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Maternal diabetes as an early life risk factor for chronic obstructive pulmonary disease
Get PDFIntroduction: Chronic obstructive pulmonary disease (COPD) is Canada’s fifth leading cause of death and is primarily caused by smoking. However, only <20% of smokers develop COPD, suggesting that other factors are important. Early-life exposures may also increase COPD risk by impairing lung development and altering response to cigarette smoke (CS). Maternal diabetes (MD) increases the risk for premature birth and childhood asthma, which are risk factors for COPD. However, the direct impact of MD on offspring susceptibility towards CS and COPD remains unexplored. I hypothesize that exposure to MD worsens CS induced lung damage in offspring.
Methods: Six-week-old C57BL/6NJ female mice were fed with a high-fat diet (HFD-45% kcal) to induce diabetes-like features or low-fat (LFD-10% kcal) control-diet for 6-weeks, and throughout pregnancy and weaning. Weaned offspring were fed standard research chow-diet until 8-weeks of age, at which point they were exposed to CS/Room air for 50 mins, twice/day, for four days. Lung function and inflammation were assessed on day five. Lung tissues were collected for DNA methylation and gene expression analysis. Data were analyzed in Prism GraphPad using two-way ANOVA, significance set at p<0.05.
Results: Offspring from diabetic pregnancy were significantly heavier at 3-weeks than controls. At 8-weeks the body weight difference maintained only in males. CS exposure significantly increased total lung resistance (14%) and airway resistance (18%) in HFD male offspring compared to control. HFD influenced CS induced immune cell infiltration in a sex-specific manner. Female HFD-CS offspring had significantly decreased neutrophils, CD4+ T-cells and NK cells compared to control-smokers. Male HFD-CS offspring had significantly elevated B-cells and NKT cells compared to HFD-control. At baseline, HFD female offspring had elevated Eotaxin and MIG but reduced IL-1α. CS induced cytokine changes in control animals, which were sex specific, were blunted in HFD exposed offspring. Additionally, I observed changes in gene abundance (Igf, Igfbp3 and Ephx1), but without specific changes in DNA methylation in smoking individuals from diabetic pregnancy.
Conclusion: MD alters offspring susceptibility towards CS-induced lung dysfunction and inflammation, in a sex-specific manner. MD may modulate response to cigarettes in early adulthood, suggesting a propensity to future COPD.February 202
The age related differences in individual joint contributions of the ankle, knee and hip in forward compensatory stepping
Get PDFProblem: Falls in older adults are prevalent in Canada which cause physical, psychological, emotional and financial stressors. With an increasingly older adult population, fall prevention is key in solving this problem. Learning how to prevent falls starts by understanding the difference(s) between older adults and younger adults in balance recovery mechanisms.
Purpose: The purpose of this study is to investigate whether there were any age-related differences in stepping-lib joint moments and powers during the execution of a single-step compensatory balance response.
Methods: A lean and release protocol was utilized to apply a balance disturbance to the participants. Participants were tasked to recover from the perturbation and restore stability using a single step with their preferred leg. The peak moment magnitude, peak moment power and timings of these peaks were recorded at the ankle, knee and hip in both the sagittal and frontal planes. Independent samples t-tests were used to compare joint-specific variables between older adults and younger adults to understand if age-related differences in stability may arise from challenges in moment generation or power absorption at specific joints.
Results: Our results showed age-related differences in peak ankle moments in the sagittal plane as well as peak ankle power magnitudes in both the sagittal and frontal plane. In addition to these findings, our results also found key age-related differences in the timing of peak moments in the sagittal plane with both the hip and the knee joints as well as differences in the timing of peak power values in both the sagittal plane and frontal plane at the ankle, knee and hip joints.
Conclusion: Age-related differences in the execution of the single-step compensatory response were found between older adults and younger adults. Our joint-specific findings can be used to further our understanding of balance control strategies in older adults but it also highlights the importance of timings in peak moment and power at the ankle, knee and hip which can be used to improve fall prevention and fall rehabilitation programs in older adults.February 202
Landfast sea ice phenology in Hudson Bay and James Bay: seasonal trends, spatial patterns, and local processes
Get PDFLandfast sea ice, essential to the ecosystems and communities in Sub-Arctic Canada, supports marine life, shapes coastal oceanographic regimes, and facilitates transportation and hunting for Indigenous communities. Understanding its dynamics is critical for developing hazard mitigation and adaptation strategies as climate change accelerates. This thesis examines landfast ice cover in Hudson Bay and James Bay, focusing on meteorological, oceanographic, and geomorphological factors affecting its growth, stability, and decay.
The study examines how landfast ice is influenced by both direct factors, such as air temperature, and indirect factors, like snowmelt timing, which shows a stronger correlation with ice break-up dates than spring temperatures alone. Additional variables, such as river discharge and coastal topography, further impact ice persistence and stability. Areas near river outflows are investigated for causes of later ice formation and earlier melt, in contrast to coastlines with specific orientations and underwater topographies that support longer-lasting ice by shielding it from wind, waves, and storms.
Analysis over the past two decades shows a decreasing duration of landfast ice in the northern and southwestern Hudson Bay, as well as parts of western and southern James Bay, while eastern Hudson Bay and James Bay exhibit stable or increasing trends. This research provides a comprehensive baseline on the spatio-temporal variability of landfast ice and the factors influencing its regime, supporting future monitoring, modeling, and policy-making for Hudson Bay and James Bay.February 202
Agent recovery and team management in dangerous domains
Get PDFSearch and rescue missions in hazardous environments are dangerous and challenging for robots. Poor communication, unpredictable events, robot failures, etc., are common adversities in such missions. Robot failures can greatly hamper the team's performance if not managed properly. Partial failures or malfunctions in robots can cause task failures or store inaccurate data about the environment, affecting future tasks and team performance. Total failures like robot deaths can lead to information loss and wasting resources. For my thesis research, I developed an agent recovery framework for heterogeneous teams of autonomous robots operating in dangerous domains like Urban Search and Rescue (USAR). It is an extension of an existing framework that addresses team and task management, recruitment strategies, robot satisfaction and rare skill management in heterogeneous teams of robots in USAR. My agent recovery framework addresses detection, diagnosis of robot failures and the recovery of robots from these failures. The recovery process allows attempts at self-recovery, attributes and roles adjustments to reflect the current capabilities and failure rates of a robot's components, and also considers human assistance in repairing robots. I evaluated my framework in a simulated post-disaster environment with random robot failures and other challenges. My results showed considerable performance gains in terms of gathering critical information about the environment while also providing useful insights into potential improvements in the framework for the future.February 202
Searching for efflux pumps in the mitochondria of Saccharomyces cerevisiae by proteomics
Get PDFBiological membranes such as the plasma membrane and those in mitochondria act as semi-permeable barriers that separate cells and their internal compartments from their surroundings. Transporter proteins facilitate selective entry and export of molecules, including antibiotics, across membranes. Both prokaryotic and eukaryotic cells can develop multidrug resistance through the use of membrane-bound efflux pumps. In Saccharomyces cerevisiae, there are pumps from the ATP-Binding Cassette (ABC) and the Major Facilitator (MFS) Superfamilies. This organism can resist high levels of mitochondria-targeting antibiotics like chloramphenicol. Our hypothesis is that there are efflux pumps in their mitochondria that remove these antimicrobials from the mitochondria or from the cells and to generate resistance. We predicted that these pumps would be overexpressed in the presence of antimicrobials. We grew cells in the presence of various concentrations of chloramphenicol, which can stop mitochondrial translation and used proteomics to help us identify the efflux pumps that were overexpressed. First, we measured the growth kinetics of the S. cerevisiae wild-type BY4741 to determine concentrations of chloramphenicol needed to inhibit growth. Then we isolated membrane-enriched protein fractions by sucrose gradient centrifugation followed by removal of peripheral proteins by washing at high pH. Preliminary LC-MS/MS experiments on these fractions isolated from drug-treated and drug-free cells detected pumps from various organelles. However, the approach did not enrich for mitochondrial membranes as well as expected and the washing step was not efficient. The data were insufficient for comparisons of drug-free and drug-treated cells, so a second approach was taken. Whole cell proteins were isolated from chloramphenicol-treated and drug-free cells and subjected to proteomics analysis; this allowed biological replicate samples to be prepared at the same time. Cytosolic and mitochondrial proteins were detected. Preliminary analysis indicates that proteins like Sis1, which is a co-chaperone for misfolded proteins were upregulated. Further studies are required to identify potential chloramphenicol transporters and to confirm the role of proteins like Sis1 in protecting the cells from chloramphenicol.February 202
Molecular characterization of effector-immunity pairs in the Salmonella Typhimurium type VI secretion system
No full textBacteria have adapted mechanisms to protect themselves from antagonists while also gathering the limited resources in their microenvironment in order to gain a competitive advantage for survival. One such mechanism is the type VI secretion system (T6SS). The T6SS is a dynamic macromolecular apparatus used by Gram-negative bacteria to deliver toxic effector proteins across multiple membranes into prey cells. Effectors of the T6SS have been extensively studied and possess functions including RNA, DNA and peptidoglycan degradation, membrane depolarization and metal ion collection. Salmonella enterica serovar Typhimurium uses its T6SS to disrupt the gut microbiome through interbacterial competition during initial infection to inevitably cause gastroenteritis and typhoid fever. The Salmonella pathogenicity island 6 (SPI-6) encodes the T6SS, including four clusters of non-core genes predicted to be effector-immunity pairs and adaptors/chaperones. The proteins studied in this thesis are the predicted effector-immunity pairs, Tlde1a-Tldi1a in the third cluster of non-core genes and Rhs2-SciX in the fourth cluster of non-core genes. My thesis objectives are to elucidate both molecular structures and biochemical functions of these effector-immunity pairs. Tlde1a studies revealed that this effector has adopted canonical folds of known transpeptidases (TPases) and carboxypeptidases (CPases) to form a single active site capable of performing both L,D-TPase and L,D-CPase activities without the requirement of additional domains. Furthermore, binding assays have allowed us to deduce that disulphide bond-forming protein A (DsbA) interacts with Tlde1a to help fold it into an active toxic state implicating an effector role in prey Dsb hijacking. My research on the putative effector-immunity pair Rhs2-SciX showed for the first time that they are a true effector-immunity pair. This was due to the clear observation of toxic inhibition of cell growth by Rhs2, and the subsequent recovery of cell viability by SciX. A structural model of Rhs2 and a crystal structure of SciX supported by point variant assays demonstrated the residues critical for Rhs2 activity as a potential RNase. Finally, a predicted complex between Rhs2-SciX revealed a significant similarity to a known contact dependent inhibition (CDI) effector-immunity pair, CdiA-CdiI.
In summary, this thesis demonstrates Salmonella adaptation of T6SS effectors through the adoption of molecular features from numerous enzymatic folds to create potent new antibacterial weapons for bacterial competition. Understanding this molecular warfare by bacteria is important for developing therapeutic delivery mechanisms for targeting pathogens, including vaccines and engineering biomolecules.Canadian Foundation for Innovation award (CFI) 37841
University of Manitoba Graduate Fellowship
University Research Grants ProgramFebruary 202
Exploring the impact of one-lung ventilation on post-operative pulmonary complications in thoracic surgery
Get PDFThis thesis investigates the predictive power of various ventilatory parameters, particularly peak
inspiratory pressure (PIP), in relation to post-operative pulmonary complications (PPCs) in
patients undergoing one-lung ventilation during thoracic surgery. This thesis demonstrates that
PIP levels during one-lung ventilation are predictive of PPCs, with results suggesting that the
rate of risk for PPCs increases exponentially as PIP levels rise.
A comprehensive exponential pressure dose-response model was developed to better describe
patient exposure, incorporating both the magnitude and duration of all PIP setpoints the patients
were exposed to during surgery. This model provided enhanced predictive power for PPCs and
correlated significantly with observed tidal volume drift (TV-Drift), a potential intraoperative
indicator of lung injury. The findings underscore the importance of considering both PIP levels
and exposure time in the management of one-lung ventilation.
Additionally, this thesis proposes TV-Drift as a potential intraoperative biomarker of lung
damage, noting that it was increased in patients who developed PPCs compared to matched
controls.
This thesis concludes with recommendations for future research, including the validation of the
exponential pressure model, further exploration of TV-Drift as a biomarker, and the development
of real-time monitoring tools to improve patient outcomes after thoracic surgery and one-lung
ventilation.February 202
Pratiques parentales positives et santé mentale des jeunes enfants (0-5 ans)
Get PDFLa santé mentale des jeunes enfants est aujourd’hui une priorité des politiques publiques, notamment dans un contexte post-pandémique marqué par une hausse des troubles psychologiques précoces. Les premières années de vie représentent une période critique où les expériences relationnelles, en particulier celles vécues avec les parents, jouent un rôle déterminant dans le développement du bien-être psychologique. Notre recherche explore l’influence des pratiques parentales positives sur la santé mentale des enfants âgés de 0 à 5 ans. À travers une analyse de modèles théoriques et de données empiriques, il met en lumière l’importance d’un soutien adapté aux familles, afin de promouvoir un environnement familial propice à l’épanouissement de l’enfant. L’étude souligne enfin la nécessité d’interventions précoces et de politiques de soutien à la parentalité pour renforcer la prévention en santé mentale dès la petite enfance.February 202
National implementation of guided self-help family-based treatment for youth with eating disorders: a study protocol
Get PDFBackground: Guided self-help family-based treatment (GSH-FBT) is emerging as a promising, more efficient alternative to traditional family-based treatment (FBT). The present study is designed to examine the real-world implementation of GSH-FBT at pediatric treatment sites across nine provinces in Canada.
Methods: Implementation teams at each site consisting of a GSH-FBT coach, a medical provider, and a program administrator will be formed. Clinician coaches will be trained in this new modality and supported with weekly GSH-FBT consultation. Each site will recruit ten families with an adolescent with anorexia nervosa and the parents will undergo ten virtual GSH-FBT sessions. The implementation approach will be evaluated using qualitative and quantitative methods. Outcomes of interest include (1) treatment fidelity, (2) treatment wait times, (3) change in adolescent symptoms and parent/caregiver self-efficacy, (4) change in provider readiness, attitudes, and confidence towards the intervention, and (5) the overall experience of the implementation of the intervention from the perspective of the provider teams, and participant families.
Discussion: The findings of this study will help to identify factors important to the acceptability and implementation of GSH-FBT in real-world clinical settings.
Trial registration: This study was first registered with clinicaltrials.gov (registration # NCT06851273) on February 12, 2025 (url: https://clinicaltrials.gov/study/NCT06851273?id=NCT06851273&rank=1 )
Exercise testing and microvascular assessment in ICU survivors to investigate ICU-acquired weakness
Get PDFBackground: After prolonged intensive care unit (ICU) admission, 50% of survivors develop ICU-acquired weakness (ICU-AW), causing disability up to 5-years post-ICU discharge. However, its underlying mechanisms remain unclear. ICU-AW research has yet to examine systemic and peripheral factors influencing the oxygen delivery pathway, commonly studied in exercise science. However, the lack of standardized follow-up protocols for this population restricts the quantitative evaluation of peak oxygen uptake (VO2peak), on/off oxygen uptake (VO2) kinetics, and skeletal muscle oxygenation. Recently, we published a standardized single-session exercise test (CPET) protocol in healthy-young-adults with unpublished near-infrared spectroscopy (NIRS) data. Objective: This thesis aims to (1) develop a standardized, single-session CPET protocol tailored to ICU-survivors for integrated assessment of VO2peak, VO2kinetics, and localized skeletal muscle oxygenation; and (2) analyze retrospective NIRS data from Santana et al., (2025). Methods: Key adaptations from Santana et al., (2025) involve: proposing a literature-derived ICU correction factor to determine constant work rate (CWR) at 30%VO2reserve; and proposing an incremental ramp protocol based on self-reported functional status to individualize each ramp protocol (5, 10, 15, or 20W.min−1); with NIRS placed on the vastus lateralis muscle to assess tissue saturation index (TSI) and deoxy-hemoglobin (HHb). Retrospective analysis of healthy NIRS data (n=11 males and n=9 females) involve reporting TSIpeak and HHb on/off-kinetics from an upright cycle ergometer combined single-session. Results: Developed and applied the ICU-Combined Assessment of cardioRespiratory Exercise (ICU-CARE) CPET protocol to collect preliminary ICU-survivor data (n=2), suggesting that NIRS data can be measured with adequate VO2 data in a single-session on/off kinetics assessment which can be fitted mono-exponentially. Supporting the application of NIRS, the healthy retrospective analysis demonstrates that TSI and HHb can be measured within the protocol proposed by Santana et al., (2025), reporting: HHb kinetics fitted monoexponentially (on-kinetics n=5 females, n=7 males; off-kinetics n=3 females, n=7 males); TSIpeak [%] at VO2peak 74.4±14.4 (n=5 females), 57.3±5.0 (n=7 males). Conclusions: Conducted a retrospective NIRS analysis and developed a standardized single-session ICU-CARE CPET protocol to quantify VO2peak, on/off VO2 kinetics, and skeletal muscle microvascular oxygenation for ICU-survivors to enable future ICU-AW research.February 202