Correlation between human ether-a-go-go-related gene channel inhibition and action potential prolongation

Background and Purpose: Human ether-a-go-go-related gene (hERG; Kv11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro-arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The interference from accompanying block of Cav1.2 and Nav1.5 channels was investigated along with an in silico AP model. Experimental Approach: Drug-induced changes in APD were assessed in hiPSC-CMs using voltage-sensitive dyes. The IC50 values for dofetilide and 13 derivatives on hERG current were estimated in an HEK293 expression system. The relative potency of each drug on APD was estimated by calculating the dose (D150) required to prolong the APD at 90% (APD90) repolarization by 50%. Key Results: The D150 in hiPSC-CMs was linearly correlated with IC50 of hERG current. In silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, and these compounds also inhibited Cav1.2 and/or Nav1.5 in a channel state-dependent manner. Adding Cav1.2 and Nav1.2 block to the in silico model recapitulated the direction but not the extent of the APD change. Conclusions and Implications: Potency of hERG current inhibition correlates linearly with an index of APD in hiPSC-CMs. The compounds that do not correlate have additional effects including concomitant block of Cav1.2 and/or Nav1.5 channels. In silico simulations of hiPSC-CMs APs confirm the principle of the multiple ion channel effects

Efficient modulation of of γ-aminobutyric acid type A (GABAA) receptors by piperine derivatives

[Image: see text] Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABA(A)R). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABA(A)R by means of a two-microelectrode voltage-clamp technique. GABA(A)R were expressed in Xenopus laevis oocytes. Structure–activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABA(A)R. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABA(A) (maximal GABA-induced chloride current modulation (I(GABA-max) = 1673% ± 146%, EC(50) = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC(50) = 13.8 ± 1.8 μM, I(GABA-max) = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABA(A)R modulators

Sputtered NbN Films for Ultrahigh Performance Superconducting Nanowire Single-Photon Detectors

Nowadays ultrahigh performance superconducting nanowire single-photon detectors are the key elements in a variety of devices from biological research to quantum communications and computing. Accurate tuning of superconducting material properties is a powerful resource for fabricating single-photon detectors with a desired properties. Here, we report on the major theoretical relations between ultrathin niobium nitride (NbN) films properties and superconducting nanowire single-photon detectors characteristics, as well as ultrathin NbN films properties dependence on reactive magnetron sputtering recipes. Based on this study we formulate the exact requirements to ultrathin NbN films for ultrahigh performance superconducting nanowire single-photon detectors. Then, we experimentally study ultrathin NbN films properties (morphology, crystalline structure, critical temperature, sheet resistance) on silicon, sapphire, silicon dioxide and silicon nitride substrates sputtered with various recipes. We demonstrate ultrathin NbN films (obtained with more than 100 films deposition) with a wide range of critical temperature from 2.5 to 12.1 K and sheet resistance from 285 to 2000 ~$\Omega$/sq, as well as investigate a sheet resistance evolution over for more than 40\% within two years. Finally, we found out that one should use ultrathin NbN films with specific critical temperature near 9 K and sheet resistance of 400 ~$\Omega$/sq for ultrahigh performance SNSPD.Comment: The following article has been submitted to APL Materials. After it is published, it will be found at https://pubs.aip.org/aip/apm. Copyright 2023 Author(s). This article is distributed under a Creative Commons Attribution (CC BY) Licens

Defensin-Like ZmES4 Mediates Pollen Tube Burst in Maize via Opening of the Potassium Channel KZM1

Species-preferential osmotic pollen tube burst and sperm discharge in maize involve induced opening of the pollen tube-expressed potassium channel KZM1 by the egg apparatus-derived defensin-like protein ZmES4

Cognitive and sociocultural aspects of robotized technology: innovative processes of adaptation

The paper dwells upon interaction between socio-cultural phenomena and cognitive characteristics of robotized technology. The interdisciplinary approach was employed in order to cast light on the manifold and multilevel identity of scientific advance in terms of robotized technology within the mental realm. Analyzing robotized technology from the viewpoint of its significance for the modern society is one of the upcoming trends in the contemporary scientific realm. The robots under production are capable of interacting with people; this results in a growing necessity for the studies on social status of robotized technological items. Socio-cultural aspect of cognitive robotized technology is reflected in the fact that the nature becomes 'aware' of itself via human brain, a human being tends to strives for perfection in their intellectual and moral dimensions