The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis

Aims: Single nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homoeostasis that predispose to spontaneous electrical activity. Methods and results: Western blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homoeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1¿±¿4.5 vs. 3.1¿±¿1.3 events/min, P¿=¿0.02), frequency of transient inward currents (ITI) (1.33¿±¿0.24 vs. 0.26¿±¿0.09 events/min, P¿<¿0.001) and incidence of spontaneous membrane depolarizations (1.22¿±¿0.26 vs. 0.56¿±¿0.17 events/min, P¿=¿0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2¿±¿1.4 vs. 7.3¿±¿0.5¿amol/pF, P¿=¿0.01), SERCA2 expression (1.37¿±¿0.13 fold, P¿=¿0.03), and RyR2 phosphorylation at ser2808 (0.67¿±¿0.08 vs. 0.47¿±¿0.03, P¿=¿0.01) but not at ser2814 (0.28¿±¿0.14 vs. 0.31¿±¿0.14, P¿=¿0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the ITI frequency and the increase in the ITI frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF. Conclusions: Here, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.Peer ReviewedPostprint (author's final draft

Ensinar e aprender português: a digital resource for learning to read and write

In Education, the use of technological resources to support students' teaching and learning is becoming more and more urgent. Teaching and Learning Portuguese [Ensinar e Aprender Português – EAP] is a structured and innovative educational resource, supported by the use of Information and Communication Technologies and based on scientific evidence. It is aimed at students (and teachers) of the four years of primary school. It aims to: i) support the teaching/learning of reading and writing in primary school; ii) signalize, in a timely manner, students at-risk of presenting difficulties in learning to read and write; and iii) support the recovery of learning. This paper will present this digital resource developed for the Portuguese context, based on the Portuguese curriculum and the legislation on inclusive education. It is also anchored in the multilevel approach whose focus on digital transition, on screening tests and monitoring of learning has introduced new challenges in the education system. As it is a digital resource whose activities are self-executable and for which explanatory and corrective feedbacks are provided, it contributes to bridge a gap in terms of digital transition which was particularly visible in a pandemic context such as the one we are going through.In Education, the use of technological resources to support students' teaching and learning is becoming more and more urgent. Teaching and Learning Portuguese [Ensinar e Aprender Português – EAP] is a structured and innovative educational resource, supported by the use of Information and Communication Technologies and based on scientific evidence. It is aimed at students (and teachers) of the four years of primary school. It aims to: i) support the teaching/learning of reading and writing in primary school; ii) signalize, in a timely manner, students at-risk of presenting difficulties in learning to read and write; and iii) support the recovery of learning. This paper will present this digital resource developed for the Portuguese context, based on the Portuguese curriculum and the legislation on inclusive education. It is also anchored in the multilevel approach whose focus on digital transition, on screening tests and monitoring of learning has introduced new challenges in the education system. As it is a digital resource whose activities are self-executable and for which explanatory and corrective feedbacks are provided, it contributes to bridge a gap in terms of digital transition which was particularly visible in a pandemic context such as the one we are going through.This work was financially supported by Portuguese national funds through the FCT (Foundation for Science and Technology) within the framework of the CIEC (Research Center for Child Studies of the University of Minho) projects under the references UIDB/00317/2020 and UIDP/00317/2020

PDBe: improved accessibility of macromolecular structure data from PDB and EMDB

© 2015 The Authors. Published by OUP. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1093/nar/gkv1047The Protein Data Bank in Europe (http://pdbe.org) accepts and annotates depositions of macromolecular structure data in the PDB and EMDB archives and enriches, integrates and disseminates structural information in a variety of ways. The PDBe website has been redesigned based on an analysis of user requirements, and now offers intuitive access to improved and value-added macromolecular structure information. Unique value-added information includes lists of reviews and research articles that cite or mention PDB entries as well as access to figures and legends from full-text open-access publications that describe PDB entries. A powerful new query system not only shows all the PDB entries that match a given query, but also shows the 'best structures' for a given macromolecule, ligand complex or sequence family using data-quality information from the wwPDB validation reports. A PDBe RESTful API has been developed to provide unified access to macromolecular structure data available in the PDB and EMDB archives as well as value-added annotations, e.g. regarding structure quality and up-to-date cross-reference information from the SIFTS resource. Taken together, these new developments facilitate unified access to macromolecular structure data in an intuitive way for non-expert users and support expert users in analysing macromolecular structure data.The Wellcome Trust [88944, 104948]; UK Biotechnology and Biological Sciences Research Council [BB/J007471/1, BB/K016970/1, BB/M013146/1, BB/M011674/1]; National Institutes of Health [GM079429]; UK Medical Research Council [MR/L007835/1]; European Union [284209]; CCP4; European Molecular Biology Laboratory (EMBL). Funding for open access charge: The Wellcome Trust.Published versio