Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signaled to DNA damage by ataxia-telangiectasia mutated kinase.

Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington's Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia-telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.

Game on: immersive virtual laboratory simulation improves student learning outcomes & motivation.

The use of gamified learning interventions is expanding in postsecondary education as a means to improve students' motivation and learning outcomes. Virtual laboratory simulations have been used in science education to supplement students' learning, as well as to increase engagement with course material. Due to COVID-19, many instructors sought to replace or supplement hands-on 'wet-lab' work in an online environment. In this paper, we explored how the use of head-mounted display technology in two laboratory simulations impacts learner motivation and learning outcomes. We used a mixed-methods approach to analyze the experience of 39 undergraduate participants, examining test scores pre- and postsimulation, qualitative feedback, and quantitative experience ratings. The head-mounted display technology was described as easy to use, with eye strain identified as a common occurrence. Participants had increased test scores following the laboratory simulations, with no significant difference between simulation groups. Very positive self-reported measures of motivation and learner engagement were documented. Ninety-one percent of participants agreed that virtual reality laboratory simulation would be a good supplement to regular teaching modalities. Overall, our results suggest that immersive virtual reality laboratory simulations experienced through head-mounted display technology can be used to enhance learning outcomes and increase learner motivation.

The impact of the COVID-19 pandemic on perceived publication pressure among academic researchers in Canada.

The phenomenon of "publish-or-perish" in academia, spurred on by limited funding and academic positions, has led to increased competition and pressure on academics to publish. Publication pressure has been linked with multiple negative outcomes, including increased academic misconduct and researcher burnout. COVID-19 has disrupted research worldwide, leading to lost research time and increased anxiety amongst researchers. The objective of this study was to examine how COVID-19 has impacted perceived publication pressure amongst academic researchers in Canada. We used the revised Publication Pressure Questionnaire, in addition to Likert-type questions to discern respondents' beliefs and concerns about the impact of COVID-19 on academic publishing. We found that publication pressure increased across academic researchers in Canada following the pandemic, with respondents reporting increased stress, increased pessimism, and decreased access to support related to publishing. Doctoral students reported the highest levels of stress and pessimism, while principal investigators had the most access to publication support. There were no significant differences in publication pressure reported between different research disciplines. Women and non-binary or genderfluid respondents reported higher stress and pessimism than men. We also identified differences in perceived publication pressure based on respondents' publication frequency and other demographic factors, including disability and citizenship status. Overall, we document a snapshot of perceived publication pressure in Canada across researchers of different academic career stages and disciplines. This information can be used to guide the creation of researcher supports, as well as identify groups of researchers who may benefit from targeted resources.

Mod3D: A low-cost, flexible modular system of live-cell microscopy chambers and holders.

Live-cell microscopy imaging typically involves the use of high-quality glass-bottom chambers that allow cell culture, gaseous buffer exchange and optical properties suitable for microscopy applications. However, commercial sources of these chambers can add significant annual costs to cell biology laboratories. Consumer products in three-dimensional printing technology, for both Filament Deposition Modeling (FDM) and Masked Stereo Lithography (MSLA), have resulted in more biomedical research labs adopting the use of these devices for prototyping and manufacturing of lab plastic-based items, but rarely consumables. Here we describe a modular, live-cell chamber with multiple design options that can be mixed per experiment. Single reusable carriers and the use of biodegradable plastics, in a hybrid of FDM and MSLA manufacturing methods, reduce plastic waste. The system is easy to adapt to bespoke designs, with concept-to-prototype in a single day, offers significant cost savings to the users over commercial sources, and no loss in dimensional quality or reliability.

Recent Microscopy Advances and the Applications to Huntington's Disease Research.

Huntingtin is a 3144 amino acid protein defined as a scaffold protein with many intracellular locations that suggest functions in these compartments. Expansion of the CAG DNA tract in the huntingtin first exon is the cause of Huntington's disease. An important tool in understanding the biological functions of huntingtin is molecular imaging at the single-cell level by microscopy and nanoscopy. The evolution of these technologies has accelerated since the Nobel Prize in Chemistry was awarded in 2014 for super-resolution nanoscopy. We are in a new era of light imaging at the single-cell level, not just for protein location, but also for protein conformation and biochemical function. Large-scale microscopy-based screening is also being accelerated by a coincident development of machine-based learning that offers a framework for truly unbiased data acquisition and analysis at very large scales. This review will summarize the newest technologies in light, electron, and atomic force microscopy in the context of unique challenges with huntingtin cell biology and biochemistry.

DNA Repair in Huntington's Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses.

The use of genome wide association studies (GWAS) in Huntington's disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.

Development of a knowledge translation platform for ataxia: Impact on readers and volunteer contributors.

BACKGROUND: Dissemination of accurate health research information to patients and families has become increasingly important with the rise of the internet as a means of finding health information. However, the public faces several barriers to accessing research information, including paywalls and technical jargon. One method to bridge this gap between patients, families, and research is using lay summaries. SCAsource is an online knowledge translation platform where peer-reviewed research papers on ataxia are translated into lay summaries. This online platform was launched in September 2018, with the goal of making ataxia research more accessible and understandable to patients and families. A secondary goal is to provide opportunities for ataxia researchers to develop and hone their knowledge translation skills, altogether improving the quality of patient communication in the ataxia community. AIM: The aim of this study was to measure the impact of SCAsource on its readers and volunteer contributors after one year of activity. This is to ensure SCAsource is meeting its goals of (1) improving access and understanding of ataxia research to lay audiences, and (2) improving knowledge translation skills of volunteer contributors. METHODS: Two online surveys were launched, one for readers and one for volunteers. Each survey had a combination of multiple-choice, Likert-scale type, and open-ended short-answer questions. Descriptive quantitative analysis was used for respondent characteristics and Likert-type data. A grounded theory coding approach was used to analyze narrative feedback data. RESULTS: We found that SCAsource has mutually beneficial outcomes for both lay person readers and volunteer contributors. Readers have an increased understanding of ataxia research and access to up-to-date information on recent publications. Volunteers develop knowledge translation skills and have increased confidence in communicating results to lay audiences. Areas of improvement were identified to be incorporated into the platform. CONCLUSION: We demonstrated that SCAsource improves access to information and understanding of research to lay audiences, while providing opportunities for researchers to develop knowledge translation skills. This framework can potentially be used by other rare disease organizations to launch and evaluate their own knowledge translation websites.