Orchestrated control of filaggrin-actin scaffolds underpins cornification

Epidermal stratification critically depends on keratinocyte differentiation and programmed death by cornification, leading to formation of a protective skin barrier. Cornification is dynamically controlled by the protein filaggrin, rapidly released from keratohyalin granules (KHGs). However, the mechanisms of cornification largely remain elusive, partly due to limitations of the observation techniques employed to study filaggrin organization in keratinocytes. Moreover, while the abundance of keratins within KHGs has been well described, it is not clear whether actin also contributes to their formation or fate. We employed advanced (super-resolution) microscopy to examine filaggrin organization and dynamics in skin and human keratinocytes during differentiation. We found that filaggrin organization depends on the cytoplasmic actin cytoskeleton, including the role for α- and β-actin scaffolds. Filaggrin-containing KHGs displayed high mobility and migrated toward the nucleus during differentiation. Pharmacological disruption targeting actin networks resulted in granule disintegration and accelerated cornification. We identified the role of AKT serine/threonine kinase 1 (AKT1), which controls binding preference and function of heat shock protein B1 (HspB1), facilitating the switch from actin stabilization to filaggrin processing. Our results suggest an extended model of cornification in which filaggrin utilizes actins to effectively control keratinocyte differentiation and death, promoting epidermal stratification and formation of a fully functional skin barrier

A FAIR based approach to data sharing in Europe

The European fusion research activities have, over recent decades, generated a vast and varied set of data. The volume and diversity of the data that need to be catalogued and annotated make the task of organising and making the data available within a broader environment very challenging. Nevertheless, there are strong scientific drivers as well as incentives and mandates from national research agencies suggesting that a more coherent approach to data referencing, dissemination and sharing would provide strong benefits to the fusion research community and beyond. Here, we discuss the technical requirements and developments needed to transition the current, and future, range of fusion research data to an open and Findable, Accessible, Interoperable, and Reusable data sharing structure guided by the principle \u27as open as possible, as closed as necessary\u27. Here we propose a set of recommendations and technical implementations needed to form a European data sharing environment for the fusion research programmes. Consistency with the emerging IMAS (ITER Integrated Modelling and Analysis Suite) infrastructure is considered to facilitate future deployments

Recent EUROfusion Achievements in Support of Computationally Demanding Multiscale Fusion Physics Simulations and Integrated Modeling

Integrated modeling (IM) of present experiments and future tokamak reactors requires the provision of computational resources and numerical tools capable of simulating multiscale spatial phenomena as well as fast transient events and relatively slow plasma evolution within a reasonably short computational time. Recent progress in the implementation of the new computational resources for fusion applications in Europe based on modern supercomputer technologies (supercomputer MARCONI-FUSION), in the optimization and speedup of the EU fusion-related first-principle codes, and in the development of a basis for physics codes/modules integration into a centrally maintained suite of IM tools achieved within the EUROfusion Consortium is presented. Physics phenomena that can now be reasonably modelled in various areas (core turbulence and magnetic reconnection, edge and scrape-off layer physics, radio-frequency heating and current drive, magnetohydrodynamic model, reflectometry simulations) following successful code optimizations and parallelization are briefly described. Development activities in support to IM are summarized. They include support to (1) the local deployment of the IM infrastructure and access to experimental data at various host sites, (2) the management of releases for sophisticated IM workflows involving a large number of components, and (3) the performance optimization of complex IM workflows.This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014 to 2018 under grant agreement 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission or ITER.Peer ReviewedPostprint (published version

Topical Gene Electrotransfer to the Epidermis of Hairless Guinea Pig by Non-invasive Multielectrode Array

Topical gene delivery to the epidermis has the potential to be an effective therapy for skin disorders, cutaneous cancers, vaccinations and systemic metabolic diseases. Previously, we reported on a non-invasive multielectrode array (MEA) that efficiently delivered plasmid DNA and enhanced expression to the skin of several animal models by in vivo gene electrotransfer. Here, we characterized plasmid DNA delivery with the MEA in a hairless guinea pig model, which has a similar histology and structure to human skin. Significant elevation of gene expression up to 4 logs was achieved with intradermal DNA administration followed by topical non-invasive skin gene electrotransfer. This delivery produced gene expression in the skin of hairless guinea pig up to 12 to 15 days. Gene expression was observed exclusively in the epidermis. Skin gene electrotransfer with the MEA resulted in only minimal and mild skin changes. A low level of human Factor IX was detected in the plasma of hairless guinea pig after geneelectrotransfer with the MEA, although a significant increase of Factor IX was obtained in the skin of animals. These results suggest geneelectrotransfer with the MEA can be a safe, efficient, non-invasive skin delivery method for skin disorders, vaccinations and potential systemic diseases where low levels of gene products are sufficient

Pitfalls in Using Electrophysiological Studies to Diagnose Neuromuscular Disorders

Electrodiagnostic testing is used widely for the full characterization of neuromuscular disorders and for providing unique information on the processes underlying the pathology of peripheral nerves and muscles. However, such testing should be considered as an extension of anamnesis and physical examination, not as pathognomonic of a specific disease entity. There are many pitfalls that could lead to erroneous interpretation of electrophysiological study results when the studies are not performed properly or if they are performed in the presence of anatomical aberrations. The diagnostic reliability of electrodiagnostic studies can be improved and the associated pitfalls overcome if the physician is familiar with all of those possible pitfalls. In this article we discuss the most common and important pitfalls associated with electrodiagnostic medicine

EUROfusion Integrated Modelling (EU-IM) capabilities and selected physics applications

International audienceRecent developments and achievements of the EUROfusion Code Development for Integrated Modelling project (WPCD), which aim is to provide a validated integrated modelling suite for the simulation and prediction of complete plasma discharges in any tokamak, are presented. WPCD develops generic complex integrated simulations, workflows, for physics applications, using the standardized European Integrated Modelling (EU-IM) framework. Selected physics applications of EU-IM workflows are illustrated in this paper

The modelling of magnetic hearth vector on the basis of the cellular ion currents

Do obliczenia magnetokardiogramów zastosowano dwuwymiarowy model komputerowy elektrycznej aktywności serca, bazujący na formalizmie zaproponowanym przez Hodg-kina i Huxleya. Wyliczano średni wektor pola magnetycznego AMFV (average magnetic field vector) otrzymany z mapy zewnętrznego pola magnetycznego, generowany przez przepływ jonów w poszczególnych komórkach mięśnia serca. Obliczona na podstawie modelu trajektoria AMFV przy normalnej pracy serca w czasie trwania zespołu QRS przyjmuje kształt kolisty z rotacją w kierunku przeciwnym do ruchu wskazówek zegara. Na podstawie modelu przedstawiono przykładowe zaburzenia trajektorii AMFV, towarzyszące określonym zaburzeniom serca.A two-dimensional computer model of the heart electrical activity, based on the formalism proposed by Hodgkin and Huxley was used to calculate magnetocardiograms. The average magnetic field vector (AMFV) from the map of extra corporeal magnetic field generated by the heart was calculated. In a normal heart, the trajectory of AMFV within duration of QRS complex as computed from the model has a form of a circle rotating anticlockwise. Abnormal trajectories of AMFV associated with some cardiac pathologies were generated from the model, as well. If properly validated in clinical conditions, the measurements of AMFV may be helpful in diagnosis