High Activation Threshold Research Articles

Ultra-broadband all-optical nonlinear activation function enabled by MoTe2/optical waveguide integrated devices

All-optical nonlinear activation functions (NAFs) are crucial for enabling rapid optical neural networks (ONNs). As linear matrix computation advances in integrated ONNs, on-chip all-optical NAFs face challenges such as limited integration, high latency, substantial power consumption, and a high activation threshold. In this work, we develop an integrated nonlinear optical activator based on the butt-coupling integration of two-dimensional (2D) MoTe2 and optical waveguides (OWGs). The activator exhibits an ultra-broadband response from visible to near-infrared wavelength, a low activation threshold of 0.94 μW, a small device size (~50 µm2), an ultra-fast response rate (2.08 THz), and high-density integration. The excellent nonlinear effects and broadband response of 2D materials have been utilized to create all-optical NAFs. These activators were applied to simulate MNIST handwritten digit recognition, achieving an accuracy of 97.6%. The results underscore the potential application of this approach in ONNs. Moreover, the classification of more intricate CIFAR-10 images demonstrated a generalizable accuracy of 94.6%. The present nonlinear activator promises a general platform for three-dimensional (3D) ultra-broadband ONNs with dense integration and low activation thresholds by integrating a variety of strong nonlinear optical (NLO) materials (e.g., 2D materials) and OWGs in glass.

Mechanoluminescent/Electric Dual-Mode Sensors Enabled by Trace Carbon Nanotubes.

Mechanoluminescence (ML)-based sensors are emerging as promising wearable devices, attracting attention for their self-powered visualization of mechanical stimuli. However, challenges such as weak brightness, high activation threshold, and intermittent signal output have hindered their development. Here, a mechanoluminescent/electric dual-mode strain sensor is presented that offers enhanced ML sensing and reliable electrical sensing simultaneously. The strain sensor is fabricated via an optimized dip-coating method, featuring a sandwich structure with a single-walled carbon nanotube (SWNT) interlayer and two polydimethylsiloxane (PDMS)/ZnS:Cu luminescence layers. The integral mechanical reinforcement framework provided by the SWNT interlayer improves the ML intensity of the SWNT/PDMS/ZnS:Cu composite film. Compared to conventional nanoparticle fillers, the ML intensity is enhanced nearly tenfold with a trace amount of SWNT (only 0.01wt.%). In addition, the excellent electrical conductivity of SWNT forms a conductive network, ensuring continuous and stable electrical sensing. These strain sensors enable comprehensive and precise monitoring of human behavior through both electrical (relative resistance change) and optical (ML intensity) methods, paving the way for the development of advanced visual sensing and smart wearable electronics in the future.

Spike desensitisation as a mechanism for high-contrast selectivity in retinal ganglion cells.

In the vertebrate retina, several dozens of parallel channels relay information about the visual world to the brain. These channels are represented by the different types of retinal ganglion cells (RGCs), whose responses are rendered selective for distinct sets of visual features by various mechanisms. These mechanisms can be roughly grouped into synaptic interactions and cell-intrinsic mechanisms, with the latter including dendritic morphology as well as ion channel complement and distribution. Here, we investigate how strongly ion channel complement can shape RGC output by comparing two mouse RGC types, the well-described ON alpha cell and a little-studied ON cell that is EGFP-labelled in the Igfbp5 mouse line and displays an unusual selectivity for stimuli with high contrast. Using patch-clamp recordings and computational modelling, we show that a higher activation threshold and a pronounced slow inactivation of the voltage-gated Na+ channels contribute to the distinct contrast tuning and transient responses in ON Igfbp5 RGCs, respectively. In contrast, such a mechanism could not be observed in ON alpha cells. This study provides an example for the powerful role that the last stage of retinal processing can play in shaping RGC responses.

Chromatic pupillometry for evaluating melanopsin retinal ganglion cell function in Alzheimer's disease and other neurodegenerative disorders: a review.

The evaluation of pupillary light reflex (PLR) by chromatic pupillometry may provide a unique insight into specific photoreceptor functions. Chromatic pupillometry refers to evaluating PLR to different wavelengths and intensities of light in order to differentiate outer/inner retinal photoreceptor contributions to the PLR. Different protocols have been tested and are now established to assess in-vivo PLR contribution mediated by melanopsin retinal ganglion cells (mRGCs). These intrinsically photosensitive photoreceptors modulate the non-image-forming functions of the eye, which are mainly the circadian photoentrainment and PLR, via projections to the hypothalamic suprachiasmatic and olivary pretectal nucleus, respectively. In this context, chromatic pupillometry has been used as an alternative and non-invasive tool to evaluate the mRGC system in several clinical settings, including hereditary optic neuropathies, glaucoma, and neurodegenerative disorders such as Parkinson's disease (PD), idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD), and Alzheimer's disease (AD). The purpose of this article is to review the key steps of chromatic pupillometry protocols for studying in-vivo mRGC-system functionality and provide the main findings of this technique in the research setting on neurodegeneration. mRGC-dependent pupillary responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower and sustained compared with rod- and cone-mediated responses, driving the tonic component of the PLR during exposure to high-irradiance and continuous light stimulus. Thus, mRGCs contribute mainly to the tonic component of the post-illumination pupil response (PIPR) to bright blue light flash that persists after light stimulation is switched off. Given the role of mRGCs in circadian photoentrainment, the use of chromatic pupillometry to perform a functional evaluation of mRGcs may be proposed as an early biomarker of mRGC-dysfunction in neurodegenerative disorders characterized by circadian and/or sleep dysfunction such as AD, PD, and its prodromal phase iRBD. The evaluation by chromatic pupillometry of mRGC-system functionality may lay the groundwork for a new, easily accessible biomarker that can be exploited also as the starting point for future longitudinal cohort studies aimed at stratifying the risk of conversion in these disorders.

Stretch response of the mechano-gated channel TMEM63A in membrane patches and single cells.

The recently discovered ion channel TMEM63A has biophysical features distinctive for mechano-gated cation channels, activating at high pressures with slow kinetics while not inactivating. However, some biophysical properties are less clear, including no information on its function in whole cells. The aim of this study is to expand the TMEM63A biophysical characterization and examine the function in whole cells. Piezo1-knockout HEK293T cells were cotransfected with human TMEM63A and green fluorescent protein (GFP), and macroscopic currents in cell-attached patches were recorded by high-speed pressure clamp at holding voltages from -120 to -20 mV with 0-100 mmHg patch suction for 1 s. HEK293 cells cotransfected with TMEM63A and GCaMP5 were seeded onto polydimethylsiloxane (PDMS) membrane, and the response to 3-12 s of 1%-15% whole cell isotropic (equi-biaxial) stretch induced by an IsoStretcher was measured by the change in intracellular calcium ([Ca2+]i) and presented as (ΔF/F0 > 1). Increasing patch pressures activated TMEM63A currents with accelerating activation kinetics and current amplitudes that were pressure dependent but voltage independent. TMEM63A currents were plateaued within 2 s, recovered quickly, and were sensitive to Gd3+. In whole cells stretched on flexible membranes, radial stretch increased the [Ca2+]i responses in a larger proportion of cells cotransfected with TMEM63A and GCaMP5 than GCaMP5-only controls. TMEM63A currents are force activated and voltage insensitive, have a high threshold for pressure activation with slow activation and deactivation, and lack inactivation over 5 s. TMEM63A has the net polarity and kinetics that would depolarize plasma membranes and increase inward currents, contributing to a sustained [Ca2+]i increase in response to high stretch.NEW & NOTEWORTHY TMEM63A has biophysical features distinctive for mechano-gated cation channels, but some properties are less clear, including no functional information in whole cells. We report that pressure-dependent yet voltage-independent TMEM63A currents in cell membrane patches correlated with cell size. In addition, radial stretch of whole cells on flexible membranes increased the [Ca2+]i responses more in TMEM63A-transfected cells. Inward TMEM63A currents in response to high stretch can depolarize plasma membranes and contribute to a sustained [Ca2+]i increase.

Modulation of transcription factor dynamics allows versatile information transmission

Cells detect changes in their environment and generate responses, often involving changes in gene expression. In this paper we use information theory and a simple transcription model to analyze whether the resulting gene expression serves to identify extracellular stimuli and assess their intensity when they are encoded in the amplitude, duration or frequency of pulses of a transcription factor’s nuclear concentration (or activation state). We find, for all cases, that about three ranges of input strengths can be distinguished and that maximum information transmission occurs for fast and high activation threshold promoters. The three input modulation modes differ in the sensitivity to changes in the promoters parameters. Frequency modulation is the most sensitive and duration modulation, the least. This is key for signal identification: there are promoter parameters that yield a relatively high information transmission for duration or amplitude modulation and a much smaller value for frequency modulation. The reverse situation cannot be found with a single promoter transcription model. Thus, pulses of transcription factors can selectively activate the “frequency-tuned” promoter while prolonged nuclear accumulation would activate promoters of all three modes simultaneously. Frequency modulation is therefore highly selective and better suited than the other encoding modes for signal identification without requiring other mediators of the transduction process.

Optimized M24B Aminopeptidase Inhibitors for CARD8 Inflammasome Activation.

Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. NLRP1 and CARD8 are related human inflammasomes that detect similar danger signals, but NLRP1 has a higher activation threshold and triggers a more inflammatory form of pyroptosis. Both sense the accumulation of intracellular peptides with Xaa-Pro N-termini, but Xaa-Pro peptides on their own without a second danger signal only activate the CARD8 inflammasome. We recently reported that a dual inhibitor of the Xaa-Pro-cleaving M24B aminopeptidases PEPD and XPNPEP1 called CQ31 selectively activates the CARD8 inflammasome by inducing the build-up of Xaa-Pro peptides. Here, we performed structure-activity relationship studies on CQ31 to develop the optimized dual PEPD/XPNPEP1 inhibitor CQ80 that more effectively induces CARD8 inflammasome activation. We anticipate that CQ80 will become a valuable tool to study the basic biology and therapeutic potential of selective CARD8 inflammasome activation.

P2X2 receptor subunit interfaces are missense variant hotspots, where mutations tend to increase apparent ATP affinity.

Background and PurposeP2X receptors are trimeric ligand‐gated ion channels that open a cation‐selective pore in response to ATP binding to their large extracellular domain. The seven known P2X subtypes can assemble as homotrimeric or heterotrimeric complexes and contribute to numerous physiological functions, including nociception, inflammation and hearing. The overall structure of P2X receptors is well established, but little is known about the range and prevalence of human genetic variations and the functional implications of specific domains.Experimental ApproachHere, we examine the impact of P2X2 receptor inter‐subunit interface missense variants identified in the human population or by structural predictions. We test both single and double mutants through electrophysiological and biochemical approaches.Key ResultsWe demonstrate that predicted extracellular domain inter‐subunit interfaces display a higher‐than‐expected density of missense variations and that the majority of mutations that disrupt putative inter‐subunit interactions result in channels with higher apparent ATP affinity. Lastly, we show that double mutants at the subunit interface show significant energetic coupling, especially if located in close proximity.Conclusion and ImplicationsWe provide the first structural mapping of the mutational distribution across the human population in a ligand‐gated ion channel and show that the density of missense mutations is constrained between protein domains, indicating evolutionary selection at the domain level. Our data may indicate that, unlike other ligand‐gated ion channels, P2X2 receptors have evolved an intrinsically high threshold for activation, possibly to allow for additional modulation or as a cellular protection mechanism against overstimulation.

Defective Allelic Exclusion by IgD in the Absence of Autoantigen.

A considerable proportion of peripheral B cells is autoreactive, and it is unclear how the activation of such potentially harmful cells is regulated. In this study, we show that the different activation thresholds or IgM and IgD BCRs adjust B cell activation to the diverse requirements during development. We rely on the autoreactive 3-83 model BCR to generate and analyze mice expressing exclusively autoreactive IgD BCRs on two different backgrounds that determine two stages of autoreactivity, depending on the presence or absence of the cognate Ag. By comparing these models with IgM-expressing control mice, we found that, compared with IgM, IgD has a higher activation threshold in vivo, as it requires autoantigen to enable normal B cell development, including allelic exclusion. Our data indicate that IgM provides the high sensitivity required during early developmental stages to trigger editing of any autoreactive specificities, including those enabling weak interaction with autoantigen. In contrast, IgD has the unique ability to neglect weakly interacting autoantigens while retaining reactivity to higher-affinity Ag. This IgD function enables mature B cells to ignore autoantigens while remaining able to efficiently respond to foreign threats.

Identification of a helix-turn-helix motif for high temperature dependence of vanilloid receptor TRPV2.

Pain and thermosensation rely on temperature-sensitive ion channels at peripheral nerve endings for transducing thermal cues into electrical signals. Members of the transient receptor potential (TRP) family are prominent candidates for temperature transducers in mammals. These thermal TRP channels possess an unprecedentedly steep temperature dependence, allowing them to discriminate small temperature variations. Thermodynamically, it is understood that the strong temperature sensitivity of the channel arises because opening of the channel undergoes reactions involving large enthalpy and entropy changes. However, the underlying molecular mechanisms have remained elusive. Here we investigated the molecular basis for heat activation of TRPV2, a thermal TRP channel in the vanilloid subfamily with the strongest temperature dependence among TRP channels. We unravel a minimum molecular region in the proximal N-terminus which dictates the slope temperature sensitivity of the channel. Structurally, the region comprises a helix-turn-helix motif and is positioned among the TRP helix from the C-terminus, the S2-S3 linker from the transmembrane domain and the ankyrin repeats from the distal N-terminus. Chimeric exchanges of the subregion alone sufficed to diminish the high temperature dependence in the wild-type TRPV2. Our results support a pivotal role for the structural assembly around the TRP domain in the gating of thermal TRP channels by temperature. The findings also shed insight into how the proximal N-terminal domain plays its role in the heat activation of vanilloid receptors. KEY POINTS: The vanilloid receptor subtype 2 (TRPV2) is a heat-sensitive transient receptor potential (TRP) channel with the strongest temperature dependence among thermal TRP channels. The channel also has a high temperature activation threshold above 50°C which has rendered it difficult to study by conventional patch-clamp methods. Here we utilize fast laser temperature jumps to address the challenges of technical accessibility and explore the molecular basis underlying the high temperature dependence of the channel. We unravel a short helix-turn-helix motif in the proximal N-terminus, which controls the heat activation profile of the channel. Chimeric exchanges of the subregion alone sufficed to diminish the high temperature dependence in the wild-type TRPV2. Our results provide insights on how the proximal N-terminal domain plays its role in the heat activation of vanilloid receptors.

Motor evoked potential latency and duration from tibialis anterior in individuals with chronic stroke.

Ipsilateral motor pathways from the contralesional hemisphere to the paretic limbs may be upregulated to compensate for impaired function after stroke. Onset latency and duration of motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS) provide insight into compensatory pathways but have been understudied in the lower limb. This study assessed MEP onset latency and duration in the lower limb after stroke, and compared ipsilateral and contralateral MEPs in the paretic and non-paretic limb. We hypothesized that: (1) onset latency would be longer for ipsilateral than contralateral MEPs and longer for the paretic than the non-paretic limb, and (2) duration would be shorter for ipsilateral than contralateral MEPs and longer for the paretic than the non-paretic limb. Data were collected as a part of a pre-test of a randomized controlled trial. TMS was applied to the ipsilateral and contralateral hemisphere of the paretic and non-paretic limb. MEP onset latency and duration were calculated from the tibialis anterior. Thirty-five participants with chronic stroke were included in the final analysis. Onset latency was longer in the paretic than the non-paretic limb (~ 6.0ms) and longer after ipsilateral than contralateral stimulation (~ 1.8ms). Duration was longer in the paretic than the non-paretic limb (~ 9.2ms) and longer after contralateral than ipsilateral stimulation (~ 5.2ms). Ipsilateral MEPs may be elicited through ipsilateral pathways with fewer fibers with a higher activation threshold and/or greater spinal branching. MEPs from the paretic limb may reflect slower central motor conduction, peripheral changes, or changes in motor pathway.

Production of Membrane-Filtered Phase-Shift Decafluorobutane Nanodroplets from Preformed Microbubbles.

There are many methods that can be used for the production of vaporizable phase-shift droplets for imaging and therapy. Each method utilizes different techniques and varies in price, materials, and purpose. Many of these fabrication methods result in polydisperse populations with non-uniform activation thresholds. Additionally, controlling the droplet sizes typically requires stable perfluorocarbon liquids with high activation thresholds that are not practical in vivo. Producing uniform droplet sizes using low-boiling point gases would be beneficial for in vivo imaging and therapy experiments. This article describes a simple and economical method for the formation of size-filtered lipid-stabilized phase-shift nanodroplets with low-boiling point decafluorobutane (DFB). A common method of generating lipid microbubbles is described, in addition to a novel method of condensing them with high-pressure extrusion in a single step. This method is designed to save time, maximize efficiency, and generate larger volumes of microbubble and nanodroplet solutions for a wide variety of applications using common laboratory equipment found in many biological laboratories.

Basal Ganglia-A Motion Perspective.

The basal ganglia represent an ancient part of the nervous system that have remained organized in a similar way over the last 500 million years and are of importance for our ability to determine which actions to choose at any given moment in time. Salient or reward stimuli act via the dopamine system and contribute to motor or procedural learning (reinforcement learning). The input stage of the basal ganglia, the striatum, is shaped by glutamatergic input from the cortex and thalamus and by the dopamine system. All intrinsic neurons of the striatum are GABAergic and inhibitory except for the cholinergic interneurons. Too little dopamine and all vertebrates show symptoms similar to that of a Parkinsonian patient, whereas too much dopamine results in hyperkinesia with involuntary movements. In this article, we discuss the detailed organization of the basal ganglia, with the different cell types, their properties, and contributions to basal ganglia functions. The striatal projection neurons represent 95% of all neurons in the striatum and are subdivided into two types, one that projects directly to the output stage, referred to as the "direct" pathway that promotes action, and the other subtype that targets the output nuclei via intercalated basal ganglia nuclei. This "indirect" pathway has an opposite effect. The striatal projection neurons express a set of ion channels that give them a high threshold for activation, whereas neurons in all other parts of the basal ganglia have a resting discharge that allows for modulation in both an increased and decreased direction. © 2020 American Physiological Society. Compr Physiol 10:1241-1275, 2020.

Intestinal intraepithelial lymphocytes: Maintainers of intestinal immune tolerance and regulators of intestinal immunity.

Intestinal immune tolerance is essential for the immune system, as it prevents abnormal immune responses to large quantities of antigens from the intestinal lumen, such as antigens from commensal microorganisms, and avoids self‐injury. Intestinal intraepithelial lymphocytes (IELs), a special group of mucosal T lymphocytes, play a significant role in intestinal immune tolerance. To accomplish this, IELs exhibit a high threshold of activation and low reactivity to most antigens from the intestinal lumen. In particular, CD8αα+TCRαβ+ IELs, TCRγδ+ IELs, and CD4+CD8αα+ IELs show great potential for maintaining intestinal immune tolerance and regulating intestinal immunity. However, if the intestinal microenvironment becomes abnormal or intestinal tolerance is broken, IELs may be activated abnormally and become pathogenic.

MiR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived Dendritic Cells

DC-SIGN+ monocyte-derived dendritic cells (mo-DCs) play important roles in bacterial infections and inflammatory diseases, but the factors regulating their differentiation and proinflammatory status remain poorly defined. Here, we identify a microRNA, miR-181a, and a molecular mechanism that simultaneously regulate the acquisition of DC-SIGN expression and the activation state of DC-SIGN+ mo-DCs. Specifically, we show that miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation and limits its sensitivity and responsiveness to TLR triggering and CD40 ligation. Mechanistically, miR-181a sustains ERK-MAPK signaling in mo-DCs, thereby enabling the maintenance of high levels of DC-SIGN and a high activation threshold. Low miR-181a levels during mo-DC differentiation, induced by inflammatory signals, do not support the high phospho-ERK signal transduction required for DC-SIGNhi mo-DCs and lead to development of proinflammatory DC-SIGNlo/- mo-DCs. Collectively, our study demonstrates that high DC-SIGN expression levels and a high activation threshold in mo-DCs are linked and simultaneously maintained by miR-181a.

Motivational salience, impulsivity and testosterone in free cycling women: An ERP-Study

Impulsivity is regarded as a personality dimension that is associated with fast acting without always thinking of its consequences. Whereas it has been associated with a lot of pathologies, its neural associations and in which way these are related to motivational- and incentive salience, are far from being clear. Furthermore, sex differences suggest some associations with different reactivity across the menstrual cycle in women, hinting to possible hormonal influences. 35 free cycling women were tested in a randomized within-subject design across three cycle-phases, recording an EEG during an Picture-Stroop-Paradigm, measuring gonadal hormones (estradiol, progesterone, testosterone), as well as assessing impulsivity with the Multidimensional Personality Questionnaire. It was hypothesized that reactivity towards highly salient pictures, indicated by the event related potentials P300 and the late positive potential (LPP), to be differing in dependence of impulsivity. Results reveal associations of high impulsivity with generally lower P300-amplitudes, blunted LPP-responses towards erotic pictures, as well as lower mean testosterone concentrations in female subjects. This is especially interesting in the context of motivational salience and might be indicating a higher threshold of activation needed in high impulsive individuals - being in line with clinical observations with associations of addictions and other disorders.

Chromatic Pupillometry Methods for Assessing Photoreceptor Health in Retinal and Optic Nerve Diseases.

The pupillary light reflex is mediated by melanopsin-containing intrinsically-photosensitive retinal ganglion cells (ipRGCs), which also receive input from rods and cones. Melanopsin-dependent pupillary light responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower to activate and de-activate compared with rod/cone-mediated responses. Given that rod/cone photoreceptors and melanopsin differ in their response properties, light stimuli can be designed to stimulate preferentially each of the different photoreceptor types, providing a read-out of their function. This has given rise to chromatic pupillometry methods that aim to assess the health of outer retinal photoreceptors and ipRGCs by measuring pupillary responses to blue or red light stimuli. Here, we review different types of chromatic pupillometry protocols that have been tested in patients with retinal or optic nerve disease, including approaches that use short-duration light exposures or continuous exposure to light. Across different protocols, patients with outer retinal disease (e.g., retinitis pigmentosa or Leber congenital amaurosis) show reduced or absent pupillary responses to dim blue-light stimuli used to assess rod function, and reduced responses to moderately-bright red-light stimuli used to assess cone function. By comparison, patients with optic nerve disease (e.g., glaucoma or ischemic optic neuropathy, but not mitochondrial disease) show impaired pupillary responses during continuous exposure to bright blue-light stimuli, and a reduced post-illumination pupillary response after light offset, used to assess melanopsin function. These proof-of-concept studies demonstrate that chromatic pupillometry methods can be used to assess damage to rod/cone photoreceptors and ipRGCs. In future studies, it will be important to determine whether chromatic pupillometry methods can be used for screening and early detection of retinal and optic nerve diseases. Such methods may also prove useful for objectively evaluating the degree of recovery to ipRGC function in blind patients who undergo gene therapy or other treatments to restore vision.

Study of the Characteristics of Elementary Processes in a Chain Hydrogen Burning Reaction in Oxygen

The characteristics of possible chain explosive hydrogen burning reactions in an oxidizing medium are calculated on the potential energy surface. Specifically, reactions H2 + O2 → H2O + O, H2 + O2 → HO2 + H, and H2 + O2 → OH + OH are considered. Special attention is devoted to the production of a pair of fast highly reactive OH radicals. Because of the high activation threshold, this reaction is often excluded from the known kinetic scheme of hydrogen burning. However, a spread in estimates of kinetic characteristics and a disagreement between theoretical predictions with experimental results suggest that the kinetic scheme should be refined.

Vibration control with a bistale nonlinear absorber

The goal of our research is to develop a nonlinear absorber that will be effective at low frequencies and low amplitudes of vibration, notably in the domain of vibroacoustics. From this perspective, the usual Nonlinear Energy Sinks (NESs) based on the idea of the internal resonance have certain limitations due to the relatively high activation threshold. In order to decrease this threshold we developed the idea of a bistable absorber. The bistability provides a chaotic regime in the absorber dynamics that leads to effective dissipation by the NES. While this energy transfer is completely different from the well-known energy pumping, the two types share the main features such as the activation threshold and the functioning region. The bistable NES that we propose consists of a clamped-clamped buckled beam and an attached mass. The experimental and numerical tests performed for our particular realization of a bistable absorber have shown its high efficiency and robustness.

Kv3.1 uses a timely resurgent K(+) current to secure action potential repolarization.

High-frequency action potential (AP) transmission is essential for rapid information processing in the central nervous system. Voltage-dependent Kv3 channels play an important role in this process thanks to their high activation threshold and fast closure kinetics, which reduce the neuron's refractory period. However, premature Kv3 channel closure leads to incomplete membrane repolarization, preventing sustainable AP propagation. Here, we demonstrate that Kv3.1b channels solve this problem by producing resurgent K+ currents during repolarization, thus ensuring enough repolarizing power to terminate each AP. Unlike previously described resurgent Na+ and K+ currents, Kv3.1b's resurgent current does not originate from recovery of channel block or inactivation but results from a unique combination of steep voltage-dependent gating kinetics and ultra-fast voltage-sensor relaxation. These distinct properties are readily transferrable onto an orthologue Kv channel by transplanting the voltage-sensor's S3–S4 loop, providing molecular insights into the mechanism by which Kv3 channels contribute to high-frequency AP transmission.