Identifying kinematic biomarkers of the dystrophic phenotype in a zebrafish model of Duchenne muscular dystrophy

Skeletal Muscle · 2025-06-20 · 1 citations

BACKGROUND: Dystrophin-deficient zebrafish larvae are a small, genetically tractable vertebrate model of Duchenne muscular dystrophy that is well suited for early-stage therapeutic development. However, current approaches for evaluating their mobility, a physiologically relevant therapeutic outcome, yield data of low resolution and high variability that provides minimal insight into potential mechanisms responsible for their abnormal locomotion. METHODS: To address these issues, we used high speed videography and deep learning-based markerless motion capture to quantify escape response (ER) swimming kinematics of two dystrophic zebrafish strains (sapje and sapje-like). Each ER was partitioned into an initiating C-start, a subsequent power stroke, and a final burst of undulatory swimming activity. RESULTS: Markerless motion capture provided repeatable, high precision estimates of swimming kinematics. Random forest and support vector machine prediction models identified overall ER distance and peak speed, the instantaneous speed conferred by the power stroke, and the average speed and distance covered during burst swimming as the most predictive biomarkers for differentiating dystrophic from wild-type larvae. For each of these predictors, mutant and wild-type larvae differed markedly with effect sizes ranging from 2.4 to 3.7 standard deviations. To identify mechanisms underlying these performance deficits, we evaluated the amplitude and frequency of propulsive tail movements. There was little evidence that tail stroke amplitude was affected by the absence of dystrophin. Instead, temporal aspects of tail kinematics, including tail maximal angular velocity during the C-start and power stroke and tail stroke frequency during burst swimming, were slowed in mutants. In fact, tail kinematics were as effective as direct, non-survival in vitro assessments of tail muscle contractility in differentiating mutant from wild-type larvae. CONCLUSIONS: ER kinematics can be used as precise and physiologically relevant biomarkers of the dystrophic phenotype, may serve as non-lethal proxies for skeletal muscle dysfunction, and reveal new insights into why mobility is impaired in the absence of dystrophin. The approach outlined here opens new possibilities for the design and interpretation of studies using zebrafish to model movement disorders.

Legislative approaches to recognising the vulnerability of young people and preventing their criminalisation

Northumbria Research Link (Northumbria University) · 2021-01-01 · 2 citations

Discusses the introduction by the Modern Slavery Act 2015 s.45 of a specific defence for children over the minimum age of criminal responsibility, (MACR) but under 18, which recognises their vulnerability, and considers its wider implications. Reviews the politicisation of youth crime, the role of the media, the position in Scotland and Wales, and the arguments for raising the MACR and introducing a further defence of developmental immaturity.
\nLegislation cited
\nModern Slavery Act 2015 (c.30)s.45

Securing CHEESEHub: A Cloud-based, Containerized Cybersecurity Education Platform

Practice and Experience in Advanced Research Computing · 2021-07-17 · 1 citations

The Cyber Human Ecosystem for Engaged Security Education (CHEESEHub) is an open web platform that hosts community-contributed containerized demonstrations of cybersecurity concepts. In order to maximize flexibility, scalability, and utilization, CHEESEHub is currently hosted in a Kubernetes cluster on the Jetstream academic cloud. In this short paper, we describe the security model of CHEESEHub and specifically the various Kubernetes security features that have been leveraged to secure CHEESEHub. This ensures that the various cybersecurity exploits hosted in the containers cannot be misused, and that potential malicious users of the platform are cordoned off from impacting not just other legitimate users, but also the underlying hosting cloud. More generally, we hope that this article will provide useful information to the research computing community on a less discussed aspect of cloud deployment: the various security features of Kubernetes and their application in practice.

PRE-CLINICAL DEVELOPMENTS IN NEUROMUSCULAR DISORDERS

Neuromuscular Disorders · 2021-09-18

CHEESE: Cyber Human Ecosystem of Engaged Security Education

2021 IEEE Frontiers in Education Conference (FIE) · 2020 · 2 citations

• Computer Science
• Computer Science
• Computer Security

This Innovative Practice Full Paper presents CHEESE, a platform for cybersecurity education that complements formal classroom instruction with hands-on experience. With the ubiquitous use of computing devices and applications today, the protection of personal and privileged information is a persistent challenge. Modern software applications are typically complex pieces of code that borrow from various preexisting software libraries. Consequently, a flaw in one piece of software can have far-reaching and often unintended security implications that malicious actors can exploit. Thus, cybersecurity education needs to be transformed from a purely academic enterprise for cybersecurity researchers into a necessary skill that is imparted to the current and future IT workforce at large. CHEESE aims to impart such skills. CHEESE is composed of CHEESEHub, a public web-platform hosting demonstrations of cybersecurity concepts, a set of lessons complementing the demonstrations, and a community-driven approach to the contribution of new demonstrations and lessons. CHEESE is intended to supplement and enhance traditional cybersecurity education with hands-on training that has been shown to improve concept retention and understanding. Instructors can incorporate CHEESE into their teaching in several ways: by utilizing one or more of the demonstrations hosted on the publicly-accessible CHEESEHub in conjunction with the web-accessible lessons; by deploying their own version of CHEESEHub with a custom set of demonstrations and lessons; or by developing their own lesson plan which borrows from and combines one or more demonstrations on CHEESEHub. The use of CHEESEHub only requires a web-browser and can hence be employed in a wide variety of educational and training settings from K-12 schools through university.

Knowledge-guided analysis of "omics" data using the KnowEnG cloud platform

PLoS Biology · 2020 · 49 citations

• Computer Science
• Data Mining
• Computer Science

We present Knowledge Engine for Genomics (KnowEnG), a free-to-use computational system for analysis of genomics data sets, designed to accelerate biomedical discovery. It includes tools for popular bioinformatics tasks such as gene prioritization, sample clustering, gene set analysis, and expression signature analysis. The system specializes in "knowledge-guided" data mining and machine learning algorithms, in which user-provided data are analyzed in light of prior information about genes, aggregated from numerous knowledge bases and encoded in a massive "Knowledge Network." KnowEnG adheres to "FAIR" principles (findable, accessible, interoperable, and reuseable): its tools are easily portable to diverse computing environments, run on the cloud for scalable and cost-effective execution, and are interoperable with other computing platforms. The analysis tools are made available through multiple access modes, including a web portal with specialized visualization modules. We demonstrate the KnowEnG system's potential value in democratization of advanced tools for the modern genomics era through several case studies that use its tools to recreate and expand upon the published analysis of cancer data sets.

Knowledge-guided analysis of ‘omics’ data using the KnowEnG cloud platform

bioRxiv (Cold Spring Harbor Laboratory) · 2019-05-19 · 7 citations

Abstract We present KnowEnG, a free-to-use computational system for analysis of genomics data sets, designed to accelerate biomedical discovery. It includes tools for popular bioinformatics tasks such as gene prioritization, sample clustering, gene set analysis and expression signature analysis. The system offers ‘knowledge-guided’ data-mining and machine learning algorithms, where user-provided data are analyzed in light of prior information about genes, aggregated from numerous knowledge-bases and encoded in a massive ‘Knowledge Network’. KnowEnG adheres to ‘FAIR’ principles: its tools are easily portable to diverse computing environments, run on the cloud for scalable and cost-effective execution of compute-intensive and data-intensive algorithms, and are interoperable with other computing platforms. They are made available through multiple access modes including a web-portal, and include specialized visualization modules. We present use cases and re-analysis of published cancer data sets using KnowEnG tools and demonstrate its potential value in democratization of advanced tools for the modern genomics era.

CHEESE

2019-09-26 · 4 citations

The CHEESE project supplements and enhances traditional cybersecurity education with hands-on, practical experience in common cybersecurity flaws and solutions. CHEESE requires only a web browser, allowing users to develop cybersecurity skills without compromising their own computer or spending hours setting up a complex virtual machine (VM) or sandbox environment. In this tutorial we will conduct a hands-on walkthrough of a couple of cybersecurity demonstrations on CHEESE and present an overview of the platform and the community-driven contribution and development process.

Container-based Analysis Environments for Low-Barrier Access to Research Data

2017-07-05 · 7 citations

The growing size of high-value sensor-born or computationally derived scientific datasets are pushing the boundaries of traditional models of data access and discovery. Due to their size, these datasets are often accessible only through the systems on which they were created. Access for scientific exploration and reproducibility is limited to file transfer or by applying for access to the systems used to store or generate the original data, which is often infeasible. There is a growing trend toward providing access to large-scale research datasets in-place via container-based analysis environments. This paper describes the National Data Service (NDS) Labs Workbench platform and DataDNS initiative. The Labs Workbench platform is designed to provide scalable and low-barrier access to research data via container-based services. The DataDNS effort is a new initiative designed to enable discovery, access, and in-place analysis for large-scale data, providing a suite of interoperable services to enable researchers, as well as the tools they are most familiar with, to access and analyze these datasets where they reside.

Caractérisation du rôle de la O-N-acétyl-glucosaminylation dans la structuration sarcomérique du muscle squelettique et de son implication dans certaines pathologies musculaires

2016-09-27

La structuration sarcomérique, essentielle au muscle squelettique, est remarquablement organisée par de nombreuses protéines myofilamentaires interagissant entre elles. Plusieurs de ces protéines sont modifiées par une glycosylation atypique, la O-N-acétyl-β-D-glucosaminylation (O-GlcNAcylation), similaire en certains aspects à la phosphorylation et connue pour être un modulateur de l’activité contractile. Cependant à ce jour, son rôle dans l’organisation sarcomérique n’a pas été caractérisé. Lors de cette thèse, des traitements pharmacologiques appliqués sur des myotubes C2C12 ont permis de moduler de manière sensible et dynamique le taux de O-GlcNAcylation du myofilament, associé à des changements de la morphométrie du sarcomère et à des remaniements de certains complexes protéiques incluant des protéines structurales clé du sarcomère. En particulier, l’interaction entre la desmine et son chaperon moléculaire, l’αB-cristalline, était modulée dépendamment de la O-GlcNAcylation dans un dialogue étroit et complexe avec la phosphorylation. De plus, certains sites de O-GlcNAcylation ont été localisés sur des protéines myofilamentaires telles que la desmine au niveau d’un site connu pour être muté dans les desminopathies, l’αB-cristalline dans un domaine d’interaction avec la desmine, et la titine où plusieurs sites ont été identifiés en cluster dans un domaine d’interaction essentiel. L’ensemble de ces résultats démontrent que la O-GlcNAcylation est impliquée dans la structure du sarcomère et de son interactome, et amènent de nouvelles données quant à la compréhension de la physiopathologie de certaines maladies musculaires caractérisées par une désorganisation du sarcomère.