to increased rates of growth and division. In addition, FAM84B may also function to direct events associated with the early developmental stages of BC. We did not, however, observe any impact of altered FAM84B expression on the development of TAM resistance in BC. Further research involving improved in vitro and in vivo studies, along with an examination of FAM84B’s impact on various oncogenic molecular signalling pathways, will help improve our understanding of the protein’s role in BC tumorigenesis.


title: Matrix Variate and Kernel Density Methods for Applications in Telematics

contributor:
McNicholas, Paul
Mathematics and Statistics

subject: telematics, matrix variate

abstract: In the last few years, telemetric data arising from embedded vehicle sensors brung an overwhelming abundance of information to companies. There is no indication that this will be abated in future. This information concerning driving behaviour brings an opportunity to carry out analysis. The merging of telemetric data and informatics gives rise to a sub-field of data science known as telematics. This work encompasses matrix variate and kernel density methods for the purposes of analysing telemetric data. These methods expand the current literature by alleviating the issues that arise with high-dimensional data.

abstract: Thesis

abstract: Master of Science (MSc)


title: Computational Fluid Dynamics Simulations of Membrane and Resin-based Chromatography

contributor:
Ghosh, Raja
Chemical Engineering

subject:
chromatography
bioseparation
computational fluid dynamics
column
flow distribution
cuboid packed-bed
laterally-fed membrane chromatography
pertactin
vaccine
affinity ligand

abstract: Many of the industrial processes, used by manufacturers to produce biologics, have not been significantly updated since their original design and conception. And thus, there is a great opportunity to update and optimize manufacturing processes. Downstream purification is often considered the bottleneck of the manufacturing process and when biologics are being purified for clinical applications, the final purity is paramount. As a result, pharmaceutical products are subjected to multiple concentration, conditioning, and chromatographic steps. The pharmaceutical industry is constantly and slowly evolving and is always looking to improve efficiency.  Simulations and modeling are becoming more commonly used in the pharmaceutical industry as a tool to strategically design and test new production and separation processes developed at the research and development scale.  In this thesis, computational fluid dynamics (CFD) modeling was used to develop more efficient bioseparation processes by (1) using a cuboid module geometry and (2) chromatographic medium with product-specific affinity ligands. The laterally-fed class of chromatography modules has a unique cuboidal geometry, with lateral feeding of the sample in the channel above the bed and lateral collection of permeate. CFD simulations and experimental results have shown that the laterally-fed class of chromatography devices can produce sharper elution peaks, have better peak resolution, and consequently purer product fractions than conventional membrane and resin-based chromatographic formats. The enhanced performance by the laterally-fed class of chromatography devices is attributed to improved system fluidics and narrow solute residence time distribution. One other approach to improving efficiency is to address the tradeoff between purity and recovered yield, due to the non-specific binding nature of many commercial resins and membranes. Purification using high-affinity biological ligands selected on specificity to the target molecule could be a feasible solution. A purification scheme for pertactin was developed with final eluate purity of 90% and approximately 100% recovery.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Understanding the Impacts of Flooding on Social Vulnerability and Analyzing the Effect of Coverage Maximums on Flood Insurance Demand

contributor:
Yiannakoulias, Niko
Earth and Environmental Sciences

subject: flooding, social vulnerability, flood insurance, risk

abstract:
This research explores geospatial patterns in social vulnerability to flooding and experimentally examines the effect of coverage maximums on flood insurance demand. In the first chapter, I analyze census data for the City of Calgary from 1991-2016 to identify trends in social vulnerability based on flood hazard level. Using a quasi-experimental design, I estimate the short-term changes in social vulnerability attributable to the 2013 Calgary flood. The results show that the Calgary flood was associated with a 2.6% increase in postsecondary education, a 1.4% decrease in the immigrant population, a 1.7% decrease in the visible minority population, a $7,100 increase in median family income, 2.8% decrease in home ownership, 3.7% increase in housing construction and 2.2% increase in recent movers. Together, these findings suggest that the highest flood hazard areas in Calgary are generally comprised of lower vulnerability populations; absolute loss potential from floods is getting higher over time due to higher property wealth in high flood hazard areas; and flooding events are associated with a decline in social vulnerability over the short-term.
In the second chapter, I examine flood insurance coverage preferences through the use of a hypothetical choice experiment. The experiment was designed to examine the effect of dwelling value and coverage limit on the probability of flood insurance purchase, while holding the probability of flooding and insurance price constant. Controlling for income, the results indicate that amount of coverage is negatively related to flood insurance demand, however, for people in high-value dwellings the opposite is observed. This may suggest an approach to flood insurance as an investment into high-value properties as a financial asset, but the trade-off in higher yearly premiums may not seem worth the investment for lower-valued dwellings. This research shows an inconsistent demand for flood insurance, dependent on dwelling value and independent of income.

abstract: Thesis

abstract: Master of Science (MSc)

abstract:
In this research I analyze the population characteristics of the City of Calgary geographically in order to determine if more vulnerable populations are exposed to the hazard of flooding. I also look at the before-and-after flood population characteristics of the flooded and non-flooded areas to see if flooding makes communities more or less vulnerable following an event. My aim is to provide context for the flooding hazard in Calgary and see if a flood changes the population vulnerability of the affected areas afterwards.
I also conduct a choice experiment where I provide participants with a devised flood insurance scenario. I keep some of the variables constant, such as flood probability and insurance price, but change the amount of coverage and dwelling value randomly to see if they influence the likelihood that people buy insurance. The goal of this is to understand how insurance maximums can influence consumer demand.


title: Maternal Calciotropic and Bone Biomarker Profiles in Response to a Nutrition+Exercise Intervention in a Randomized Controlled Trial in Pregnancy

title: Bone metabolic response to Nutrition+Exercise intervention in pregnancy

contributor:
Atkinson, Stephanie
Medical Sciences

subject: bone

subject: nutrition

subject: exercise

subject: pregnancy

subject: developmental origins of health and disease

subject: vitamin D

abstract:
Background: Pregnancy induces transient bone mass loss. Dairy foods might promote bone health, yet few interventions have been conducted to optimize maternal bone health in the perinatal period.

Objectives: To conduct a Nutrition+Exercise randomized controlled trial (RCT) in pregnant women to assess the impact on maternal bone health by measures of calciotropic and bone biomarkers at the end of pregnancy and in the post-partum period.

Study design: In the Be Healthy in Pregnancy (BHIP) RCT, 203/241 women consented at randomization (12-17 weeks (wk) gestation) to the bone health sub-study and received either usual care or a Nutrition+Exercise intervention that provided an individualized high protein diet (50% as dairy products) and a walking program throughout pregnancy. Maternal characteristics and fasting blood samples were obtained at 12-17 wk and 36-38 wk gestation, and at six months post-partum. Vitamin D status from the BHIP participants was compared to the FAMILY birth cohort participants (assessed at 24-36 wk gestation) to assess changes over a ten-year span. The response of the calciotropic and bone biomarkers to the RCT intervention was assessed at the end of pregnancy and in the post-partum period.

Results: Adequate vitamin D status in pregnancy was observed in 322 participants from the FAMILY and 191 from the BHIP study, impacted by season and supplement intake. For participants in the BHIP study, serum 1,25-dihydroxyvitamin D concentrations increased throughout pregnancy and were not associated with serum 25(OH)D. Participants from the intervention group had lower serum bone resorption marker CTX compared to control group, which was reflected in cord serum. No differences were observed with other bone biomarkers at the end of pregnancy or in the post-partum period.

Conclusion: Higher protein and calcium intake compared to the control group during pregnancy minimized bone resorption, thus protecting maternal bone health in the perinatal period.

abstract: Thesis

abstract: Doctor of Philosophy (Medical Science)

abstract:
Background: Adaptations in maternal bone metabolism during pregnancy and the post-partum period provide the offspring with the nutrients needed to mineralize their bones. Maternal diet and hormonal changes influence these metabolic changes.
Method: In 203 women recruited to the Bone-Be Healthy in Pregnancy Study randomized controlled trial, we compared changes in bone metabolism during pregnancy and at six months post-partum between women randomized to an individualized and monitored Nutrition + Exercise intervention or usual care (control) throughout pregnancy.
Results: The intervention group consumed more protein and calcium, but had similar and adequate vitamin D status. At the end of pregnancy, women in the intervention group had less bone loss compared to the control group, but all measures were similar at 6 months post-partum.
Clinical significance: The nutrition and exercise intervention reduced maternal bone loss during pregnancy, and could be a feasible intervention to support bone health of pregnant women.


title: Inference for Bivariate Conway-Maxwell-Poisson Distribution and Its Application in Modeling Bivariate Count Data

contributor:
Balakrishnan, Narayanaswamy
Mathematics and Statistics

subject:
bivariate Conway–Maxwell–Poisson
bivariate count data

abstract: In recent actuarial literature, the bivariate Poisson regression model has been found to be useful for modeling paired count data. However, the basic assumption of marginal equi-dispersion may be quite restrictive in practice.  To overcome this limitation, we consider here the recently developed bivariate Conway–Maxwell–Poisson (CMP) distribution. As a distribution that allows data dispersion, the bivariate CMP distribution is a flexible distribution which includes the bivariate Poisson, bivariate Bernoulli and bivariate Geometric distributions all as special cases. We discuss inferential methods for this CMP distribution. An application to automobile insurance data demonstrates its usefulness as an alternative framework to the commonly used bivariate Poisson model.

abstract: Thesis

abstract: Master of Science (MSc)


title: TUNING THE INTERFACIAL PROPERTIES OF CELLULOSE AND SILICONES THROUGH TRIAZINYL AND THIOACETAL CHEMISTRY

contributor:
Brook, Michael A.
Moran-Mirabal, Jose M.
Chemistry and Chemical Biology

subject:
Functional Cellulose and Silicones
Triazinyl and thioacetal chemistry

abstract:
Interest in the incorporation of renewable, environmentally friendly materials, particularly nanocellulose due to its unique mechanical, optical, electrical and magnetic properties, into consumer products has progressed rapidly because these materials could lead to nanocomposites with enhanced functionality and mechanical properties. However, a well documented challenge that prevents nanocellulose from being widely used is the fact that cellulose is insoluble, relatively inert, and difficult to disperse in non-aqueous solvents and polymeric matrices. Available methods for the surface modification of cellulose to make it dispersible in polar and non-polar systems are complex, cost-prohibitive and difficult to implement on a large scale.
To address these challenges accordingly, the first part of this thesis aims to explore a cost-effective chemistry that is versatile and allows the installation of a broad range of functionalities onto nanocelluloses including cellulose nanocrystals/microfibrils while preserving their individual nature. Chapter 2 demonstrates a simple one-step triazinyl surface modification approach for tuning the interfacial properties of cellulosic materials using cyanuric chloride as a versatile linker to graft aliphatic (C18), polymeric (oligo-polyethylene glycol), alkyne (propargyl) chains and aromatic rings (benzyl) onto nanocelluloses, including CNCs and BMCC. We observed that the crystallinity of all triazine-modified CNCs was preserved, while the thermal stability was slightly enhanced compared to unmodified nanoparticles. CNCs modified with different triazinyl derivatives also formed colloidal suspensions in chloroform, isopropanol, ethanol, and methanol, which were stable over periods of months. In addition, propargyl-modified BMCC was linked to an azido fluorescein dye via a coper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction, demonstrating for the first time the production of triazinyl-based reactive nanocellulose.
Next, a companion study, examines the development of a colorimetric and fluorescent “off-on” cellulose based chemosensors for heavy metal detection in water as a potential lab-on-a-molecule system for biomedical and environmental diagnostics. The use of cyanuric chloride as a covalent linker to install pegylated rhodamine Schiff bases onto cellulose filter paper was explored. The factors required to create on demand selectivity and sensitivity towards specific heavy metals was determined. This resulted into the detection of Cu2+ and Hg2+ ions in 100% aqueous environment within 5 seconds of contact with 6.3 ppb and 20 ppb as the limit of colorimetric detection respectively.
Lastly, in addressing the challenges of traditional preparative methods for silicone elastomers largely dependent on several issues associated with current cure strategies mainly cost, toxicity and functional group intolerance of these heavy metal catalyzed reactions (platinum, tin or titanium). Alternative routes based on organic chemistry have been exploited to mitigate these effects. The second part of this thesis introduces organic cure chemistries based on triazinyl and thioacetal linkages as catalyst-free and organic acid catalyzed silicone elastomer preparative methods to control physical properties of silicones while chapter 6 focuses on the preparation of self-driven microfluidic devices tuning the interfacial properties and water wettability of silicones.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: EQUITABLE ACCESS TO WATER IN A RURAL COMMUNITY IN KENYA

contributor: Clinical Epidemiology/Clinical Epidemiology & Biostatistics

subject:
Accessibility
Water
Diarrhoea
Discrete Choice Analysis

abstract:
Water, a fundamental human right, impacts human health through its quantity (i.e., physical amount and ability to access it) and quality. Consumption of poor-quality water can lead to a variety of waterborne illnesses, often manifested as diarrhoea. Millions of individuals worldwide lack access to drinking water that is free from contaminants and is available and accessible when needed. In areas where water is not piped to homes, several physical, demographic, socio-economic and health factors affect access to potable water. These factors may also influence which water point an individual fetches water (i.e. their waterpoint choice) from in the presence of multiple alternative waterpoints. Through this study, effects of various physical, health, demographic and socio-economic factors on waterpoint choice were explored.
This study, based on datasets from a rural Maasai community in Kenya, implements a multinomial logit model to explore effects of various physical (travel time and water quality), health (aggregate frequency of self-reported diarrhoea stratified by age groups), demographic (average household age, household population, number of children under 5, number of women between 8-45 years of age and ratio of household population to number of women between 8-45) and socio-economic factors (education and income) on waterpoint choice. Travel time to the most probable waterpoint as predicted by the model was compared with the travel time to a household’s chosen waterpoint. Both travel times were calculated using the least-resistance path function incorporating slope and landcover.
Results from model optimization showed that combinations of travel time, average household age, diarrhoea among adult women, income, education and number of women between 8-45 years were significant contributors to the three waterpoint choice models. The expected travel time to the most probable waterpoint predicted by these models and actual travel time to chosen waterpoint fit well, showing that the models explain waterpoint choice well.

abstract: Thesis

abstract: Master of Public Health (MPH)


title: AN ANALYTICAL FRAMEWORK FOR OPTIMAL PLANNING OF LONG-TERM CARE FACILITIES IN ONTARIO

contributor:
Huang, Kai
Computational Engineering and Science

subject:
Prescriptive Analytics
Long-Term Care
Mathematical Programming
Optimization
Simulation

abstract: Long-term care facility network in Ontario, and in Canada as a whole, encounters critical issues regarding balancing demand with capacity. Even worse, it is faced with rising demand in the coming years. Moreover, there is an urgent need to provide long-term care for patients in their own language (particularly French). This study proposes a dynamic Mixed-Integer Linear Programming model based on the current standing of the long-term care system in Ontario, which simultaneously optimizes the time and location of constructing new long-term care facilities, adjusting the capacity (namely, human resources and beds) of each facility dynamically, and the assignment of patients to the facilities based on their demand region, gender, language, and age group over a finite time horizon. We apply the diversity-support constraints, based on patients’ gender and language, to save patients from loneliness and to comply with the Canadian values of providing care. Finally, we validate the model by performing a case study in Hamilton, Ontario. An extensive set of numerical analyses are explored to provide deeper insights into the whole issue. One set of such analysis is an extensive simulation study to examine the effect of distributional uncertainty in some of the input parameters on the optimal results, hence providing a much more realistic understanding of the optimization model.

abstract: Thesis

abstract: Master of Science (MSc)


title: THE CHALLENGE OF ALTERNATE LEVEL OF CARE (ALC) FACING OLDER ADULTS IN ONTARIO: IMPLICATIONS FOR GOVERNMENT AND POLICY MAKERS USING A DESCRIPTIVE DATA ANALYTICS APPROACH

contributor:
Zargoush, Manaf
eHealth

subject:
ALC
Alternate Level of Care
Delayed Discharge
Older Adults
Seniors

abstract:
Introduction: Alternate Level of Care (ALC) patients are those who are kept hospitalized although they are medically well enough to be discharged. Those patients wait in acute care because they cannot access an appropriate alternative level of care outside the hospital. ALC leads to the improper consumption of valuable resources that are needed for patients waiting in other departments such as emergency rooms. This reflects poor quality outcomes of the healthcare system and represents a significant economic burden. Moreover, particularly when it concerns older adults, longer stay in hospital results in worsening their health outcomes, declining their functional status and increasing their needs for long-term care. Therefore, ALC is costly from both patient and health care system perspective. Objectives: The main objective of this study was to assess the impact of the Home First strategy on the incidence of ALC. Moreover, the study addressed both the specialized clinical needs (such as dialysis, chemotherapy and mechanical ventilation) and socioeconomic status of ALC patients in order to unveil their association with the ALC length of stay.
Methods: This study involved a secondary analysis of data from the Institute for Clinical Evaluation (ICES). The analyzed dataset included a cohort of 6,059,033 hospitalization records of Ontario citizens, aged 65 years and older, who were admitted to an acute care facility between April 2004 and March 2017. The study involved descriptive analytics grouping the dataset into ALC and non-ALC subsets and examined the percentage of ALC hospitalizations, ALC days and reported odds ratios across several patients' characteristics.
Results: From 2004 until 2016, ALC patients waited to access an appropriate destination for 10.7 million days. Those numbers represented 19.7% of all hospitalization days across Ontario. ALC was more likely among seniors aged 75-84 (OR 1.36, 95% CI 1.35-1.36), aged 85-94 (OR 2.16, 95% CI 2.15-2.17), aged 95+ (OR 2.46, 95% CI 2.40-2.50), females (OR 1.37, 95% CI 1.35-1.36), those who were hospitalized 90 days prior to their current admission (OR 1.22, 95% CI 1.21-1.22), and those who were admitted to hospital through Emergency Department (OR 2.64, 95% CI 2.62-2.67). Moreover, ALC was 10 times more likely in the subgroup of patients who were discharged to long-term care (LTC) (OR 9.71, 95% CI 9.66-9.77). For the socioeconomic characteristics, this study showed that patients were more likely to have ALC days when they lived in urban areas, had a lower income, and were highly unstable and dependent. Furthermore, patients with special clinical needs spent from 10% to 25% of their total hospitalization length of stay waiting to be discharged to an appropriated alternative level of care. Finally, the study revealed that although the implementation of a Home First strategy resulted in a 26% reduction of ALC hospitalizations and a 13% decrease in ALC days, the percent of patients discharged to LTC did not change. For the subgroup having the highest percentage of ALC hospitalizations (53.4%) and ALC days (40.3%), this reflects a partial failure of the Home First strategy in achieving its main objective of facilitating the discharge of patients to their homes.
Conclusions: Policy makers and health care practitioners may benefit from the findings of this study by considering the needs of the ALC patients while planning, allocating resources, and developing polices for discharge, LTC and community care. However, more work is required to quantify the impact of the ALC determinants suggested in this study and assess the efficiency of the current policies and procedures.
Introduction: Alternate Level of Care (ALC) patients are those who are kept hospitalized although they are medically well enough to be discharged. Those patients wait in acute care because they cannot access an appropriate alternative level of care outside the hospital. ALC leads to the improper consumption of valuable resources that are needed for patients waiting in other departments such as emergency rooms. This reflects poor quality outcomes of the healthcare system and represents a significant economic burden. Moreover, particularly when it concerns older adults, longer stay in hospital results in worsening their health outcomes, declining their functional status and increasing their needs for long-term care. Therefore, ALC is costly from both patient and health care system perspective. Objectives: The main objective of this study was to assess the impact of the Home First strategy on the incidence of ALC. Moreover, the study addressed both the specialized clinical needs (such as dialysis, chemotherapy and mechanical ventilation) and socioeconomic status of ALC patients in order to unveil their association with the ALC length of stay.
Methods: This study involved a secondary analysis of data from the Institute for Clinical Evaluation (ICES). The analyzed dataset included a cohort of 6,059,033 hospitalization records of Ontario citizens, aged 65 years and older, who were admitted to an acute care facility between April 2004 and March 2017. The study involved descriptive analytics grouping the dataset into ALC and non-ALC subsets and examined the percentage of ALC hospitalizations, ALC days and reported odds ratios across several patients' characteristics.
Results: From 2004 until 2016, ALC patients waited to access an appropriate destination for 10.7 million days. Those numbers represented 19.7% of all hospitalization days across Ontario. ALC was more likely among seniors aged 75-84 (OR 1.36, 95% CI 1.35-1.36), aged 85-94 (OR 2.16, 95% CI 2.15-2.17), aged 95+ (OR 2.46, 95% CI 2.40-2.50), females (OR 1.37, 95% CI 1.35-1.36), those who were hospitalized 90 days prior to their current admission (OR 1.22, 95% CI 1.21-1.22), and those who were admitted to hospital through Emergency Department (OR 2.64, 95% CI 2.62-2.67). Moreover, ALC was 10 times more likely in the subgroup of patients who were discharged to long-term care (LTC) (OR 9.71, 95% CI 9.66-9.77). For the socioeconomic characteristics, this study showed that patients were more likely to have ALC days when they lived in urban areas, had a lower income, and were highly unstable and dependent. Furthermore, patients with special clinical needs spent from 10% to 25% of their total hospitalization length of stay waiting to be discharged to an appropriated alternative level of care. Finally, the study revealed that although the implementation of a Home First strategy resulted in a 26% reduction of ALC hospitalizations and a 13% decrease in ALC days, the percent of patients discharged to LTC did not change. For the subgroup having the highest percentage of ALC hospitalizations (53.4%) and ALC days (40.3%), this reflects a partial failure of the Home First strategy in achieving its main objective of facilitating the discharge of patients to their homes.
Conclusions: Policy makers and health care practitioners may benefit from the findings of this study by considering the needs of the ALC patients while planning, allocating resources, and developing polices for discharge, LTC and community care. However, more work is required to quantify the impact of the ALC determinants suggested in this study and assess the efficiency of the current policies and procedures.

abstract: Thesis

abstract: Master of Science (MSc)


title: VERSATILE FUNCTIONAL NUCLEIC ACIDS AND THEIR APPLICATIONS IN BIOSENSING

contributor:
Li, Yingfu
Biochemistry and Biomedical Sciences

subject:
functional nucleic acids
in vitro selection
DNAzyme
G-quadruplex

abstract: It is now widely known that some nucleic acid molecules, either DNA or RNA, are capable of forming intricate three-dimensional structures and carrying out functions of molecular recognition and catalysis. Most of known functional nucleic acids are isolated from DNA or RNA pools with random sequences using the technique of in vitro selection. With intensive research for the past three decades, a variety of functional nucleic acids have been discovered and examined for potential applications. The general objective of this thesis is to expand the repertoire of functional nucleic acids via new in vitro selection experiments and pursue their biosensing applications. I started by asking the question of whether it is possible to develop a new kind of functional nucleic acids: chimeric RNA/DNA substrates that have high activity for ribonuclease H2 from the important bacterial pathogen Clostridium difficile but much reduced activity towards the same enzymes from other bacterial species. The key rationale behind pursuing these special functional nucleic acids is my hypothesis that these molecules can eventually be developed into useful biosensors for diagnosing Clostridium difficile infection. For this reason, in my first project, I applied the in vitro selection technique to a random-sequence DNA pool, obtained several highly selective chimeric RNA/DNA substrates, and carried out in-depth analysis of their reactivities and their structural properties.  During this study, I accidentally discovered a family of highly guanine-rich DNA molecules that are able to form an unusual guanine-quadruplex structure in 7 molar urea, a strong denaturing condition for nucleic acid structures. This discovery constitutes a novel observation and therefore, in my second project, I fully characterized the sequence and structural properties of these special DNA molecules and established the conditions that allow these molecules to create stable structures in 7 molar urea. I then got interested in devising a unique application to take advantage of the urea-resistant property exhibited by these molecules. Towards this end, in my third project, I used one such DNA molecule to set up a DNA detection method capable of detecting single nucleotide polymorphism in very long DNA sequences, a desired application that has never been demonstrated before. The findings made in these projects contribute to the ever-growing appreciation of functional capability and practical utility of nucleic acids.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Microfluidic devices for high-resolution whole brain imaging of Drosophila larvae using light-sheet fluorescence microscopy

contributor:
Selvaganapathy, P. Ravi
Biomedical Engineering

abstract: Improving the understanding of the way neurons interact at the whole-brain level is of great interest to neuroscientists. These “circuit diagrams” of the human brain could revolutionize the way neurological diseases are treated, but before this level of study can be conducted, neuroimaging technology must be improved. Using the model organism Drosophila melanogaster, improvements in spatiotemporal resolution of microscopy techniques are being made. Microfluidic devices have been created to improve the spatial resolution of live neuroimaging in Drosophila 3rd instar larva using confocal microscopy, but the desired high temporal resolution has not yet been demonstrated in a live organism. In this research, the high spatial resolution possible using an immobilization device for live larvae is combined with the high temporal resolution of the light-sheet microscope. A microfluidic device was designed to be compatible with the physical constraints of the light-sheet microscope while simultaneously incorporating a 3D-segmental pinning immobilization channel to ensure minimized motion of the CNS of the larvae. The device achieved single-cell resolution (< 5 μm) of the whole brain of a live, intact larva. Z-stack images and time-series captures demonstrated the capability of the microscope to record volumetric images and high image acquisition rates of the live, intact larval CNS respectively.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: NONSTRUCTURAL COMPONENT DEMANDS IN BUILDINGS WITH CONTROLLED ROCKING STEEL BRACED FRAMES

contributor:
Wiebe, Lydell
Konstantinidis, Dimitrios
Civil Engineering

subject:
Controlled Rocking
Nonstructural Components
Seismic Demands
Self-Centring
High-Performance System
Buckling Restrained Braces

abstract:
Controlled Rocking Steel Braced Frames (CRSBFs) have been developed as a high-performance structural solution to resist seismic forces, due to their ability to minimize structural damage and self-centre the structure back to its original position after an earthquake. A CRSBF is intentionally allowed to uplift and rock on its foundation, which acts as the nonlinear mechanism for the system rather than member yielding and buckling. While the CRSBF is in the rocking phase, the response of the system is controlled by prestressing which anchors the frame to the foundation and energy dissipation devices which are engaged by uplift. Although CRSBFs have shown promising structural performance, an assessment of the overall effectiveness of this system must also consider the performance of nonstructural components which have a significant impact on the safety and economic performance of the system.
The purpose of this thesis is to compare the performance of nonstructural components in buildings with CRSBFs to their performance in a conventional codified system such as a buckling restrained braced frame (BRBF), while also investigating which design parameters influence nonstructural component demands in CRSBFs. The responses of various types of nonstructural components, including anchored components, stocky unanchored components that slide, and slender unanchored components that rock, are determined using a cascading analysis approach where absolute floor accelerations generated from nonlinear time-history analyses of each structural system are used as input for computing the responses of nonstructural components. The results show that the trade-off of maintaining elastic behaviour of the CRSBF members is, in general, larger demands on nonstructural components compared to the BRBF system. The results also show that the stiffness of the frame and vibration of the frame in its elastic higher modes are the main influencers for nonstructural component demands in buildings with CRSBFs, while energy dissipation has a minimal impact.

abstract: Thesis

abstract: Master of Applied Science (MASc)

abstract:
Controlled Rocking Steel Braced Frames (CRSBFs) have been proposed as a high-performance structural system that resists earthquake forces on buildings. This system has the ability to minimize damage to structural members and self-centre the building back to its original position after an earthquake, two characteristics that are typically not achieved by current conventional systems. However, an assessment of the CRSBF’s overall effectiveness cannot be limited to the consideration of only the structural skeleton, as the performance of nonstructural components (e.g. architectural elements, mechanical and electrical equipment, furnishings, and building contents) that are not part of the structural skeleton can have a significant impact on the safety and economic performance of earthquake resisting systems.
This thesis compares the demands on nonstructural components in buildings with CRSBFs to their demands in a more conventional system during earthquake motions. The results show that the trade-off for avoiding damage to structural members in the CRSBFs is often higher demands on the nonstructural components.


title: Three Essays in Economics

contributor:
Johri, Alok
Economics

subject: Economic Policy, Macroeconomics

abstract:
This thesis attempts to answer three important questions: 1) Why did India's relative price of investment rise in 80s and fall in 1990s and afterwards? 2) Why is agricultural productivity very low in India? and 3) Did the pro-natalist policy in Quebec accomplish its goal of increasing fertility? Specifically, this thesis comprises of three essays. Chapter 1 builds a simple dynamic general equilibrium model calibrated to Indian data, in order to explore the impact of capital import substitution policies and their reform post-1991. The model delivers a 23% rise before reform and a 28% fall thereafter. Chapter 2 develops a tractable quantitative framework by incorporating one potential explanation - if residing in a village provides access to a network that effectively insures against income fluctuations, then households are less willing to live in cities where labor income risk is uninsured. This chapter shows that implementation of a social insurance system in the urban area could have raised the labor productivity agricultural sector.
Chapter 3 studies the effects of a pro-natalist policy in Quebec and finds Quebec’s baby bonus accomplished its goal of increasing fertility. It finds a large response for third and higher-order births for which the bonus was more generous. Interestingly, it also finds a stronger response if there were two previous sons or a previous son and daughter rather than two previous daughters.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: UNCOVERING THE LOCAL SOCIAL RELATIONS OF UNPAID OVERTIME WORK OF SOCIAL WORKERS IN NON-PROFIT SOCIAL SERVICE ORGANIZATIONS

contributor:
La Rose, Tara
Social Work

subject:
Unpaid overtime
Social work labour

abstract:
This study seeks to uncover the local social relations of unpaid overtime work of social workers working in non-profit social service organizations in Ontario.  Previous research has identified unpaid overtime work performed by social workers as an ongoing labour issue.  For example, Baines, MacKenzie Davis, & Saini (2009) found that 71% of social workers surveyed were ‘donating’ one-six hours of time to their jobs a day. Institutional ethnography is used as a theoretical and methodological framework for this inquiry.  Accordingly, this research project focuses on uncovering knowledge about the social organization of unpaid overtime work.  This knowledge may be useful for those seeking to make specific changes to the organization of the work of social workers to further prevent or eliminate unpaid overtime work.
During this study, three Ontario social workers were interviewed about their jobs and unpaid overtime, and provided further written information over email.  One particular account of a problematic, or topic for IE research, was not formulated in this thesis as originally intended. However, three accounts of the everyday experience of unpaid overtime work of social workers are presented and could each be used to formulate a problematic for future IE research into this topic.  Potential threads of ruling which are visible in the local setting are discussed, with particular emphasis on the ruling relations of non-payment of overtime work.  Other potential threads of ruling identified and discussed include the social organization of ‘an endless workload’ and the social organization of social work ethics.

abstract: Thesis

abstract: Master of Social Work (MSW)

abstract:
Recent research in Ontario has demonstrated that many social workers who work for non-profit organizations such as government social services or community-based non-profits regularly perform unpaid overtime work.  The objective of this study was to understand more about how social workers come to work unpaid overtime hours at their jobs in non-profit social service organizations.  To accomplish this, Institutional Ethnography (IE) was used as a theoretical and methodological framework for research.  IE is a critical sociology which is used to uncover the social organization of a part of every day life, rather than knowledge about the people who experience it.
Studying this research topic contributes to the knowledge of those seeking improved labour justice for social workers. The information discovered in the course of this research about how unpaid overtime work comes to happen for social workers can be useful for those trying to change and prevent unpaid overtime work.


title: MOLECULAR AND CULTURE-BASED PROFILING OF SPUTUM MICROBIOTA FROM CYSTIC FIBROSIS PATIENTS

contributor:
Surette, Michael
Medical Sciences

subject:
Cystic Fibrosis
Microbiology

abstract:
Background/Objectives: Chronic airway infections, characterized by pulmonary exacerbations, are responsible for >90% of morbidity and mortality in CF. Although conventional CF pathogens are targets of antibiotic therapy, colonization by complex polymicrobial communities is now recognized. Our previous research has observed novel pathogens in CF, and polymicrobial interactions, where increased P. aeruginosa virulence may contribute to airway infections. However, these culture-based findings are not recapitulated in culture-independent microbiome profiling studies. Because expectorated sputum produces highly heterogeneous mucous plugs, only a percentage is representative of the active subpopulation driving the disease. To distinguish populations, culture will be compared with DNA and RNA based molecular profiling.
Methods: Spontaneous sputum produced by adult patients attending regular CF clinic visits were obtained within 30 min and processed. Aliquots were treated for quantitative culture and processed for DNA and RNA extraction. Bacterial composition was determined by profiling of the v3 variable region of the 16S rRNA gene (DNA) and 16S rRNA (RNA), and sequenced on an Illumina MiSeq and processed using DADA2. Results: Quantitative culture allowed for recovery of majority of the CF airway microbiome and resulted in distinct cultured organisms at each fractionation conditions for each patient. This individual specific composition was recapitulated in molecular profiles; however, DNA and RNA profiles were dissimilar at each fractionation step. Conclusions: Each bacterial profiling method resulted in distinct bacterial composition. Processing allowed for varying areas of sputum to be isolated resulting in high microbial diversity within the sample, highlighting high sputum microbiome heterogeneity.Incongruent DNA and RNA profiles across sputum suggest viable bacterial populations, represented by the RNA profile, may be more representative of disease state. Overall, the microbiology of sputum is highly patient specific and very difficult to identify a unifying pattern.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Cystic fibrosis is a deleterious, genetically inherited disease affecting 1 in every 3600 children born in Canada with 4300 individuals attending specialized clinics. CF most severely impacts the lungs, accounting for over 90% of mortality. In an attempt minimize irreversible decline in lung function, patients are prescribed aggressive antibiotic treatments. The issue is that conventional pathogens are targets of treatment and uncommon bacterial populations of low abundance are not of primary concern. Furthermore, expectorated sputum is used as a prognostic tool for estimating disease progression. Sputum is highly heterogeneous, containing mucous and saliva components. By fractionating the sputum, we can characterize active bacterial populations, which potentially contribute to disease progression, and dormant populations, which may be a result of chronic infection. Such analysis has emphasized high heterogeneity both within a single sample and across patient populations. This highlights the need for tailored treatment and management of disease for each individual.


title: Pragmatics and Semantics of Free Choice Disjunction

contributor:
Hitchcock, David
Philosophy

subject: Logic; Philosophy of Language; Linguistics; Pragmatics; Semantics; Modal Logic; Dynamic Logic; Epistemic Logic; Disjunction; Free Choice Disjunction

abstract:
A disjunction is an expression using ‘or’, such as ‘Anne has a Ford or a Tesla’. From such a statement, we cannot usually infer either disjunct, for example, that ‘Anne has a Ford’. However, in choice situations like ‘You may have coffee or tea’ we can infer either option. The problem of free choice disjunction is to determine why these choice inferences are legitimate (von Wright 1968, Kamp 1973, Meyer 2016).

Central to this discussion is the observation that a modal possibility operator ranging over a disjunction sometimes implies a conjunction of possibilities. In the case of permission, we express this as the choice principle ‘May (P or Q)’ entails ‘May P and May Q’ (Zimmerman 2000). Unfortunately, this inference cannot hold in a logical language without significant modification of the systems involved.

I explore the history of proposed solutions to this problem, including semantic solutions that assign a distinctive meaning to free choice disjunctions and pragmatic solutions that use features of their utterance to solve the problem. I draw connections between semantics and pragmatics and, using the tools of dynamic logic (Baltag et al. 1998, van Benthem 2010), I present a formal account of one major (Gricean) approach to the problem (Kratzer & Shimoyama 2002).

Ultimately, I explore the role of logic in this debate and argue that we should formally represent the meaning of these expressions directly as conjunctions of possibilities. Thus, rather than trying to account for the choice principle within a logical system, we must instead account for the fact that, in choice situations, the meaning of ‘May (P or Q)’ translates into logical formalism as (May P & May Q).

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract:
A disjunction is a statement using ‘or’, like ‘Anne has a Ford or a Tesla’. From such a statement, we cannot infer either disjunct—e.g. ‘Anne has a Ford’. In choice situations like ‘You may have coffee or tea’ we can infer either option. Why this choice inference is legitimate is the problem of free choice disjunction.

I explore the history of solutions to the problem, including semantic solutions that propose a special meaning to choice disjunctions and pragmatic solutions that appeal to the circumstances in which they are uttered. I draw connections between semantics and pragmatics and present a formal account of one major pragmatic approach to the problem.

Where others have sought to explain how 'May(P or Q)' entails 'May P and May Q', I argue instead that the meaning of ‘May (P or Q)’ in choice scenarios translates directly into logical formalism as ‘May P & May Q’.


title: Investigations of the function of the Pit-accessory protein (Pap) in Sinorhizobium meliloti

contributor:
Finan, Turlough
Biology

subject:
phosphate
membrane protein
microbiology
translational coupling
transporter
Pit

abstract: Phosphate (PO4-3 or Pi) is an essential molecule necessary for sustaining life and it plays important roles in nucleic acid and cell membrane integrity. However, phosphate is found in growth-limiting concentrations in most environments. Bacteria have developed a diverse set of transport systems to uptake and scavenge phosphate from their environment for use in cellular processes. In the soil bacterium, Sinorhizobium meliloti, one such Pi transport system is the Pap-Pit system. Pit is a membrane transporter for Pi and is associated with a cytosolic protein of unknown function known as Pap (Pit-accessory protein). Interestingly, the stop codon of pap overlaps with the start codon of pit by a single nucleotide. In previous work, the pap gene appeared to be required immediately upstream of pit in an operon for functional Pi transport. Thus, in a pap deletion mutant, when pap is present in trans, there is no Pi transport. This suggests a possible translational coupling mechanism between Pap and Pit, in which the translation of Pap is required for the translation of Pit. Here, an alkaline phosphatase (phoA/lacZ) and a β-glucuronidase (gusA) translational reporter were fused to Pit as a measure of its translation and to understand the role of translational coupling in the Pap-Pit system. Growth complementation experiments with a conditionally Pi transport deficient S. meliloti mutant carrying various mutations in both pap and pit have also been performed in an attempt to determine the function of Pap in Pi uptake. The results presented here provide evidence that pap and pit are translationally coupled, and this is necessary for functional Pi transport via Pap-Pit.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Microbes require phosphorus in the form of inorganic phosphate (Pi) as an essential nutrient, but it is often found in growth-limiting concentrations in the environment. Bacteria have developed a diverse set of Pi transport systems to scavenge and take up phosphate from the environment. In the soil bacterium, Sinorhizobium meliloti, one such Pi transport system is the Pap-Pit system. Pit is a membrane transporter for Pi and is associated with a cytosolic protein of unknown function known as Pap. Various mutations in both pap and pit have been constructed in an attempt to determine the function of Pap in Pi uptake via Pit. The pap gene appears to be required immediately upstream of pit in an operon for functional Pi transport.  The pap and pit genes overlap by a single nucleotide and this may suggest a translational coupling mechanism that is required for functional Pi transport via Pap-Pit.


title: Early Childhood Research across Cultures: A Scoping Study of Early Childhood Interventions across Language and Country Boundaries

contributor:
Janus, Magdalena
Banfield, Laura
Galleguillos, Nibaldo
Lavis, John N.
Global Health

subject:
early childhood
early childhood development
early intervention
early childhood intervention
Spanish
Portuguese
scoping study
scoping review
global health
knowledge transfer
cross-cultural research
comparative research
early childhood care and education
Mexico
Brazil
Latin America
Spain
Portugal
Central America
South America

abstract: A scoping study of early childhood research in Spanish and Portuguese-speaking countries for improved well-being worldwide through collaboration and knowledge transfer

abstract:
ABSTRACT
BACKGROUND: Research evidence strongly supports the influence of quality nutrition, cognitive stimulation and nurturing care on the extent that a child reaches full development. Reaching developmental milestones results in positive outcomes for individual health and well-being as well as communal stability and prosperity. Interventions to improve early childhood development are not a recent concept; however, the interaction of one early childhood development outcome on others form a complex, often interdependent, relationship. The complexity of a child's development also includes the child's family, home environment, community and national context. The complex and dynamic setting for implementing early childhood interventions requires more than efficiency or knowledge. It requires patience, cultural competency and a compassion to engage and support a child's family, society and nation. Interventions that are effective in multiple cultures or can be scaled up to a regional or global level are rare and usually focus on one aspect of early childhood development (ECD), like protein intake to prevent stunting. Context does matter, and ECD research is dispersed over vastly different political systems and often focused on specific people groups or subcultures. The scope and intensity of ECD research in the world has not been described and is often unknown to English-speaking researchers who are not personally connected by relationship or literacy to other languages and cultures.

PURPOSE: The purpose of this scoping study is to answer the research question: "What is being researched related to early childhood development interventions with children six years old and younger in Spanish and Portuguese-speaking countries?” A scoping study of published, peer-reviewed literature on interventions in early childhood development in English, Spanish and Portuguese was performed to understand the concepts in research on early childhood development (ECD). The thesis presents interventions in early childhood development and their usage in Mexico, Central and South America in particular and also in Europe and Africa because of the Spanish and Portuguese languages spoken there. The thesis highlights risk factors, assessment tools and interventions from peer-reviewed research providing a scope of ECD interventions for this world area.
SEARCH METHODS
: Databases searched were related to global health, health sciences, nursing and allied health, psychology and education. They were Global Health, Embase, Medline with PubMed e-ahead of print, PsycInfo, CINAHL, ERIC, LILACS and IBECS. The search strategy and data collection was guided by the research question to be thorough and methodical. Exclusion criteria were utilized to screen more than seven hundred articles to retrieve eighty-six articles that included the correct populations, relevant countries, ECD interventions and early childhood outcomes.

FINDINGS: Macro and micro-context risk factors in early childhood development were highlighted across the literature. They were lower maternal education, informal maternal employment, larger household size, lower wealth index and rural residence. Findings related to child or home-centered interventions revealed varied but some positive outcomes in national programmes in Mexico, Brazil, Ecuador, Nicaragua, Colombia and Portugal. The research across all countries in literature found positive impact on early childhood development from age-dependent nutrition, higher socio-economic status and education in mothers, stimulating parent-child interactions and nurturing home environment.
CONCLUSIONS:
While a scoping study of ECD provides an overview of the work happening and of the relevant key concepts, the eighty-six included studies can hardly be considered representative of all childhood development interventions being implemented or researched. Some state or national governments and non-government organizations implement early childhood interventions without publishing in a peer-reviewed journal. Many more interventions are not evaluated or monitored. Increased collaboration and networking between researchers and countries is needed. Necessary partnerships between educators, researchers and policy-makers based on national strengths across the globe can facilitate better sharing of knowledge and assessment of appropriate interventions for a population's needs. Further monitoring, evaluation and publishing of interventions in this region of the world is required. M.Sc. Thesis - Brandon James Chapman; McMaster University - Global Health

abstract: Thesis

abstract: Master of Science (MS)

abstract: Development during the earliest years of life includes physical, mental and social development. This thesis is a study on the research for early childhood development in Spanish and Portuguese-speaking countries and describes what is happening with a global health perspective. The thesis discusses how research can impact knowledge and what is done to support and improve development for children, their families and their country.


title: Randomized Computation Offloading Algorithms for Mobile Cloud Computing

contributor:
Szymanski, Ted
Electrical and Computer Engineering

abstract:
Computation offloading occurs when a mobile application arranges for tasks to be
executed remotely, rather than running them locally on the device itself. This mechanism
can be used to reduce mobile device energy consumption, resulting in improved
battery lifetime. In this thesis, new algorithms that generate offloading decisions for
mobile device applications are presented. Randomization is the main technique that
is explored, where the algorithms iteratively improve an offloading decision vector by
generating random bit strings that represent the task offload decisions. If fragments
of these bit strings improve the performance, they are incorporated into the decision
vector in a process similar to genetic optimization. In the experiments reported in
this thesis, the proposed algorithm typically find good to excellent quality solutions,
with low computational overhead compared to existing algorithms. Furthermore, the
algorithms scale gracefully as the problem size grows, maintaining high computational
efficiency and good solution quality.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract:
Many applications envisioned for mobile devices require intensive computing power
for application execution. Executing these computation intensive tasks on the mobile
device leads to large delays and requires substantial energy from the limited battery
storage on the device. Mobile Cloud Computing provides data processing and storage
in powerful and centralized computing platforms located in the cloud. Having access
to these cloud resources helps the mobile devices to run the application faster and
with less battery usage. Computation offloading is a technique by which some of the
tasks in a mobile application can be offloaded for execution on a remote server, so
that mobile energy use can be reduced. There are different parameters that can affect
the procedure of offloading and it is the responsibility of the mobile device to decide
which tasks from the application should be executed locally and which ones should be
executed remotely in order to reduce the energy consumption on the mobile device
and reduce the time delay of the computation. The algorithms that are designed
to make these decisions regarding the task execution location are called offloading
algorithms. The goal of this thesis is to design efficient offloading algorithms for
mobile cloud computing.


title: Function and Regulation of Fish CYP3 Genes

title: Characterizing the Function and Regulation of Orphan CYP3 Genes in Zebrafish (Danio Rerio)

contributor:
Wilson, Joanna Y.
Biology

subject:
Cytochrome P450
function of orphan CYPs
regulation of cytochrome P450s
CYP3C1
CYP3A65
xenobiotic metabolism
zebrafish
pharmaceutical metabolism
high throughput screening
Aryl hydrocarbon receptor
Estrogen Receptor

abstract: Genome sequencing has resulted in the identification of >55,000 cytochrome P450 enzymes, many of which have an unknown function and regulation. In mammals, CYP3 genes appear in only one subfamily (CYP3A), which metabolize >50% of pharmaceuticals and some steroids in humans. Unlike mammals, fish contain genes in the CYP3A, CYP3B, CYP3C and CYP3D subfamilies. While it is commonly assumed that fish and mammalian CYP3A are functional similar, the function and regulation of fish CYP3 remains largely unknown. In this thesis, the receptors and compounds that regulate CYP3C genes in zebrafish were assessed. The induction of CYP3C genes in response to the aryl hydrocarbon (AHR) and estrogen receptor (ER) ligands, β-naphthoflavone and 17β-estradiol, was measured using quantitative PCR in intestine, liver and gonads. Zebrafish CYP3C genes were inducible by β-naphthoflavone and 17β-estradiol, implicating the aryl hydrocarbon and estrogen receptor in CYP3C gene regulation and suggesting that regulation of CYP3 genes in fish differs from that in mammals. To define the function of zebrafish CYP3A65 and CYP3C1, fluorogenic compounds which are specific markers of CYP1 and CYP3A activity in humans, were screened for metabolism by CYP3A65 and CYP3C1. Both CYP3A65 and CYP3C1 had the capacity to metabolize several of these compounds and the substrate profile overlapped with zebrafish CYP1A, suggesting that these compounds are not specific in fish. A high throughput approach was employed to screen ~4000 small biologically and pharmacologically active compounds for metabolism by CYP3A65 and CYP3C1, using NADPH consumption to assess catalytic activity. The substrate profiles of CYP3A65 and CYP3C1 largely overlapped and were different than mammalian CYP3A4. CYP3A65 and CYP3C1 appeared to have a bias for quinone-based compounds but further studies are required to confirm quinones as substrates and to assess a strong structure-activity relationship. Overall, this study provides insight on the regulation, function and evolution on CYP3 genes in fish.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)

abstract: Cytochrome P450 (CYP) enzymes break down compounds such as hormones and pharmaceuticals. While mammals have genes in the CYP3A subfamily, fish have unique subfamilies not found in mammals. The function and regulation of the CYP3 family in fish is unknown, but commonly assumed to be like human CYP3. The purpose of this thesis was to identify what receptors and compounds regulate CYP3C enzymes in zebrafish. We found that regulation of CYP3C enzymes in zebrafish is different than humans. Zebrafish CYP3C genes are regulated by the aryl hydrocarbon receptor and estrogen receptor, while human CYP3A is regulated by the pregnane-x-receptor. I used a high throughput approach to screen thousands of compounds to identify the function of CYP3A65 and CYP3C1 from zebrafish. CYP3A65 and CYP3C1 metabolize several plant-based and pharmaceutical compounds. CYP3A65 and CYP3C1 are more functionally similar to each other than to CYP3A in humans.


title: Validation and Characterization of TCF7L1-SALL4 Protein-Protein Interaction in Mouse Embryonic Stem Cells

contributor:
Doble, Bradley
Biochemistry and Biomedical Sciences

subject: mESC Embryonic Stem Cells TCF7L1 SALL4 Wnt Signaling Cell Biology Protein-Protein-Interaction Protein Co-IP PLA qPCR

abstract: Here, we validate novel protein interactors of TCF7L1 (also known as TCF3), a downstream transcription factor in the Wnt/β-catenin signaling pathway, from an initial protein interaction screen that utilized the BioID system in mouse embryonic stem cells. The BioID-TCF7L1 screen identified multiple proteins including several transcription factors and numerous epigenetic regulators. Notably, SALL4, a key embryonic stem cell factor belonging to the SPALT family of transcription factors was validated to interact with TCF7L1 through Proximity Ligation Assay (PLA), and Co-Immunopreciptation (Co-IP). Analysing mRNA transcriptomic signatures of TCF7L1-null mEScs and SALL4 overexpressing mESCs, we observed similarly increased output of the pluripotency-gene, Tbx3, suggesting a transcriptionally opposing function between TCF7L1 and SALL4. Furthermore, we identified that SALL4 also interacted with TCF7, suggesting that SALL4 may interact with all four members of the TCF/LEF transcription factor family to regulate Wnt targets. This work further validates the utility and effectiveness of screening transcription factor interactors through the BioID system and provides important insights into SALL4 mediated Wnt regulation through the TCF/LEFs.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: The biology of cells is highly complex. The genes within are under tight regulation to promote balance that is critical to the growth and status of the cell. Cells communicate with one another to support this balance through molecule secretion signaling which dictates biology. Understanding the complex biology within cells is critical, and therefore here we study one of many signaling pathways known as the Wnt Signaling Pathway. This work contributes to the knowledge of Wnt signaling by validating the interaction of proteins that dictate the onset or offset of important genes in mouse embryonic stem cells.


title: Neural Correlates of Autobiographical Memory in PTSD

contributor:
McKinnon, Margaret
Psychology

abstract: This thesis examines the neural correlates of autobiographical memory retrieval among individuals with military-related PTSD, a population with increased illness burden and decreased treatment response. Although cognitive deficits, including in autobiographical recall, have been identified in PTSD, the mechanisms underlying these deficits remains unclear. Here, a series of studies have pointed towards alterations in the neural pathways underlying autobiographical recall in PTSD. Despite these observations, it remains unclear how key clinical variables, such as dissociation and early life trauma, might impact patterns of neural response during autobiographical recall in PTSD.  The original work presented in this thesis examines emotional and traumatic memory retrieval in a sample of patients with military-related PTSD, trauma-exposed participants, and healthy controls and includes analysis of the relation between patterns of neural activation during autobiographical memory retrieval and key clinical variables associated previously with disease-related alterations in cognitive functioning. Our findings of increased lingual activity point towards aberrant implicitly cued memory function in military members and veterans with PTSD during traumatic memory retrieval. In addition, activation in the frontal operculum suggests that trauma-exposed military members and veterans without PTSD showed increased engagement of emotion regulatory strategies during retrieval of negative memories. Finally, we found an association between dissociative symptoms and activation observed in frontal and posterior regions during trauma memory retrieval in trauma-exposed military members and veterans. In addition to increasing core scientific knowledge surrounding the neural correlates of autobiographical memory recall in trauma-exposed military members with and without PTSD, our results highlight the urgent need to characterize further the role of dissociative symptoms in cognitive dysfunction among individuals with PTSD.

abstract: Thesis

abstract: Master of Science (MSc)


title: THE SYNTHESIS AND EVALUATION OF NEW RADIOPHARMACEUTICALS AND MULTIMODAL IMAGING PROBES

title: THE SYNTHESIS, EVALUATION AND MECHANISTIC STUDY OF NEW 99mTc(I)-TETRAZINES FOR THE DEVELOPMENT OF NEW RADIOPHARMACEUTICALS AND MULTIMODAL IMAGING PROBES

contributor:
Valliant, John F
Chemistry and Chemical Biology

subject:
Radiopharmaceuticals
Chemistry
Chemical Biology
Technetium-99m
Bioorthogonal Chemistry
Multimodal Imaging
Molecular Imaging
Pretargeted Imaging

abstract:
Technetium-99m (99mTc) radiopharmaceuticals are widely used for diagnostic imaging of heart, kidney, and liver disease, and cancer. Evolution from perfusion type tracers to targeted agents however has proven difficult. 99mTc labeled antibodies for imaging specific disease biomarkers would be of great interest, however the disparity between the isotopes half-life (6 hours) and the long circulation time of most antibodies (multiple days) has been a significant barrier. Furthermore, the conjugation of bifunctional 99mTc-chelate complexes to small molecules often has a detrimental impact on targeting.  The use of bioorthogonal chemistry derived from tetrazines and trans-cyclooctene derivatives, along with pretargeting has the potential to overcome these issues and create a new generation of targeted 99mTc radiopharmaceuticals.
	Initially, the synthesis of three generations of imidazole based tridentate chelates linked to a tetrazine was completed. These new ligands were labeled with 99mTc under mild conditions (60 °C, 20 min, pH 3.5) with modest to good radiochemical yields ranging from 31 to 83%. Biodistribution studies revealed that compound 14, which contains a polyethylene glycol 5 (PEG5) linker had the best clearance from non-target tissues. Compound 14 was also used successfully in a pretargeting strategy along with a transcyclooctene (TCO) derivative of the bone targeting bisphosphonate, alendronate (ALN). One hour following the administration of TCO-ALN to BALB/c mice, compound 14 was injected intravenously where uptake at sites of high calcium turn over (i.e. the joints) was observed. At 6 hours post injection, for example, uptake reached as high as 20.1 ± 4.91 and 16.1 ± 4.84 %ID/g in the knee and shoulder, respectively.
	Pretargeted imaging studies were performed subsequently with a TCO-functionalized huA33 antibody in mice bearing SW122 xenografts. The TCO-huA33 antibody was injected 24 hours before the administration of two radiolabeled tetrazines at high and low specific activities. At 6 hours post injection tumour uptake was minimal, with tumour: blood ratios <1 in all cases. Blood clearance studies determined that the tetrazines were being cleared rapidly, with a blood residence half-life of 1.3-2.1 minutes. The hypothesis is that the low concentration of the antibody (owing to its high molecular weight), combined with the rapid clearance of the tetrazine and significant off-target uptake resulted in unfavorable kinetics and low tumor binding.
	Studies of the clearance pathway of 14 were investigated with clinically approved hepatobiliary transport inhibitors to help understand the mechanism of clearance, which could in turn be used to optimize the pharmacokinetics of the tetrazine ligands. A range of different inhibitors of key clearance pathways were evaluated with limited success. However, co-administration of 14 with ALN resulted in a 75% decrease in gall bladder uptake of 14 (216 ± 75.9 to 33.6 ± 3.93 %ID/g). Pretargeting studies of 14 with TCO-ALN in the presence of excess ALN revealed that ALN did not hinder the uptake of TCO-ALN in the bone, with all organs and tissues having the same uptake with TCO-ALN or TCO-ALN + ALN (knee: 20.1 ± 4.91 and 14.9 ± 2.43 %ID/g, respectively). There was also a concomitant decrease in gall bladder uptake (91.5 ± 17.1 to 28.8 ± 2.63 %ID/g).
Further work on improving the distribution of the tetrazine ligands involved investigating the effect of the chelate. The core chelate found in 14 without the tetrazine moiety (compound 11a) was labeled with 99mTc to produce 11b in a 31% radiochemical yield. Biodistribution studies of 11b and 14 at 6 hours post injection demonstrated that the imidazole-based 99mTc-chelate was a major factor in the rapid and significant uptake and retention in the liver and gallbladder. A new triazole based chelate with optimal clearance from Kluba and coworkers was synthesized in 45% yield and successfully labeled with 99mTc (compound 23a). Biodistribution studies were performed where at 6 hours post injection, 23a had five times lower uptake in all non-target organs compared to 11b. The synthesis of a tetrazine derivative of 23a (compound 32) unfortunately demonstrated high hepatobiliary uptake compared to the original triazole chelate (gall bladder: 228 ± 251 and 8.77 ± 0.73 %ID/g, large intestine: 85.5 ± 83.5 and 6.88 ± 0.30 %ID/g, respectively). This particular derivative had a lipophilic linker as a result of the synthetic challenges faced during the preparation of a more hydrophilic triazole-tetrazine derivative.
	In addition to pretargeting applications, the 99mTc-tetrazine was used as a reagent to create multimodal imaging agents. Nanoscale gas vesicle (GV) ultrasound contrast agents were functionalized with TCO via an amide coupling to lysine residues. TCO-GVs were then radiolabeled by adding compound 6 where the desired product, a new multimodal probe, was obtained in 59% radiochemical yield. SPECT imaging and biodistribution studies in mice were completed where the labeled GV’s showed uptake in the gall bladder (120 ± 29.1 %ID/g), liver (16.8 ± 7.50 %ID/g), lungs (3.26 ± 1.53 %ID/g), small intestines (14.5 ± 5.30 %ID/g), and spleen (5.47 ± 2.71 %ID/g) at 120 min post injection. In addition to radiolabelling, the TCO-GVs were also functionalized with a near IR-tetrazine dye to produce a multimodal ultrasound/photoacoustic (US/PA) imaging agent in a 68% yield.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: ACHIEVING A PATIENT-CENTERED APPROACH TO THE TESTING OF PULMONARY EMBOLISM IN THE EMERGENCY DEPARTMENT

title: PATIENT-CENTERED CARE FOR PULMONARY EMBOLISM TESTING IN THE EMERGENCY DEPARTMENT

contributor:
de Wit, Kerstin
Linkins, Lori Ann
Chan, Teresa
Mercuri, Mathew
Medicine

subject:
Emergency medicine
pulmonary embolism
patient-centered care

abstract:
Acknowledgements

First and foremost, I am very grateful to my supervisor, Dr. Kerstin de Wit, for her mentorship and guidance throughout my time as a graduate student. It has been a pleasure to work with someone so innovative and passionate about clinical research. Her ability to bridge thrombosis and emergency medicine research to improve and change clinical practice is inspiring.

I am grateful to my supervisory committee members, Dr. Teresa Chan, Dr. Lori-Ann Linkins, and Dr. Mathew Mercuri, for their continuous support throughout this process. Our scientific discussions were always insightful, and motivated me to push myself as a researcher.

I am very thankful to the entire EMeRGE Research Group for creating such a helpful and friendly environment. Their diligence and commitment to conducting high-quality research motivated me to do the same, and greatly expanded my knowledge on clinical research. Working with this team made my experience as a graduate student very memorable.

I would like to thank my family and friends for all of the support they gave me throughout this entire process. Their constant encouragement and emotional support helped me overcome challenges and persevere, for which I am infinitely grateful.

abstract:
Background: There is an evidence-practice gap between guidelines for diagnosing pulmonary embolism (PE) and emergency physician practice. This is concerning because computed tomography (CT) scanning is being overused to exclude PE in the emergency department (ED). It is possible that the answer behind this lies within the physician-patient relationship. Past research on shared decision-making strategies have shown to decrease use of hospital resources, and improve patient outcomes.
Objective: The aim of this three-part MSc thesis was to achieve a patient-centered approach to the testing of PE in the ED.
Method: 1) A systematic review on existing shared decision-making models used for testing and/or treatment of medical decisions in the ED was conducted. 2) Qualitative interviews with ED patients being tested for PE identified patient-specific values and preferences which may present as barriers to patient-centered care in the ED. 3) Both the systematic review and patient interviews informed the development of a new shared information tool to be used in the ED.
Results: The systematic review found that shared decision-making interventions in ED patients tested for acute coronary syndrome and clinically-important traumatic brain injuries can potentially reduce hospital admissions and increase discharge rates without negatively affecting health outcomes. The qualitative interviews highlighted four major themes: 1) patient satisfaction comes from addressing their primary concern; 2) preference for imaging over clinical examination; 3) patients expect 100% certainty when given a diagnosis; and 4) patients expect individualized care throughout their entire ED visit. This data led to the formation of a shared information sheet which ensures that testing decisions for low-risk PE patients align with patient-specific values.
Conclusion: By placing the focus on patient-centered care, this study incorporates evidence-based medicine with patient priorities in order to improve patient outcomes in the ED.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Pulmonary embolism occurs when blood clots form in veins of the legs, and travel to the lungs, causing chest pain and shortness of breath. There are well-established, evidence-based guidelines on how to diagnose pulmonary embolism. Diagnostic tools such as the Wells score and D-dimer have been proven to be safe and effective in ruling out pulmonary embolism in low risk patients preventing the need for a CT scan. However, CT scans are still being overused to diagnose pulmonary embolism in low risk patients. Unnecessary testing in the emergency department (ED) exposes patients to the harms associated with CT scanning: such as increased risk of cancer, and diagnosing blood clots that are not actually there, resulting in unnecessary treatment. It is possible that the answer behind the over-testing of PE in the ED lies within the physician-patient relationship. This three-part study first reviewed all prior studies on shared decision-making strategies, which are techniques used to help physician align medical decisions with patient-specific values, in the ED. Second, we employed qualitative methods to identify patient-specific values and preferences on PE testing in the ED. Finally, both of these aims informed the development of a patient-centered shared information tool to overcome barriers to patient-centered care. Ultimately, the goal of this study is to achieve a patient-centered approach to the testing of pulmonary embolism in the ED.


title: Conformer Searching

title: Conformer Searching using an Evolutionary Algorithm

contributor:
Ayers, Paul W.
Chemistry and Chemical Biology

subject:
conformers
evolutionary algorithms
amino acids
potential energy surface
software
Kaplan
structure search
RMSD
forcefield

abstract: This thesis discusses Kaplan, a free conformer searching package, available at github.com/PeaWagon/Kaplan

abstract: Conformer searching algorithms find minima in the Potential Energy Surface (PES) of a molecule, usually by following a torsion-driven approach. The minima represent conformers, which are interchangeable via free rotation around bonds. Conformers can be used as input to computational analyses, such as drug design, that can convey molecular reactivity, structure, and function. With an increasing number of rotatable bonds, finding optima in the PES becomes more complicated, as the dimensionality explodes. Kaplan is a new, free and open-source software package written by the author that uses a ring-based Evolutionary Algorithm (EA) to find conformers. The ring, which contains population members (or pmems), is designed to allow initial PES exploration, followed by exploitation of individual energy wells, such that the most energetically-favourable structures are returned. The strengths and weaknesses of existing publicly available conformer searchers are discussed, including Balloon, RDKit, Openbabel, Confab, Frog2, and Kaplan. Since RDKit is usually considered to be the best free package for conformer searching, its conformers for the amino acids were optimised using the MMFF94 forcefield and compared to the conformers generated by Kaplan. Amino acid conformers are well characterised, and provide insight for protein substructure. Of the 20 molecules, Kaplan found a lower energy minima for 12 of the structures and tied for 5 of them. Kaplan allows the user to specify which dihedrals (by atom indices) to optimise and angles to use, a feature that is not offered by other programs. The results from Kaplan were compared to a known dataset of amino acid conformers. Kaplan identified all 57 conformers of methionine to within 1.2Å, and found identical conformers for the 5 lowest-energy structures (i.e. within 0.083Å), following forcefield optimisation.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: A conformer search affords the low-energy arrangements of atoms that can be obtained via rotation around bonds. Conformers provide insight about the chemical reactivity and physical properties of a molecule. With increasing molecule size, the number of possible conformers increases exponentially. To search the space of possible conformers, this thesis presents Kaplan, which is a software package that implements a novel directed, stochastic, sampling technique based on an Evolutionary Algorithm (EA). Kaplan uses a special type of EA that stores sets of conformers in a ring-based structure. Unlike other conformer-specific packages, Kaplan provides the means to analyse and interact with found conformers. Known conformers of amino acids are used to verify Kaplan. Other tools for generating conformers are discussed, including a comparison of freely available software. Kaplan effectively finds the conformers of small molecules, but requires additional parametrisation to find the conformers of mid-sized molecules, such as Penta-Alanine.


title: CHILD AND ADOLESCENT MENTAL HEALTH IN LMIC: APPLICATION OF TASK-SHARING APPROACHES AND AN EXAMINATION OF INTERGENERATIONAL TRANSMISSION OF RISK

contributor:
Hall, Geoffrey
Gonzalez, Andrea
Neuroscience

subject: ACES

subject: Adverse Childhood Experiences

subject: LMIC

subject: Global Mental Health

subject: Intergenerational Transmission of Psychiatric Risk

subject: Maternal Mental Health

subject: Child Mental Health

subject: Poverty

subject: Task-sharing

subject: Assessment

abstract:
Children and adolescents in low- and middle-income countries (LMIC) suffer heightened vulnerability for the development of mental health conditions which is exacerbated due to enduring socioemotional, economic, and biological risk factors. The constellation of co-occurring adverse childhood experiences (ACEs; e.g. poverty, maltreatment, household dysfunction, exposure to violence) confer heightened vulnerability for the development of mental health disorders that may persist into adulthood. Although the mechanisms for transmission from one generation to the next has not yet been fully elucidated, contemporary evidence has converged primarily on maternal mental health as a key mediator between childhood exposure to ACEs, and the subsequent mental health of her children. Access to mental health assessment or treatment resources in Kenya are limited or non-existent. Due to the heightened risk for intergenerational transmission of mental health problems across generations, with support from the World Health Organization and key stakeholders in Kenya, the development of task-sharing approaches to address the unmet psychological needs of children and mothers has been advocated for. Task-sharing involves the rational redistribution of mental health care tasks from higher cadres of mental health professionals to non-specialized community health care workers in order to increase the capacity for, and access to, mental health services across Kenya.
This dissertation seeks to explore: 1) the development of a partnership between the Africa Mental Health Research and Training Foundation and McMaster University to explore the use of task-sharing in the development of a technology-supported assessment for common mental disorders in children and adolescents; 2) the validity and reliability of the newly developed International Mobile Assessment for Children and Teens (IMPACT) administered by non-specialized community health workers when compared to a gold-standard assessment, the MINI-KID, when administered by trained psychology graduate students, and finally; 3) the association between maternal exposure ACEs and the subsequent mental health of her children, mediated by maternal mental health.
The first study outlines the process of the development of the IMPACT using a novel blending of emic-etic approaches, and the practical evaluation of the IMPACT by ten local community health workers. Results from this study demonstrated the demand for, and utility of, the IMPACT and outlined the practical considerations of conducting field work of this nature. The second study examined the diagnostic agreement (e.g. validity) of mental health conditions in Kenyan school children (n=189) between the IMPACT and the MINI-KID. The results of this study demonstrated relatively high agreement between the diagnosis of common mental disorders in children between the IMPACT and the MINI-KID. The third study explores the relationship between ACEs (Y-VACS) of mothers (n=149) and the socioemotional wellbeing of her children (e.g. internalizing and externalizing problems; CBCL), mediated by maternal mental health (CBCL). The results of this study demonstrate the association between maternal ACEs and child internalizing and externalizing behaviours, mediated by maternal mental health and moderated by maternal education. Collectively, the results of these dissertation studies support the use of task-sharing approaches for the assessment of common mental disorders in children and adolescents, by non-specialized community health workers and that the transmission of mental health problems between generations is associated with a multitude of complex and inter-related factors (e.g. maternal ACEs and maternal mental health), exacerbated by chronic and co-occurring adversity. Additionally, the results of these studies demonstrated the need for further research that prioritizes the equitable accessibility interventions that target the mental health related-sequelae experienced by maternal-child dyads exposed to chronic and enduring adversity in LMIC.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)

abstract: Children who grow up in circumstances of chronic poverty and adversity suffer heightened risk for mental health problems as they grow up. This is especially true of children who live in low- and middle-income countries, where children are more likely to experience chronic and co-occurring forms of adversity. Access to mental health services in these contexts are limited or non-existent, conferring heightened vulnerability for mental health problems that may persist across the lifespan. The risk for mental health problems can be transmitted across generations. Although it is not fully understood how mental health problems can be transmitted from a mother to a child, one commonly studied mechanism is the role of maternal adversity and maternal mental health. Because the barriers to mental health care are abundant, the needs of children and mothers with mental health problems are frequently left unmet. The World Health Organization proposes a task-sharing solution, whereby less specialized community health care workers are trained to provide services to improve access to assessment and treatment in low income countries. Using data collected in rural Kenya, this dissertation seeks to explore: 1) the development of a partnership between the Africa Mental Health Research and Training Foundation and McMaster University with the aim of working together to create mental health assessment for children, using a task-sharing approach, 2) to compare the results of the novel mental health assessment to a gold-standard, and 3) to evaluate maternal adversity, maternal mental health, and the transmission of mental health problems between mothers and children in Kenya. Collectively, the results of this dissertation demonstrate that utilizing a task-sharing model for the development of a mental health assessment for use by community health workers is a valid method for assessing and diagnosing mental health problems in children, and that the transmission of mental health problems across generations is associated complex factors (e.g. maternal exposure to adversity and maternal mental health) as a result of exposure to chronic and enduring adversity in LMIC.