Permeation through the Cell Membrane of a Boron-Based β-Lactamase Inhibitor

Bacteria express beta-lactamases to counteract the beneficial action of antibiotics. Benzo[b]-thiophene-2-boronic acid (BZB) derivatives are β-lactamase inhibitors and, as such, promising compounds to be associated with β-lactam antibacterial therapies. The uncharged form of BZB, in particular, is suggested to diffuse through the outer membrane of Gram negative bacteria. In this study, through the combination of electrophysiological experiments across reconstituted PC/n-decane bilayers and metadynamics-based free energy calculations, we investigate the permeation mechanism of boronic compounds. Our experimental data establish that BZB passes through the membrane, while computer simulations provide hints for the existence of an aqueous, water-filled monomolecular channel. These findings provide new perspectives for the design of boronic acid derivatives with high membrane permeability

Dynamic fracture model for acoustic emission

We study the acoustic emission produced by micro-cracks using a two-dimensional disordered lattice model of dynamic fracture, which allows to relate the acoustic response to the internal damage of the sample. We find that the distributions of acoustic energy bursts decays as a power law in agreement with experimental observations. The scaling exponents measured in the present dynamic model can related to those obtained in the quasi-static random fuse model

Growth-induced compatible strains

We studied the time evolution problem driven by growth for a non-Euclidean ball which at its initial state is equipped with a non-compatible distortion field. The problem is set within the framework of non-linear elasticity with large growing dis- tortions. No bulk accretive forces are considered, and growth is only driven by the stress state. We showed that, when stress-driven growth is considered, distortions can evolve along different trajectories which share a common attracting manifold; moreover, they eventually attain a steady and compatible form, to which there corresponds a stress-free state of the ball

A Novel Approach to the Investigation of Passive Molecular Permeation through Lipid Bilayers from Atomistic Simulations

Predicting the permeability coefficient (<i>P</i>) of drugs permeating through the cell membrane is of paramount importance in drug discovery. We here propose an approach for calculating <i>P</i> based on bias-exchange metadynamics. The approach allows constructing from atomistic simulations a model of permeation taking explicitly into account not only the “trivial” reaction coordinate, the position of the drug along the direction normal to the lipid membrane plane, but also other degrees of freedom, for example, the torsional angles of the permeating molecule, or variables describing its solvation/desolvation. This allows deriving an accurate picture of the permeation process, and constructing a detailed molecular model of the transition state, making a rational control of permeation properties possible. We benchmarked this approach on the permeation of ethanol molecules through a POPC membrane, showing that the value of <i>P</i> calculated with our model agrees with the one calculated by a long unbiased molecular dynamics of the same system

School closures and mental health, wellbeing and health behaviours among children and adolescents during the second COVID-19 wave: a systematic review of the literature

to evaluate the impact of school closures, as a measure to contain the transmission of SARS-CoV-2 infection, on the psychological well-being of students of all levels starting from the 2020-2021 school year

A highly virulent variant of HIV-1 circulating in the Netherlands

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence