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Uncovering the potential for oxidized phosphatidylcholines as unique drivers of asthma pathobiology
No full textAsthma pathobiology is characterized by persistent oxidative stress in the lungs that causes oxidative damage in the cell membrane and extracellular phospholipids. This damage results in the accumulation of oxidized phosphatidylcholines (OxPC), potent mediators of oxidative stress. We recently discovered that allergen challenge causes OxPC accumulation in the lungs of human participants that correlates with airway hyperresponsiveness (AHR). OxPC also play a significant role in the pathophysiology of human airway smooth muscle (HASM) cells. The research projects outlined in this thesis aimed to elucidate the functional effects of OxPC on HASM cells, and to identify the downstream effector(s) and/or signaling pathway(s) mediating these effects. Furthermore, we investigated the potential impact of OxPC on the pathophysiologic hallmarks of allergen-induced ‘asthma’ in a murine model.
Our findings demonstrate that OxPC directly induce airway narrowing in murine thin-cut lung slices (TCLS) and activate the contractile machinery within HASM cells. OxPC mediate both transient and sustained cytosolic Ca2+ flux through two distinct pathways: intracellular ryanodine receptors and plasma membrane transient receptor potential ankyrin 1 (TRPA1) channels. These pathways are interdependently required for OxPC-induced HASM contraction and airway narrowing. Next, we demonstrated that OxPC selectively attenuate HASM relaxation in response to bronchodilators (β2-adrenergic receptor (β2AR) agonists; isoproterenol, albuterol) using both ex vivo (murine tracheal rings and TCLS) and in vivo models. These effects correlate with a diminished cyclic-adenosine-monophosphate (cAMP) signaling cascade within HASM cells. The results from this study revealed that OxPC uncouple β2AR signaling from downstream effectors via activation of protein kinase-C (PKC), a mechanism contributing to the development of bronchodilator insensitivity. Furthermore, we characterized the exacerbation of oxidative burden within the lungs of a murine model of allergic asthma, observing a concomitant increase in OxPC accumulation. In this model, we showed that immuno-pharmacological neutralization of OxPC using intranasal E06 monoclonal antibody can prevent allergen-induced airway inflammation and AHR.
Collectively, our results indicate that bioactive OxPC are pivotal mediators of oxidative stress-associated allergic lung pathophysiology. These molecules directly contribute to airway contraction and induce bronchodilator insensitivity by modulating airway smooth muscle function, an implication for the phenotype of poorly controlled asthma.Research Manitoba; Children’s Hospital Research Institute of Manitoba (CHRIM); Canadian Respiratory Research Network; Canadian Lung Association; Rady Faculty of Health Sciences, Faculty of Graduate Studies, and Department of Physiology and Pathophysiology, University of ManitobaMay 202
Association between pre-existing chronic conditions and severity of first SARS-CoV-2 infection symptoms among adults living in Canada: a population-based survey analysis from January 2020 to August 2022
Get PDFAbstract Background Individuals living with chronic conditions (CC) typically have a higher risk of more severe outcomes when exposed to infection. Although many studies have investigated the relationship between CCs and COVID-19 severity, they are generally limited to clinical or hospitalized populations. There is a need to estimate the impact of pre-existing CCs on the severity of acute SARS-CoV-2 infection symptoms among the general population. Methods Data from the Canadian COVID-19 Antibody and Health Survey – Cycle 2, a population-based cross-sectional probability survey across 10 provinces capturing the COVID-19 experiences of respondents from January 2020 to August 2022, were used to assess whether pre-existing CCs increased the odds of more severe self-reported infection symptoms among adults living in Canada. Multivariable regression modelling identified which CCs were independently associated with more severe infection symptoms after adjusting for sex, age at infection, and other significant covariates. Results Chronic lung disease (aOR = 1.64, 95% CI: 1.09, 2.46), high blood pressure (aOR = 1.35, 95% CI: 1.13, 1.62), weakened immune system (aOR = 1.46, 95% CI: 1.08, 1.98), chronic fatigue syndrome or fibromyalgia (aOR = 2.20, 95% CI: 1.39, 3.50), and arthritis (aOR = 1.28, 95% CI: 1.04, 1.56) were associated with a higher odds of more severe infection, whereas osteoporosis (aOR = 0.58, 95% CI: 0.39, 0.87) was associated with a lower odds. Limiting modelling to adults with confirmed SARS-CoV-2 infections affected some of the variables retained and adjusted associations. Conclusion Our findings contribute to a growing evidence base of associations between pre-existing CCs and adverse outcomes after SARS-CoV-2 infection. Identifying factors associated with more severe infection allows for more targeted prevention strategies and early interventions that can minimize the impact of infection
Reconciliation may occur: treaty narratives as entwined disconnection
No full textThis thesis presents an in-depth exploration of Treaty Number One and its broader implications regarding the conflicting narrative frameworks that shape Indigenous-settler relations in Canada. Central to this exploration is the understanding that Treaty Number One, the first Numbered Treaty signed between Indigenous nations and the Canadian state, embodies narratives that remain unresolved and contested. Further I argue that these narratives are multifaceted and oftentimes irreconcilable due to their distinct cultural, historical, and political contexts. In developing this argument I demonstrate how the treaty was perceived by the Crown as a means to assert colonial control and expand settlement, while Indigenous perspectives considered it an agreement beginning a relationship of coexistence and mutual respect. Next, utilizing critical and decolonial theories, I explore the utility in conceiving of Indigenous peoples as subaltern groups resisting the hegemonic narrative of the colonial state and argue that Canada’s approach has been one of reinforcing its dominance through coercion and assimilation. Finally engaging with the TRC’s Calls to Action, I propose that reconciliation cannot be achieved by combining or assimilating narratives into one dominant story. Instead, I call for an ongoing dialogue valuing diverse perspectives that acknowledge the complex interplay of narratives that constitute our understanding of treaties. Ultimately, this thesis concludes that a more comprehensive understanding of treaties can only be achieved through recognizing and valuing the multiplicity of narratives, grounded within material conditions and understanding of colonial power dynamics. In other words, a reconceptualization of treaty relations that embraces the possibility of multiple truths coexisting, rather than striving for a singular reconciled narrative which defines the nation.Aboriginal Issues Press ScholarshipMay 202
Establishment of novel stem cell and pharmacological therapies for traumatic spinal cord injury
No full textSpinal cord injury (SCI) is a leading cause of long-term neurological impairment due to extensive post-injury cell loss, disorganization of the neuroglial network, and disruption of spinal circuits. Transplantation of neural precursor cells (NPCs) has emerged as a promising approach since NPCs possess the ability to differentiate into the three main neural lineages. However, the outcomes of NPC engraftment for SCI remain modest due to 1) low long-term survival of transplanted NPCs, 2) restricted neurogenesis, and 3) limited functional integration of newly generated neurons into the host spinal network. Our group originally discovered that upregulation and deposition of chondroitin sulfate proteoglycans (CSPGs) inhibit the regenerative capacity of transplanted NPCs. In addition, activation of serotonin receptor 5-HT1/2/7 increases neuronal maturity and synapse formation, and it enhances circuit re-assembly following SCI. Thus, we hypothesized that combining NPC transplantation with inhibition of CSPGs signaling and activation of 5-HT1/2/7 receptors would optimize survival, neurogenesis, and circuit integration of NPC-derived neurons.
Using extensive in vitro and in vivo experiments, we demonstrated that pharmacological blockade of CSPG signaling substantially enhances the survival and neurogenesis of transplanted NPCs, and significantly improves functional recovery in SCI rats. Although this approach increases neurogenesis in NPCs, a sizable number of NPCs still differentiate into astrocytes. In the second part of this thesis, we showed that NPC-derived astrocytes exhibit a pro-regenerative phenotype, supporting the NPC-mediated repair process and neuronal replacement. Lastly, our extensive animal studies reveal that suppressing CSPG signaling combined with activation of 5-HT1/2/7 receptors significantly enhances the integration of transplanted NPC-derived neurons into the host's local network and supraspinal tracts. Altogether, this thesis provides new insights into the mechanisms of exogenous NPC-mediated repair in the injured spinal cord and establishes a novel, targeted, and effective cellular and pharmacological approach to enhance neuronal replacement and circuit reintegration following SCI.Wings for Life Foundation for Spinal Cord InjuryMay 202
Formers’ understandings of why they engaged with and disengaged from violent social movements in settler-colonial North America and Europe
Get PDFThis qualitative research studied how former violent extremists understand the drivers that led them into and out of violent extremist, and terrorist movements in Canada, the USA and Europe, which are continents that are also affected by settler-colonialism. The PI is also a former extremist and used critical autoethnographic, intersectional feminist and Indigenous methodologies. Methods included gathering from interviews with former Incel, Neo Nazi, anti-government and violent, political Islamists, their family members, and non-governmental organizations (NGO) staff, and a talking circle/focus group with formers. The research findings increase knowledge about how to better prevent and intervene into violent extremist and terrorist social movements with more effective practitioner efforts at micro, meso and macro levels of society. Research results demonstrated complex and intersecting drivers of entry and exit from violent social movements, and the importance of systemic policies and praxis, such as improved anti-bullying, mental health and educational resources, policy, and PVE/exit programming to teach effective critical thinking training, cross cultural conflict resolution and dialogue skills. Key findings also suggest that mental health and faith systems assist communities affected by intergenerational effects of colonialism/occupation, war, racism, and patriarchy to build identities, cultural and gender relationships where there is equity and powersharing.May 202
Impact of discontinuation of lactation consultant program on early infant feeding in Manitoba
Get PDFAbstract Background Lactation Consultants (LC) at Health Sciences Centre (HSC) and St Boniface General Hospitals (SBGH) supported the lactation of 2/3 of Manitoba newborns since 1994. The LC program in HSC was discontinued in 2018. Its impact on infant feeding in the province remains unclear. Methods To assess the influence of the LC program cessation on the feeding of newborns in postpartum wards via a retrospective administrative database cohort. Results A total of 126,285 infants were delivered in all Manitoban hospitals during 2014–2021 [First Nations (FN): 21%, all others: 79%, urban: 55%, rural: 41% and remote: 4%]. The rates of breastfeeding were lower and formula feeding were higher in FN and all other newborns after the program cessation (2018–2021) compared to that during 2014–2017 (p < 0.01). The intensity of the changes in infant feeding among FN or remote-living newborns during 2018–2021 were 2–threefold greater than that among all others or urban/rural-living newborns delivered in HSC (p < 0.01). In contrast, infant feeding status stayed stable for those delivered at SBGH where the LC program did not withdraw. The cessation of LC program decreased adjusted odds ratio (aOR) for exclusive breastfeeding in FN infants (aOR 0.93, 95% CI: 0.88–0.98) and urban-living infants (aOR 0.96, 95% CI: 0.94–0.98), but not in all others, rural- or remote-living infants. Increased odds for formula feeding was detected in FN and all other infants living in various regions in the province during 2018–2021 compared to that during 2014–2017 (p < 0.05). Conclusion The findings suggest that the discontinuation of LC program decreased breastfeeding and increased formula feeding, and the unfavorable changes in infant feeding was most profound among FN and remote-living infants
The impact of ghost crab predation on loggerhead sea turtles: environmental influences and management approaches
Get PDFPredation is one of the greatest threats to the eggs and hatchlings of threatened loggerhead sea turtles (Caretta caretta). Management efforts tend to focus on removing mammalian predators, and invertebrate predators have largely been overlooked. Yet ghost crabs (Ocypode spp.) can become prolific predators of sea turtle eggs when they become abundant. Current methods used to quantify egg predation by crabs may underestimate predation, and nest-to-surf mortality of hatchlings rarely quantified. Additionally, ghost crab abundance is difficult to estimate due to their complex behavior shaped by environmental variables, but understanding these factors would aid in effective management. This study, conducted on the Atlantic coast of Florida from 2021 to 2023, explored the effects of environmental variables on ghost crab abundance and how ghost crab abundance affects egg and hatchling predation rates. We found that crabs predated 5-10% of all eggs and attacked 6-13% of hatchlings. Higher crab densities led to increased hatchling predation, particularly among disoriented hatchlings, but egg predation was unaffected by crab density. We quantified crab abundance using two methods, through visual surveys of live crabs and burrow counts. We explored the effects of environmental variables on these indices of crab abundance, and found interactive effects of temperature, moon luminosity, and ambient lighting. Our findings highlight the importance of considering multiple environmental variables when assessing ghost crab abundance and activity, because crab behavior, such as burrow construction and foraging activity, changes with these environmental variables. We found that these two indices were unrelated when comparisons included these other environmental variables, suggesting that it may not be appropriate to use them interchangeably. We attempted to reduce crab density through two methods, live capture and the use of a sod roller to dispatch crabs. While live capture did not significantly reduce crab abundance, the sod roller method had a significant impact, which lowered predation on hatchlings by 75%. Our study demonstrates the importance of invertebrate predators of sea turtle eggs and hatchlings, as well as the importance of including both eggs and hatchlings in predation estimates, when considering conservation strategies for this threatened species.Funding provided by the United States Space Force and United States Fish and Wildlife Service.October 202
Rural community-based participatory research with families of people who use drugs: key considerations from a multi-provincial research partnership
Get PDFAbstract Background North America continues to contend with an unregulated drug crisis that is impacting communities of all sizes. Community-based participatory research that meaningfully engages people who use drugs, families, and their wider communities is one way of advancing social justice and improving population health. As more community-academic partnerships are formed in this space, some organizations have launched guidelines and considerations for engaging in community-based participatory research (CBPR). However, to our knowledge, none provide guidance for engaging in CBPR with people who use drugs and their families in rural settings. Main body This paper presents insights gained from our experiences collaborating to conduct CBPR with families providing unpaid support for people who use drugs in rural Canada. Key considerations are thematically organized in four sections: Dreaming (Building the team and setting a vision), Designing (Key definitions, budget and ethical consideration), Doing (Bringing research to life), and Disseminating (Moving research into action). Conclusions By building on existing principles and guidelines for working with PWUD and their families, these considerations will be a valuable resource for other partnerships seeking to engage in community-based participatory substance use research in rural settings
Genetic analysis and genomic selection models for leaf rust resistance in western Canadian winter wheat
Get PDFLeaf rust, caused by the fungus Puccinia triticina Eriks., is a prevalent disease of wheat that affects grain yield and quality. Leaf rust resistance is an important trait that is evaluated in the registration of wheat varieties in western Canada and is an effective strategy for sustainable disease management. However, the genetic basis of this resistance is not fully understood in Canada Western Red Winter (CWRW) wheat.
This study aimed to identify the quantitative trait loci (QTL) controlling leaf rust resistance using genome-wide association studies (GWAS) and develop genomic selection (GS) models for improving leaf rust resistance in winter wheat. The wheat GWAS panel consisted of approximately 300 western Canadian winter wheat breeding lines and cultivars and 100 winter wheat breeding lines and cultivars from the USA, eastern Canada, and Europe. The panel was evaluated for leaf rust resistance in seedling tests using five different races of P. triticina, namely 12-3 MBDS, 128-1 MBRJ, 74-2 MGBJ, 06-1-1 TDBG, and 77-2 TJBJ. The same population was also tested for resistance in inoculated field trials located in Winnipeg and Morden, Manitoba, following randomized complete block designs (RCBD), with two replicates per field trial in the 2022-23 and 2023-24 growing seasons. Genotyping was done using the Illumina Infinium Wheat Barley 40K SNP array and the 25K wheat Infinium array. The DNA marker and leaf rust datasets were used for GWAS. Putative Quantitative Trait Nucleotides (QTNs) associated with leaf rust resistance have been detected from the GWAS analyses, which indicated the presence of Lr genes in the GWAS panel. The results indicated that the leaf rust-resistant genes Lr16 and Lr24 are likely present in the GWAS panel.
The leaf rust and SNP marker data were also used to develop genomic selection (GS) models for estimating leaf rust resistance in CWRW breeding germplasm. The accuracy of these GS models for predicting the leaf rust resistance of wheat germplasm was assessed via five-fold cross-validation. Overall, prediction accuracies, indicated by Pearson’s correlation coefficient (r), ranged from 0.66 to 0.67 for disease severity (DS), 0.59 to 0.60 for infection type (IT), and 0.65 to 0.67 for the average coefficient of infection (ACI) in field trials. The r values for IT data from seedling tests varied between 0.45 and 0.86 for different GS models. Improved knowledge of the resistance genes in Canadian winter wheat and DNA markers for selecting these genes will improve the efficiency of wheat breeding programs.Alberta Grains
Manitoba Crop Alliance
Results Driven Agriculture ResearchOctober 202
Optimizing high-throughput detection of temperate phages that infect Enterococcus spp. and Staphylococcus spp.
Get PDFBacteriophage (phage) therapy is currently being explored as an alternative treatment strategy to combat infections caused by antibiotic-resistant bacteria. However, considerable emphasis has been placed on utilizing only strictly virulent phages for treatment whereas the use of temperate phages has been largely inadvisable due to their potential to transmit antibiotic resistance genes. Unfortunately, the current process of isolating and deducing the lifecycle of newly-isolated phages is often labour-intensive, costly, and time-consuming, highlighting the need for a more streamlined process. Therefore, the aim of this study was to develop a PCR-based assay to screen out temperate phages that infect Enterococcus faecalis and Staphylococcus aureus during high-throughput phage isolation. Using the integrase gene in temperate phages as a molecular marker, cluster analysis was performed to identify conserved sequences and design cluster-specific degenerate primers. Multiplex PCRs (mPCRs) were then optimized using a set of short DNA sequences representing the integrase genes, and tested on a panel of plaque picks from phages isolated against E. faecalis and S. aureus. mPCR results were compared with whole genome and amplicon sequencing to verify the presence integrase genes. Overall, this study revealed that specific primers can be designed to target integrase genes in a simple and rapid mPCR assay. However, host-encoded prophages were detected from contaminating host nucleic acid in plaque picks, resulting in false positives as indicated by the sequencing results. This method may still be adopted – albeit, with careful consideration – by assuming that any same-sized band amplified from both the plaque picks and bacterial hosts are the result of contamination, and are therefore negative results. Ultimately, the findings of this research showed that a PCR screening method that detects homologues present only in virulent phages may be a better alternative.October 202