Biology subjects

Estarellas, C.

Publications and source records attributed to Estarellas, C..

2 recordsLinked to original sources

bioRxiv2023

Somatic disinhibition of granule cells improves information transmission and pattern separation in the dentate gyrus

Cortical circuits operate in a tight excitation/inhibition balance. This balance is relaxed during learning processes, but neither the mechanism nor its impact on network operations are well understood. In the present study, we combined in-vivo and in-vitro neuronal recordings with computational modelling and demonstrated that synaptic plasticity in the afferents from the entorhinal cortex (EC) to the dentate gyrus (DG), in addition to strengthening the glutamatergic inputs into granule cells (GCs), depressed perisomatic inhibition. Computational modelling revealed a functional reorganization in the inhibitory network that explained several experimental findings, including depression of the feed-forward inhibition. In vitro results confirmed a perisomatic dominance of the inhibitory regulation with important functional consequences. It favoured GCs burst firing, improved reliability of input/output transformations and enhanced separation and transmission of temporal and spatial patterns in the EC-DG-CA3 network.

neuroscience↗

bioRxiv2022

Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography

Non-structural protein 1 (Nsp1) is a main pathogenicity factor of - and {beta}-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive Molecular Dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous {beta}-coronaviruses.

biophysics↗