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Parallels and Divergences in Multisystem Proteinopathy Genes: Stress Granules, Autophagy, and Myogenic Deficits
(2025-01-31) Pontifex, Carly Sabine; Pfeffer, Gerald; Whelan, Patrick; Shutt, Timothy; Corcoran, Jenn; Milone; Margherita; Greenway; Clive, Steven
Multisystem Proteinopathy (MSP) is a disease that causes some combination of inclusion body myopathy with rimmed vacuoles, Paget’s disease of bone, and ALS/FTD. Several different genes give rise to the unique phenotypic expression of MSP. Given the variety of genes that cause MSP and the specificity of the phenotype and tissue involvement, we asked; what are the unifying pathogenic features of MSP? To address this, we examined three areas of interest: stress granules, autophagy, and myogenesis. The currently identified roster of MSP genes have several structural and functional commonalities which fall into two categories: LC3B-intracting domain containing autophagy adaptors (SQSTM1, VCP, OPTN) and prion-like domain containing stress granule proteins (HNRNPA2B1, HNRNPA1, MATR3, TIA1). Previous studies identified that a non-pathogenic variant of the non-classical MSP protein, TIA1 N357S , can act as a phenotype modifier with SQSTM1P392L leading to distal muscle weakness rather than proximal muscle weakness seen with monogenic SQSTM1 mutations. Here we show that the same TIA1 variant is able to act as a modifier with VCP R159H to produce the same distal weakness. We established three major findings: 1) The non-classical MSP gene TIA1 N357S can modify the myopathy phenotype of both VCP and SQSTM1 to produce distal rather than proximal muscle weakness at the onset of disease, and that TIA1b expression drives the increase of TIA1 expression in diseased muscle and also fails to colocalize with SQSTM1—implying that upregulation of TIA1b is important for muscle stress response and also that TIA1b stress granules have reduced clearance by autophagy. 2) VCP and SQSTM1 both exhibit lysosome accumulation, which may be an emergent feature of inclusion body myopathies. 3) Impaired myogenesis via resistance to the master regulator of myogenesis MyoD, is a feature of MSP.
Proceedings of the 8th International Conference of STEM in Education (STEM 2024)
(University of Calgary, 2024) Pratim Sengupta; Douglas Clark; Jennifer Lock
Proceedings of the 8th International Conference of STEM in Education (STEM 2024)
Evaluating Mass Spectrometry Approaches for Identifying Proteomic Changes in Maternal Urine in Pregnancy and Labour
(2025-01-31) Sonali; Dufour, Antoine; Slater, Donna; MacDonald, Justin; Sycuro, Laura
Preterm birth (PTB) is a critical global health issue, contributing to significant neonatal mortality and long-term complications. Almost half of the preterm births occur due to spontaneous preterm labour (PTL). Despite substantial research efforts, our knowledge of labour onset and progression leading to either preterm and term delivery is limited. With the intent of exploring more about the physiological processes of pregnancy and labour, we performed label-free shotgun proteomics on maternal urinary samples using two different modes of mass spectrometer – data- dependent acquisition (DDA) and data-independent acquisition (DIA). The goal was to assess what approach resulted in high quality and reproducible data by detecting and quantifying large number of proteins for a discovery study using urine samples. Comparative analysis of DDA and DIA demonstrated superior performance of DIA. DIA resulted in better data in terms of consistency of protein detection, retaining higher number of total proteins and uniquely detected proteins for downstream analysis and presence of fewer number of missing values. To investigate further, we expanded our discovery cohort and performed DIA proteomics. Proteomics data analysis revealed elevated levels of Defensin alpha 1 (DEFA1) and Kallikrein 1 (KLK1) in the Labour group while the Non Labour group showed elevated levels of Endosialin (CD248) and Leucine-rich alpha-2-glycoprotein (LRG1). To identify the proteomics changes with respect to gestational age, we compared Preterm Non Labour (PTNL) group with Term Non Labour (TNL) group. The PTNL group was found significantly enriched in Fatty acid binding protein 5 (FABP5) and Keratin type 1 cytoskeletal 16 (KRT16) while TNL group showed significant enrichment in Calmodulin (CALM1). Differential levels of aforementioned proteins seem to be associated with labour and changes with gestational age. Future studies are required to validate the observed trends in protein abundances in the study groups and to determine the potential of these proteins for prediction of preterm labour or preterm birth.
Indigenous Stories on Screen: The Effects of Film Narratives on Identity Formation and Reconciliation in Classrooms
(2024) Goreham, Alexandra
Through this research, I focus on the connection between film, identity, and reconciliation efforts within secondary humanities-based Western classrooms. This topic was chosen because of how historical stereotypes have been adapted and used in films, affecting the identity formation of Indigenous students and reconciliation efforts within classrooms. Using ideas from the area known as public pedagogy, I explore how popular films have become a learning tool to help teachers and students connect real-world understandings to classroom learnings. For my qualitative analysis, I conducted an in-depth analysis of two films produced in different decades, to highlight the curricular implications of film being used as a tool within Western classrooms. In setting up and outlining my analysis, I connect to relevant literature that discusses film as public pedagogy and identity formation. I also note a series of shifts that were occurring in both society and pedagogical thinking and practice and comment on the potential for films to become a tool in positive identity formation for Indigenous students, contribute to the building of essential abilities such as critical analysis and peer collaboration, and aid in forming community connections and advancing reconciliation efforts.
Bovine milk-derived extracellular vesicles reduce oxidative stress and ferroptosis induced by Klebsiella pneumoniae in bovine mammary epithelial cells
(2025-02-14) Liang, Bingchun; Xiong, Yindi; Cobo, Eduardo R.; Kastelic, John; Tong, Xiaofang; Han, Bo; Gao, Jian
Abstract Background Ferroptosis is characterized by increased production of reactive oxygen species (ROS) and membrane lipid peroxidation that can exacerbate inflammatory damage. Extracellular vesicles (EVs) isolated from bovine milk have many biological functions, including antioxidant properties. However, the role of EVs on Klebsiella pneumoniae-induced ferroptosis and oxidative stress in bovine mammary epithelial cells (bMECs) and murine mammary tissue is unclear. In this study, EVs were isolated from bovine colostrum, mature milk and clinical mastitis milk (defined as C-EVs, M-EVs and CM-EVs, respectively) and assessed by transmission electron microscopy, Western blot and transcriptome sequencing. Effects of EVs on K. pneumoniae-induced ferroptosis and oxidative stress in bMECs were evaluated with immunofluorescence and Western blot. Results In bMECs, infection with K. pneumoniae induced oxidative stress, decreasing protein expression of Nrf2, Keap1 and HO-1 plus SOD activity, and increasing ROS concentrations. However, protein expression of GPX4, ACSL4 and S100A4 in bMECs, all factors that regulate ferroptosis, was downregulated by K. pneumoniae. Furthermore, this bacterium compromised tight junctions in murine mammary tissue, with low expression of ZO-1 and Occludin, whereas protein expression of Nrf2 and GPX4 was also decreased in mammary tissue. Adding C-EVs, M-EVs or CM-EVs reduced oxidative stress and ferroptosis in K. pneumoniae-infected bMECs in vitro and murine mammary tissues in vivo. Conclusion In conclusion, all 3 sources of milk-derived EVs alleviated oxidative stress and ferroptosis in K. pneumoniae-infected bMECs and mammary tissues.