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How functional amyloids are regulated to restrict their activity is poorly understood. The cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that adopts an amyloid state key for memory persistence. Its monomer represses the translation of synaptic target mRNAs while phase separated, whereas its aggregated state acts as a translational activator. Here, we have explored the sequence-driven molecular determinants behind the functional aggregation of human CPEB3 (hCPEB3). We found that the intrinsically disordered region (IDR) of hCPEB3 encodes both an amyloidogenic and a phase separation domain, separated by a poly-A-rich region. The hCPEB3 amyloid core is composed by a hydrophobic region instead of the Q-rich stretch found in the Drosophila orthologue. The hCPEB3 phase separation domain relies on hydrophobic interactions with ionic strength dependence, and its droplet ageing process leads to a liquid-to-solid transition with the formation of a non-fibril-based hydrogel surrounded by starburst droplets. Furthermore, we demonstrate the differential behavior of the protein depending on its environment. Under physiological-like conditions, hCPEB3 can establish additional electrostatic interactions with ions, increasing the stability of its liquid droplets and driving a condensation-based amyloid pathway.

The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using O’Hara-Rudy human myocyte model with sex phenotypes of Yang and Clancy. A systematic comparison between detailed vs smooth anatomies, male vs female normal hearts was carried out. The heart with a myocardial infarction was subjected to a programmed stimulus protocol to identify the effects of sex and anatomical detail on ventricular tachycardia inducibility. All female hearts presented QT-interval prolongation however the prolongation interval in comparison to the male phenotypes was anatomy-dependent and was not correlated to the size of the heart. Detailed geometries showed QRS fractionation and increased T-wave magnitude in comparison to the corresponding smoothed geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified. Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from cardiac electrophysiology simulations. The assumption that the cardiac endocar, JA-S, FS, GH and MV are supported by the European Union’s Horizon 2020 research and innovation programme under grant agreements No 675451 (Compbiomed project phase 1) and No 823712 (CompBioMed project, phase 2) and project No 777204 (SilicoFCM project). Part of the simulation computing hours were provided by the CompBioMed project phase 1. JA-S was awarded computation time from Red Espanola de Supercomputacion (RES). (Activity IDs: FI-2018-2-0049 and BCV-2019-2-0014) JA-S is funded by a Ramon y Cajal fellowship (RYC-2017-22532), Ministerio de Ciencia e Innovacion, Spain; and by Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2017-2020 from the Ministerio de Ciencia e Innovacion y Universidades (PID2019-104356RBC41/AEI/10.13039/501100011033): meHeart ME PID2019-104356RB-C44. CB is funded by the Torres Quevedo Program (PTQ2018-010290), Ministerio de Ciencia e Innovacion, Spain. MV, GH and CB are funded by the Spanish Neotec project EXP - 00123159/SNEO-20191113 Generador de corazones virtuales. LKGM was funded by Fundacion Carolina-BBVA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study., Peer Reviewed, "Article signat per 11 autors/es: Pablo Gonzalez-Martin,Federica Sacco,Constantine Butakoff,Ruben Doste,Carlos Bederian,Lilian K. Gutierrez Espinosa de los Monteros,Guillaume Houzeaux,Paul A. Iaizzo,Tinen L. Iles,Mariano Vazquez,Jazmin Aguado-Sierra", Postprint (published version)

Impact simulations for damage resistance analysis are computationally intensive due to contact algorithms and advanced damage models. Both methods, which are the main ingredients in an impact event, require refined meshes at the contact zone to obtain accurate predictions of the contact force and damage onset and propagation through the material. This work presents the application of the partial Dirichlet–Neumann contact algorithm to simulate low-velocity impact problems on composite structures using High-Performance Computing. This algorithm is devised for parallel finite element codes running on supercomputers, and it is extended to explicit time integration schemes to solve impact problems including damage. The proposed framework is validated with a standard test for damage resistance on fiber-reinforced polymer matrix composites. Moreover, the parallel performance of the proposed algorithm has been evaluated in a mesh of 74M of elements running with 2400 processors, This work has received funding from the Clean Sky 2 Joint Undertaking (JU) under grant agreements No. 807083 and No. 945521 (SHERLOC project). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the Clean Sky 2 JU members other than the Union. The authors gratefully acknowledge Hellenic Aerospace Industry for manufacturing of the coupons made of T800S/M21 material and Kirsa Muñoz and Miguel Ángel Jiménez from Element Materials Technology Seville, Peer Reviewed, Postprint (author's final draft)

Structural Preferences of the Protein hCPEB3 in the Prelude to Memory Consolidation 1213 Douglas Laurents , Daniel Ramírez De Mingo , David Pantoja Uceda , Rubén Hervás , Mariano Carrión Vázquez 1) "Rocasolano" Institute for Physical Chemistry, Madrid, Spain 2) Instituto Cajal, IC-CSIC, Madrid, Spain 3) School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China How are memories stored in the brain? Neurospecific forms of the cytoplasmic polyadenylation element binding protein (CPEB) are thought to promote memory consolidation by undergoing a disordered to functional amyloid conformational transformation at specific dendritic spines(1). This alters local mRNA translation and leads to a strengthening of particular dendritic spines(2). Whereas the structure of the Drosophila CPEB homolog has been recently elucidated(3), how amyloid formation occurs in the human homolog (hCPEB3) is still unclear. To address this question, we have characterized the partial structure and dynamics of the 426- residue disordered region in hCPEB3 by NMR spectroscopy(4). Five segments with partial ¿- helix formation, two with moderate polyproline II helix populations and a rigid hydrophobic segment were observed in the first 250 residues. Biophysical assays evince that residues 251- 426 can promote biomolecular condensateformation (5). Some evidence for interactions among the elements of partly populated ¿-helices and between the polyproline II helices with profilin were observed. Profilin binds both polyproline II helices and actin and could mediate dendritic spine specific fortification of the actincytoskeleton. These results provide a hypothetical working model for understanding hCPEB3 amyloid formation and its role in memory consolidation. 1. Si K, Linquist S, Kandel ER (2003) Cell 115: 897-891 2. Si K & Kandel ER (2016) Cold Spring Harb Perspect Biol. 8:a021774 3. Hervás R. ..et al.. Si K. (2020) Science 367: 1230-1234 4. Ramírez de Mingo D. ..et al.. Laurents