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Physician-scientists (PS) are the backbone of translational research and groundbreaking medical developments in many developed countries. Formalized PS training programs in the form of MD-PhD/MD-MSc programs in Canada have had a longstanding tradition of producing many exceptional PS researchers, staff, and faculty. However, despite these programs’ growth in size and popularity, PS trainees have consistently reported high rates of burnout, attrition, and lack of adequate mentorship and financial support. Additionally, there has been no formalized research examining the needs and prevalence of PS trainees who identify as having a marginalized identity, who may present different unaddressed needs. For the first time, this work captures the demographics, satisfaction, and needs of Canadian MD-PhD/MD-MSc trainees at the intersection of multiple marginalized identities. The authors utilized data from a cross-sectional survey conducted between June to December 2021 by the Clinician Investigator Trainee Association of Canada. Authors examined five marginalized identities covered by the survey: identifying as a woman, living with a disability, a visible minority, not being born in Canada, and being a primary caregiver during training. Results show that 78% of PS trainees self-identify with a marginalized identity and 47% with at least two identities, a proportion higher than previously published. In addition, specific marginalized identity groups reported differing needs as top priority. Moreover, PS trainees who identified with having a disability and who were primary caregivers during training reported significant dissatisfaction within their training programs. In addition to unique needs for each identity group, certain needs were expressed by all marginalized identity groups such as lack of adequate and specific mentorship during training. This research contributes novel data by examining an underrepresented group of PS trainees and supports previous calls to action within the literature expressing the need for greater oversight and infrastructure to support PS training in Canada.

α-Synuclein seed amplification assays are a promising diagnostic tool for synucleinopathies such as Parkinson’s disease and multiple system atrophy. Standardized conditions are required to ensure a high degree of inter- and intra-laboratory reproducibility when performing these assays. A significant issue that hinders the utility of seed amplification assays is the de novo aggregation propensity of the α-synuclein substrate as well as inter-batch heterogeneity. While much work has focused on determining appropriate seed amplification assay buffer compositions as well as the type and amount of seed used, a robust comparison of α-synuclein substrate purification methods has not been reported. We therefore compared the utility of recombinant α-synuclein purified using four different methods as seed amplification assay substrates across two laboratories. Osmotic shock-purified α-synuclein monomer substrate showed the lowest propensity for de novo aggregation, which translated into being the best substrate for seed amplification assay reactions seeded with α-synuclein preformed fibrils or patient brain homogenates. Furthermore, osmotic shock α-synuclein monomer showed the best inter-batch reproducibility compared to all other substrates tested. As α-synuclein seed amplification assays continue to evolve and move towards adoption in the clinical realm, this work showcases the vital importance of standardizing the production and characterization of recombinant α-synuclein substrate. We encourage the widespread adoption of osmotic shock α-synuclein monomer as the universal substrate for seed amplification assays to maximize intra- and inter-laboratory reproducibility.

The adoption of CRISPR-Cas9 technology for functional genetic screens has been a transformative advance. Due to its modular nature, this technology can be customized to address a myriad of questions. To date, pooled, genome-scale studies have uncovered genes responsible for survival, proliferation, drug resistance, viral susceptibility, and many other functions. The technology has even been applied to the functional interrogation of the non-coding genome. However, applications of this technology to neurological diseases remain scarce. This shortfall motivated the assembly of a review that will hopefully help researchers moving in this direction find their footing. The emphasis here will be on design considerations and concepts underlying this methodology. We will highlight groundbreaking studies in the CRISPR-Cas9 functional genetics field and discuss strengths and limitations of this technology for neurological disease applications. Finally, we will provide practical guidance on navigating the many choices that need to be made when implementing a CRISPR-Cas9 functional genetic screen for the study of neurological diseases.

In prion diseases, the species barrier limits the transmission of prions from one species to another. However, cross-species prion transmission is remarkably efficient in bank voles, and this phenomenon is mediated by the bank vole prion protein (BVPrP). The molecular determinants of BVPrP’s ability to function as a universal prion acceptor remain incompletely defined. Building on our finding that cultured cells expressing BVPrP can replicate both mouse and hamster prion strains, we systematically identified key residues in BVPrP that permit cross-species prion replication. We found that residues N155 and N170 of BVPrP, which are absent in mouse PrP but present in hamster PrP, are critical for cross-species prion replication. Additionally, BVPrP residues V112, I139, and M205, which are absent in hamster PrP but present in mouse PrP, are also required to enable replication of both mouse and hamster prions. Unexpectedly, we found that residues E227 and S230 near the C-terminus of BVPrP severely restrict prion accumulation following cross-species prion challenge, suggesting that they may have evolved to counteract the inherent propensity of BVPrP to misfold. PrP variants with an enhanced ability to replicate both mouse and hamster prions displayed accelerated spontaneous aggregation kinetics in vitro . These findings suggest that BVPrP’s unusual properties are governed by a key set of amino acids and that the enhanced misfolding propensity of BVPrP may enable cross-species prion replication.

Dr. Amy Metcalfe is an Associate Professor in the Departments of Obstetrics and Gynecology, Medicine, and Community Health Sciences at the University of Calgary. She is also the Maternal and Child Health Program Director with the Alberta Children’s Hospital Research Institute. Dr. Metcalfe’s training is a perinatal epidemiologist whose research broadly focuses on the management of chronic illness during pregnancy, and how events in pregnancy impact women’s health and wellbeing throughout the life course. Current major projects include co-leading the P3 Cohort study (https://p3cohort.ca), a longitudinal pregnancy cohort study, and the GROWW (Guiding interdisciplinary Research On Women’s and girls’ health and Wellbeing) Training Program (https://www.growwprogram.com).

[alpha]-Synuclein seed amplification assays are a promising diagnostic tool for synucleinopathies such as Parkinson's disease and multiple system atrophy. Standardized conditions are required to ensure a high degree of inter- and intra-laboratory reproducibility when performing these assays. A significant issue that hinders the utility of seed amplification assays is the de novo aggregation propensity of the [alpha]-synuclein substrate as well as inter-batch heterogeneity. While much work has focused on determining appropriate seed amplification assay buffer compositions as well as the type and amount of seed used, a robust comparison of [alpha]-synuclein substrate purification methods has not been reported. We therefore compared the utility of recombinant [alpha]-synuclein purified using four different methods as seed amplification assay substrates across two laboratories. Osmotic shock-purified [alpha]-synuclein monomer substrate showed the lowest propensity for de novo aggregation, which translated into being the best substrate for seed amplification assay reactions seeded with [alpha]-synuclein preformed fibrils or patient brain homogenates. Furthermore, osmotic shock [alpha]-synuclein monomer showed the best inter-batch reproducibility compared to all other substrates tested. As [alpha]-synuclein seed amplification assays continue to evolve and move towards adoption in the clinical realm, this work showcases the vital importance of standardizing the production and characterization of recombinant [alpha]-synuclein substrate. We encourage the widespread adoption of osmotic shock [alpha]-synuclein monomer as the universal substrate for seed amplification assays to maximize intra- and inter-laboratory reproducibility. Keywords: Neurogenerative diseases, Diagnostics, Prions, RT-QuIC, PMCA, [alpha]-Synuclein, Purification, Osmotic shock

The 2022 Annual Joint Meeting (ajm) and Young investigators’ Forum of the Canadian Society for Clinical investigation / Société Canadienne de recherches clinique (CSCI/SCRC) and Clinician Investigator Trainee Association of Canada/Association des cliniciens-chercheurs en formation du Canada (CITAC/ACCFC) was held in Montréal, November 13-14, 2022. The theme of this year's AJM was “Strength in Perseverance” and focused on highlighting clinician-investigator trainee achievements and resilience in research engagement through recent challenging and unprecedented times. The opening remarks were given by Nicola Jones (president of CSCI/SCRC) and Heather Whittaker (past president of CITAC/ACCFC). The keynote speaker was Dr. Michael Strong, who delivered the presentation “The Future of Clinician Scientists in Canada.” Dr. Caroline Quach (Université de Montréal) received the CSCI Distinguished Scientist Award and Dr. Amy Metcalfe (university of Calgary) received the CSCI Joe Doupe Young investigator Award. Each of the clinician-scientists delivered presentations on their award-winning research. The four interactive workshops included “Social Media in Science and Medicine,” “Diversity in Science and Medicine,” “Running a Successful Research Program,” and “Mentorship in Action.” The AJM also included presentations from clinician investigator trainees from across the country. Over 90 abstracts were showcased at this year's meeting, most of which are summarized in this review. Six outstanding abstracts were selected for oral presentations during the President's Forum.

The 2022 Annual Joint Meeting (AJM) and Young Investigators' Forum of the Canadian Society for Clinical Investigation / Société Canadienne de recherches clinique (CSCI/SCRC) and Clinician Investigator Trainee Association of Canada/Association des cliniciens-chercheurs en formation du Canada (CITAC/ACCFC) was held in Montréal, November 13-14, 2022. The theme of this year's AJM was \"Strength in Perseverance\" and focused on highlighting clinician-investigator trainee achievements and resilience in research engagement through recent challenging and unprecedented times. The opening remarks were given by Nicola Jones (president of CSCI/SCRC) and Heather Whittaker (past president of CITAC/ACCFC). The keynote speaker was Dr. Michael Strong, who delivered the presentation \"The Future of Clinician Scientists in Canada.\" Dr. Caroline Quach (Université de Montréal) received the CSCI Distinguished Scientist Award and Dr. Amy Metcalfe (University of Calgary) received the CSCI Joe Doupe Young Investigator Award. Each of the clinician-scientists delivered presentations on their award-winning research. The four interactive workshops included \"Social Media in Science and Medicine,\" \"Diversity in Science and Medicine,\" \"Running a Successful Research Program,\" and \"Mentorship in Action.\" The AJM also included presentations from clinician investigator trainees from across the country. Over 90 abstracts were showcased at this year's meeting, most of which are summarized in this review. Six outstanding abstracts were selected for oral presentations during the President's Forum.

The α-synuclein protein, encoded by SNCA gene, is a major constituent of pathological intracellular inclusions such as Lewy bodies found in the brains of patients with Parkinson’s disease and other synucleinopathies. Whereas α-synuclein phosphorylation has been much studied, comparatively less work has been devoted to other post-translational modifications such as acetylation, especially given that N-terminally acetylated α-synuclein is the most abundant endogenous form of the protein in the brain. In this study, using multiple in vitro and in vivo models, we sought to better understand the role of N-terminal acetylation in the pathogenesis of synucleinopathies. We found that N-terminal acetylation slowed aggregation of both α-synuclein monomers and pre-formed fibrils in vitro. Uptake of acetylated α-synuclein pre-formed fibrils into both immortalized cell lines and iPSC-derived dopamine neurons was also slowed compared non-acetylated fibrils. In addition, exposure to acetylated pre-formed fibrils induced less seeding of endogenous α-synuclein, as measured by the accumulation of Serine129-phosphorylated α-synuclein inclusions in both iPSC-derived dopamine neurons and mouse brain. Finally, mice injected with N-terminally acetylated α-synuclein pre-formed fibrils survived significantly longer than mice injected with non-acetylated fibrils. Taken together, our study indicates that N-terminal acetylation reduces α-synuclein aggregation, uptake into cells, seeding of endogenous α-synuclein, and toxicity in vivo, suggesting that this prevalent post-translational modification represents a potent, physiologically relevant protective mechanism, which has thus far largely not been taken into consideration in most experimental paradigms of Parkinson’s disease and synucleinopathies.

α-Synuclein seed amplification assays are a promising diagnostic tool for synucleinopathies such as Parkinson’s disease and multiple system atrophy. Standardized conditions are required to ensure a high degree of inter- and intra-laboratory reproducibility when performing these assays. A significant issue that hinders the utility of seed amplification assays is the de novo aggregation propensity of the α-synuclein substrate as well as inter-batch heterogeneity. While much work has focused on determining appropriate seed amplification assay buffer compositions as well as the type and amount of seed used, a robust comparison of α-synuclein substrate purification methods has not been reported. We therefore compared the utility of recombinant α-synuclein purified using four different methods as seed amplification assay substrates across two laboratories. Osmotic shock-purified α-synuclein monomer substrate showed the lowest propensity for de novo aggregation, which translated into being the best substrate for seed amplification assay reactions seeded with α-synuclein preformed fibrils or patient brain homogenates. Furthermore, osmotic shock α-synuclein monomer showed the best inter-batch reproducibility compared to all other substrates tested. As α-synuclein seed amplification assays continue to evolve and move towards adoption in the clinical realm, this work showcases the vital importance of standardizing the production and characterization of recombinant α-synuclein substrate. We encourage the widespread adoption of osmotic shock α-synuclein monomer as the universal substrate for seed amplification assays to maximize intra- and inter-laboratory reproducibility.