Sodium channel activation underlies transfluthrin repellency in Aedes aegypti

Background Volatile pyrethroid insecticides, such as transfluthrin, have received increasing attention for their potent repellent activities in recent years for controlling human disease vectors. It has been long understood that pyrethroids kill insects by promoting activation and inhibiting inactivation of voltage-gated sodium channels. However, the mechanism of pyrethroid repellency remains poorly understood and controversial. Methodology/Principal findings Here, we show that transfluthrin repels Aedes aegypti in a hand-in-cage assay at nonlethal concentrations as low as 1 ppm. Contrary to a previous report, transfluthrin does not elicit any electroantennogram (EAG) responses, indicating that it does not activate olfactory receptor neurons (ORNs). The 1S-cis isomer of transfluthrin, which does not activate sodium channels, does not elicit repellency. Mutations in the sodium channel gene that reduce the potency of transfluthrin on sodium channels decrease transfluthrin repellency but do not affect repellency by DEET. Furthermore, transfluthrin enhances DEET repellency. Conclusions/Significance These results provide a surprising example that sodium channel activation alone is sufficient to potently repel mosquitoes. Our findings of sodium channel activation as the principal mechanism of transfluthrin repellency and potentiation of DEET repellency have broad implications in future development of a new generation of dual-target repellent formulations to more effectively repel a variety of human disease vectors.

Robust switches in thalamic network activity require a timescale separation between sodium and T-type calcium channel activations

Switches in brain states, synaptic plasticity and neuromodulation are fundamental processes in our brain that take place concomitantly across several spatial and timescales. All these processes target neuron intrinsic properties and connectivity to achieve specific physiological goals, raising the question of how they can operate without interfering with each other. Here, we highlight the central importance of a timescale separation in the activation of sodium and T-type calcium channels to sustain robust switches in brain states in thalamic neurons that are compatible with synaptic plasticity and neuromodulation. We quantify the role of this timescale separation by comparing the robustness of rhythms of six published conductance-based models at the cellular, circuit and network levels. We show that robust rhythm generation requires a T-type calcium channel activation whose kinetics are situated between sodium channel activation and T-type calcium channel inactivation in all models despite their quantitative differences.

Robust switches in thalamic network activity require a timescale separation between sodium and T-type calcium channel activations

Switches in brain states, synaptic plasticity and neuromodulation are fundamental processes in our brain that take place concomitantly across several spatial and timescales. All these processes target neuron intrinsic properties and connectivity to achieve specific physiological goals, raising the question of how they can operate without interfering with each other. Here, we highlight the central importance of a timescale separation in the activation of sodium and T-type calcium channels to sustain robust switches in brain states in thalamic neurons that are compatible with synaptic plasticity and neuromodulation. We quantify the role of this timescale separation by comparing the robustness of rhythms of six published conductance-based models at the cellular, circuit and network levels. We show that robust rhythm generation requires a T-type calcium channel activation whose kinetics are situated between sodium channel activation and T-type calcium channel inactivation in all models despite their quantitative differences.

Effect of puerarin on action potential and sodium channel activation in human hypertrophic cardiomyocytes

Objective: To study the effect of puerarin on electrophysiology using a hypertrophic cardiomyocyte (HC) model. Materials and methods: Human urine epithelial cells were used to generate the HC model (hiPSC-CM). Cardiomyocyte hypertrophy was induced by applying 10 nM endothelin-1 (ET-1). Effects of puerarin pre-treatment (PPr) and post-treatment (PPo) on action potential, sodium current (INa) activation and inactivation, and recovery following INa inactivation were tested using patch clamp electrophysiology. Results: Depolarization to repolarization 50% time (APD50) and repolarization 30% time (APD30) were significantly prolonged in the PPo and PPr groups compared with the controls. However, there were no significant differences in the action potential depolarization amplitude (APA) or the maximum depolarization velocity (Vmax) in phase 0. The PPr group had a slightly shortened APD90, and an extended APD50 and APD30, but did not exhibit any significant changes in stage A of APA and Vmax. The PPo group did not exhibit any significant changes in INa, while 12 h of PPr improved INa. However, puerarin did not significantly affect the activation, inactivation, or recovery of the sodium channel. Conclusions: Cardiomyocyte hypertrophy significantly decreased the Vmax of the action potential and the peak density of INa. PPr inhibited the decrease in Vmax and increased the peak density of INa. Thus, puerarin could be used to stabilize the electrophysiological properties of hypertrophic cardiomyocytes and reduce arrhythmias.

Pathway analysis identifies altered mitochondrial metabolism, neurotransmission, structural pathways and complement cascade in retina/RPE/ choroid in chick model of form-deprivation myopia

Purpose RNA sequencing analysis has demonstrated bidirectional changes in metabolism, structural and immune pathways during early induction of defocus induced myopia. Thus, the aim of this study was to investigate whether similar gene pathways are also related to the more excessive axial growth, ultrastructural and elemental microanalytic changes seen during the induction and recovery from form-deprivation myopia (FDM) in chicks and predicted by the RIDE model of myopia. Methods Archived genomic transcriptome data from the first three days of induction of monocularly occluded form deprived myopia (FDMI) in chicks was obtained from the GEO database (accession # GSE6543) while data from chicks monocularly occluded for 10 days and then given up to 24 h of normal visual recovery (FDMR) were collected. Gene set enrichment analysis (GSEA) software was used to determine enriched pathways during the induction (FDMI) and recovery (FDMR) from FD. Curated gene-sets were obtained from open access sources. Results Clusters of significant changes in mitochondrial energy metabolism, neurotransmission, ion channel transport, G protein coupled receptor signalling, complement cascades and neuron structure and growth were identified during the 10 days of induction of profound myopia and were found to correlate well with change in axial dimensions. Bile acid and bile salt metabolism pathways (cholesterol/lipid metabolism and sodium channel activation) were significantly upregulated during the first 24 h of recovery from 10 days of FDM. Conclusions The gene pathways altered during induction of FDM are similar to those reported in defocus induced myopia and are established indicators of oxidative stress, osmoregulatory and associated structural changes. These findings are also consistent with the choroidal thinning, axial elongation and hyperosmotic ion distribution patterns across the retina and choroid previously reported in FDM and predicted by RIDE.