A pharmacological master key mechanism that unlocks the selectivity filter gate in K channels

Science

Potassium (K) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K channels gated at their selectivity filter (SF), including many two-pore domain K (K2P) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca2)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K channel activators and highlight a filter gating machinery that is conserved across different families of K channels with implications for rational drug design.



Optimizing organic electrosynthesis through controlled voltage dosing and artificial intelligence

#artificialintelligence

Organic electrosynthesis can transform the chemical industry by introducing electricity-driven processes that are more energy efficient and that can be easily integrated with renewable energy sources. However, their deployment is severely hindered by the difficulties of controlling selectivity and achieving a large energy conversion efficiency at high current density due to the low solubility of organic reactants in practical electrolytes. This control can be improved by carefully balancing the mass transport processes and electrocatalytic reaction rates at the electrode diffusion layer through pulsed electrochemical methods. In this study, we explore these methods in the context of the electrosynthesis of adiponitrile (ADN), the largest organic electrochemical process in industry. Systematically exploring voltage pulses in the timescale between 5 and 150 ms led to a 20% increase in production of ADN and a 250% increase in relative selectivity with respect to the state-of-the-art constant voltage process.


An Analog VLSI Model of Periodicity Extraction

Neural Information Processing Systems

This paper presents an electronic system that extracts the periodicity of a sound. It uses three analogue VLSI building blocks: a silicon cochlea, two inner-hair-cell circuits and two spiking neuron chips. The silicon cochlea consists of a cascade of filters. Because of the delay between two outputs from the silicon cochlea, spike trains created at these outputs are synchronous only for a narrow range of periodicities. In contrast to traditional bandpass filters,where an increase in' selectivity has to be traded off against a decrease in response time, the proposed system responds quickly, independent of selectivity. 1 Introduction The human ear transduces airborne sounds into a neural signal using three stages in the inner ear's cochlea: (i) the mechanical filtering of the Basilar Membrane (BM), (ii) the transduction of membrane vibration into neurotransmitter release by the Inner Hair Cells (IHCs), and (iii) spike generation by the Spiral Ganglion Cells (SGCs), whose axons form the auditory nerve.


Activation of methane to CH3 : A selective industrial route to methanesulfonic acid

Science

Direct methane functionalization to value-added products remains a challenge because of the propensity for overoxidation in many reaction environments. Sulfonation has emerged as an attractive approach for achieving the necessary selectivity. Here, we report a practical process for the production of methanesulfonic acid (MSA) from only two reactants: methane and sulfur trioxide. We have achieved 99% selectivity and yield of MSA. The electrophilic initiator based on a sulfonyl peroxide derivative is protonated under superacidic conditions, producing a highly electrophilic oxygen atom capable of activating a C–H bond of methane.