The free energy landscape of GABA binding to a pentameric ligand-gated ion channel and its disruption by mutations

Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop superfamily are important neuroreceptors that mediate fast synaptic transmission. They are activated by the binding of a neurotransmitter, but the details of this process are still not fully understood. As a prototypical pLGIC, here we choose the insect resistance to dieldrin (RDL) receptor, involved in the resistance to insecticides, and investigate the binding of the neurotransmitter GABA to its extracellular domain at the atomistic level. We achieve this by means of $\mu$-sec funnel-metadynamics simulations, which efficiently enhance the sampling of bound and unbound states by using a funnel-shaped restraining potential to limit the exploration in the solvent. We reveal the sequence of events in the binding process, from the capture of GABA from the solvent to its pinning between the charged residues Arg111 and Glu204 in the binding pocket. We characterize the associated free energy landscapes in the wild-type RDL receptor and in two mutant forms, where the key residues Arg111 and Glu204 are mutated to Ala. Experimentally these mutations produce non-functional channels, which is reflected in the reduced ligand binding affinities, due to the loss of essential interactions. We also analyze the dynamical behaviour of the crucial loop C, whose opening allows the access of GABA to the binding site, while its closure locks the ligand into the protein. The RDL receptor shares structural and functional features with other pLGICs, hence our work outlines a valuable protocol to study the binding of ligands to pLGICs beyond conventional docking and molecular dynamics techniques.Comment: accepted (May 2016); 27 pages, 6 figures, Table of contents graphic, Journal of Chemical Theory and Computation (2016

WIKI COURSE BUILDER, A SYSTEM FOR MANAGING AND SHARING DIDACTIC MATERIAL AND CONCEPT MAPS

In this article we present an evolution of Wiki course Builder, a system for building courses, sharing and sequencing learning material taken from Wikipedia pages. The system has been expanded through the implementation of two new modules to provide teachers with different tools that optimize the course creation process. Taking advantage of the user model implemented in the system starting from Grasha\u2019s teaching styles, we have implemented a module that visualizes the graph of all the courses created by the teaching community and makes it possible to compare it with others. This graph can be filtered by macro categories of arguments (eg. History, Philosophy...) and by teacher archetypes (eg. expertize delegator ...). The second module is a graphical interface that makes it possible to design and build concept maps for the generation of different courses (alternative learning paths through the map). The comparison between these maps will enrich the model of the teacher who will receive recommendations more refined on the basis of the course method you prefer to make. For the future it will be interesting to extend the user model through the comparison of the concept maps generated by the creation of the course and the clustering of the teachers on the basis of this data. Furthermore, the study of the density of concepts within the materials and the complexity of learning difficulties would complete the user model by optimizing again the recommendation process

Towards a Deeper Understanding: EEG and Facial Expressions in Museums

Although personalization is a staple in several online settings, achieving an ad-hoc experience in some environments is impossible based on personal tastes. One such environment is the museum. In our view, visitors’ facial reactions in front of artworks can play a crucial role. In this context, we want to study visitor behavior with an even finer-grained approach, identifying the most activated brain areas and how they relate to facial expressions. This paper describes how we intend to create a multimodal dataset to validate our study. We aim to fill a gap in personalizing the heritage experience with multidisciplinary research that combines neuroscience and computer science

Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1

Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD341 cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells