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Voltage-gated sodium channels (VGSCs) initiate action potentials in electrically excitable cells and tissues. Surprisingly, some VGSC genes are aberrantly expressed in a variety of cancers, derived from "non-excitable" tissues that do not generate classic action potentials, showing potential as a promising pharmacological target for cancer. Most of the previous review articles on this topic are limited in scope, and largely unable to provide researchers with a comprehensive understanding of the role of VGSC in cancers. Here, we review the expression patterns of all nine VGSC α-subunit genes (SCN1A-11A) and their four regulatory β-subunit genes (SCN1B-4B). We reviewed data from the Cancer Genome Atlas (TCGA) database, complemented by an extensive search of the published papers. We summarized and reviewed previous independent studies and analyzed the VGSC genes in the TCGA database regarding the potential impact of VGSC on cancers. A comparison between evidence gathered from independent studies and data review was performed to scrutinize potential biases in prior research and provide insights into future research directions. The review supports the view that VGSCs play an important role in diagnostics as well as therapeutics of some cancer types, such as breast, colon, prostate, and lung cancer. This paper provides an overview of the current knowledge on voltage-gated sodium channels in cancer, as well as potential avenues for further research. While further research is required to fully understand the role of VGSCs in cancer, the potential of VGSCs for clinical diagnosis and treatment is promising. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignant primary brain cancer that, despite recent advances in the understanding of its pathogenesis, remains incurable. GBM contains a subpopulation of cells with stem cell-like properties called cancer stem cells (CSCs). Several studies have demonstrated that CSCs are resistant to conventional chemotherapy and radiation thus representing important targets for novel anti-cancer therapies. Proton sensing receptors expressed by CSCs could represent important factors involved in the adaptation of tumours to the extracellular environment. Accordingly, the expression of acid-sensing ion channels (ASICs), proton-gated sodium channels mainly expressed in the neurons of peripheral (PNS) and central nervous system (CNS), has been demonstrated in several tumours and linked to an increase in cell migration and proliferation. In this paper we report that the ASIC3 isoform, usually absent in the CNS and present in the PNS, is enriched in human GBM CSCs while poorly expressed in the healthy human brain. We propose here a novel therapeutic strategy based on the pharmacological activation of ASIC3, which induces a significant GBM CSCs damage while being non-toxic for neurons. This approach might offer a promising and appealing new translational pathway for the treatment of glioblastoma. [ABSTRACT FROM AUTHOR]

The article features an interview with M. H. D. Fouad Zakaria, the first author of a paper on the role of NaV1.1 in regulating the cell cycle of human mesenchymal stem cells. Zakaria, a PhD student at Kyushu University, discusses his research findings and the significance of his work in cell biology. He credits his mentor, Hiroki Kato, for his scientific development and shares his motivation for pursuing a career in science to impact medical science on a broader scale. Zakaria will continue his research as an assistant professor at Kyushu University Graduate School of Dental Science in Japan. [Extracted from the article]

The transitional epithelial cells (urothelium) that line the lumen of the urinary bladder form a barrier between potentially harmful pathogens, toxins, and other bladder contents and the inner layers of the bladder wall. The urothelium, however, is not simply a passive barrier, as it can produce signaling factors, such as ATP, nitric oxide, prostaglandins, and other prostanoids, that can modulate bladder function. We investigated whether substances produced by the urothelium could directly modulate the contractility of the underlying urinary bladder smooth muscle. Force was measured in isolated strips of mouse urinary bladder with the urothelium intact or denuded. Bladder strips developed spontaneous tone and phasic contractions. In urothelium-intact strips, basal tone, as well as the frequency and amplitude of phasic contractions, were 25%, 32%, and 338% higher than in urothelium-denuded strips, respectively. Basal tone and phasic contractility in urothelium-intact bladder strips were abolished by the cyclooxygenase (COX) inhibitor indomethacin (10 µM) or the voltage-dependent Ca2+ channel blocker diltiazem (50 µM), whereas blocking neuronal sodium channels with tetrodotoxin (1 µM) had no effect. These results suggest that prostanoids produced in the urothelium enhance smooth muscle tone and phasic contractions by activating voltage-dependent Ca2+ channels in the underlying bladder smooth muscle. We went on to demonstrate that blocking COX inhibits the generation of transient pressure events in isolated pressurized bladders and greatly attenuates the afferent nerve activity during bladder filling, suggesting that urothelial prostanoids may also play a role in sensory nerve signaling. NEW & NOTEWORTHY: This paper provides evidence for the role of urothelial-derived prostanoids in maintaining tone in the urinary bladder during bladder filling, not only underscoring the role of the urothelium as more than a barrier but also contributing to active regulation of the urinary bladder. Furthermore, cyclooxygenase products greatly augment sensory nerve activity generated by bladder afferents during bladder filling and thus may play a role in perception of bladder fullness. [ABSTRACT FROM AUTHOR]

A sodium current (INa) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on INa in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on INa and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak INa of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Nav1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak INa density, or the INa voltage dependence of (in)activation. Importantly, the increase in the peak INa density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases INa density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore INa and cardiac conduction. [ABSTRACT FROM AUTHOR]

An optimised approach is presented in this study for the fabrication of a polymer-dispersed liquid crystal (PDLC) device with a low driving voltage and high contrast ratio (CR). This method involves a two-step process utilising Michael addition and radical polymerisation, employing a reaction-selective orthogonal photoinitiated system. The impact of incorporating low surface energy monomers on PDLC performance is thoroughly investigated, and the driving voltage is further reduced through selective reaction-induced interface modification. The polymer morphology can be finely tuned by adjusting the thiol content, leading to various PDLC properties. This paper introduces a novel surface modification technique within the polymer-liquid crystal system, presenting a fresh perspective on regulating PDLC performance. By choosing monomer structures, the sequence of reactions can be precisely controlled, allowing for the introduction of structural units with distinct functionalities at the polymer interface. This approach facilitates interfacial functionalization and enables the design of multi-layer structures for synthetic polymers, realising innovative functionalities. [ABSTRACT FROM AUTHOR]

Phantom Limb Syndrome (PLS) can be defined as the disabling or painful sensation of the presence of a body part that is no longer present after its amputation. Anatomical changes involved in Phantom Limb Syndrome, occurring at peripheral, spinal and brain levels and include the formation of neuromas and scars, dorsal horn sensitization and plasticity, short-term and long-term modifications at molecular and topographical levels. The molecular reorganization processes of Phantom Limb Syndrome include NMDA receptors hyperactivation in the dorsal horn of the spinal column leading to inflammatory mechanisms both at a peripheral and central level. At the brain level, a central role has been recognized for sodium channels, BDNF and adenosine triphosphate receptors. In the paper we discuss current available pharmacological options with a final overview on non-pharmacological options in the pipeline. [ABSTRACT FROM AUTHOR]

The volume and composition of airway surface liquid (ASL) is regulated by liquid secretion and absorption across airway epithelia, controlling the pH, solute concentration, and biophysical properties of ASL in health and disease. Here, we developed a method integrating explanted tracheal tissue with a micro-machined device (referred to as "ex vivo trachea-chip") to study the dynamic properties of ASL volume regulation. The ex vivo trachea-chip allows real-time measurement of ASL transport (Jv) with intact airway anatomic structures, environmental control, high-resolution, and enhanced experimental throughput. Applying this technology to freshly excised tissue we observed ASL absorption under basal conditions. The apical application of amiloride, an inhibitor of airway epithelial sodium channels (ENaC), reduced airway liquid absorption. Furthermore, the basolateral addition of NPPB, a Cl-channel inhibitor, reduced the basal rate of ASL absorption, implicating a role for basolateral Cl- channels in ASL volume regulation. When tissues were treated with apical amiloride and basolateral methacholine, a cholinergic agonist that stimulates secretion from airway submucosal glands, the net airway surface liquid production shifted from absorption to secretion. This ex vivo trachea-chip provides a new tool to investigate ASL transport dynamics in pulmonary disease states and may aid the development of new therapies targeting ASL regulation. [ABSTRACT FROM AUTHOR]

[Display omitted] • The internal channels of the crystal structure are extended by the introduction of larger radius Ce3+, which increases the transport rate of Na+. • The introduction of Mo6+ replacing the V site leads to a beneficial n -type doping effect and facilitates the transportation of electrons. • CeO 2 functions as an n -type semiconductor and a conductive additive to significantly enhance the electrical conductivity. • CeO 2 acts as an oxygen buffer, aiding in the preservation of active metal dispersion during operation and facilitating efficient electron transfer between CeO 2 and [VO 6 ]. • CeMo0.07@8wt.%CeO 2 sample has excellent sodium storage performance at both half and asymmetric full cells. Na 3 V 2 (PO 4) 3 (NVP) is highly valued based on the stable construction among the polyanionic compounds. Nevertheless, the drawback of low intrinsic conductivity has been impeded its further application. In this paper, the internal channels of the crystal structure are extended by the introduction of larger radius Ce3+, which increases the transport rate of Na+. The introduction of Mo6+ replacing the V site leads to a beneficial n -type doping effect and facilitates the transportation of electrons. Besides, CeO 2 cladding is introduced to further enhance the electronic conductivity of NVP system. Initially, CeO 2 serves as an n -type semiconductor and functions as a conductive additive to significantly enhance the electronic conductivity of the electrode, thereby improving the electrochemical characteristics. Moreover, CeO 2 functions as an oxygen buffer, aiding in the maintenance of active metal dispersion during operation and enabling efficient electron transfer between CeO 2 and [VO 6 ] octahedra in NVP, thus fostering outstanding electrical connectivity between the oxides. CeO 2 cladding can be effectively integrated with the carbon layer to stabilize the NVP system. Comprehensively, the modified Na 3 V 1.79 Ce 0.07 Mo 0.07 (PO 4) 3 /C@8wt.%CeO 2 (CeMo0.07@8wt.%CeO 2) composite exhibits excellent rate and cycling properties. It delivers a capacity of 113.4 mAh/g at 1C with a capacity retention rate of 80.3 % after 150 cycles. Even at 10C and 40C, it also submits high capacities of 84.7 mAh/g and 76 mAh/g, respectively. Furthermore, the CHC//CeMo0.07@8wt.%CeO 2 asymmetric full cell possesses excellent sodium storage property, indicating its prospective application potentials. [ABSTRACT FROM AUTHOR]

This document is an editorial from the International Journal of Molecular Sciences that highlights various research articles related to ion channels as a therapeutic target. The articles cover topics such as the synthesis of compounds for GluK Kainate receptors, the role of sodium channels in heart pathologies, the involvement of calcium channels in chondrogenic differentiation, the study of transient receptor potential vanilloid subtype 3 in calcium homeostasis, the connection between potassium channels and cancer metabolism, and the use of computational approaches in studying ion channels. The authors provide a summary of each article and emphasize the contributions made by the researchers in their respective fields. [Extracted from the article]

Microglia, the primary immune cells in the central nervous system, play a critical role in regulating neuronal function and fate through their interaction with neurons. Despite extensive research, the specific functions and mechanisms of microglia-neuron interactions remain incompletely understood. In this study, we demonstrate that microglia establish direct contact with myelinated axons at Nodes of Ranvier in the spinal cord of mice. The contact associated with neuronal activity occurs in a random scanning pattern. In response to axonal injury, microglia rapidly transform their contact into a robust wrapping form, preventing acute axonal degeneration from extending beyond the nodes. This wrapping behavior is dependent on the function of microglial P2Y12 receptors, which may be activated by ATP released through axonal volume-activated anion channels at the nodes. Additionally, voltage-gated sodium channels (NaV) and two-pore-domain potassium (K2P) channels contribute to the interaction between nodes and glial cells following injury, and inhibition of NaV delays axonal degeneration. Through in vivo imaging, our findings reveal a neuroprotective role of microglia during the acute phase of single spinal cord axon injury, achieved through neuron-glia interaction. The mechanisms underlying microglia-neuron interactions are incompletely understood. Utilizing in vivo multimodal microscopy and optical clearing technology, here the authors show a distinct neuroprotective function of microglia during the acute phase of a single spinal cord axon injury. [ABSTRACT FROM AUTHOR]

Background: The Anopheles Hyrcanus group, which transmits Plasmodium vivax, consists of six confirmed species in South Korea. An epidemiological study revealed differences in the seasonal occurrence patterns of each species. Pyrethroid resistance in An. sinensis dates back to the early 2000s, whereas information on pyrethroid resistance in other species is lacking despite their greater significance in malaria epidemiology. Methods: Anopheles mosquitoes were collected from two malaria-endemic regions in South Korea for 2 years and their knockdown resistance (kdr) mutations were genotyped. The larval susceptibility to λ-cyhalothrin was compared in six Anopheles species and its seasonal changes in three species were investigated. The full-length sequences of the voltage-sensitive sodium channel (VSSC) were compared across six species to evaluate potential target-site insensitivity. The contribution of the kdr mutation to phenotypic resistance was confirmed by comparing median lethal time (LT50) to λ-cyhalothrin between populations of Anopheles belenrae with distinct genotypes. Results: The composition and seasonal occurrence of rare species (Anopheles kleini, Anopheles lestri, and Anopheles sineroides) varied considerably, whereas An. sinensis occurs continuously throughout the season. A kdr mutation in the form of heterozygous allele was newly identified in An. belenrae, An. lesteri, An. pullus, and An. sineroides. The baseline susceptibility to λ-cyhalothrin was the highest in An. belenrae, followed by An. lesteri, An. sineroides, An. kleini, An. pullus, and An. sinensis, with median lethal concentration (LC50) values ranging from 6.0- to 73.5-fold higher than that of An. belenrae. The susceptibility of An. sinensis and An. pullus varied by season, whereas that of An. belenrae remained stable. The kdr-heterozygous An. belenare population exhibited 5.1 times higher LT50 than that of the susceptible population. Species-specific VSSC sequence differences were observed among the six species. Conclusions: Our findings suggest that the status and extent of pyrethroid resistance vary among Anopheles Hyrcanus group species. While An. sinensis, the predominant species, developed a considerable level of pyrethroid resistance through kdr mutation, the resistance levels of other species appeared to be less pronounced. Large-scale monitoring is crucial to fully understand species-specific seasonal occurrence and resistance status for effective management strategies, considering the ongoing impact of climate change on their vectorial capacity. [ABSTRACT FROM AUTHOR]

Non-excitable cells express sodium voltage-gated channel alpha subunit 1 gene and protein (known as SCN1A and NaV 1.1, respectively); however, the functions of NaV 1.1 are unclear. In this study, we investigated the role of SCN1A and NaV 1.1 in human mesenchymal stem cells (MSCs). We found that SCN1A was expressed in MSCs, and abundant expression of NaV 1.1 was observed in the endoplasmic reticulum; however, this expression was not found to be related to Na+ currents. SCN1A-silencing reduced MSC proliferation and delayed the cell cycle in the S phase. SCN1A silencing also suppressed the protein levels of CDK2 and AKT (herein referring to total AKT), despite similar mRNA expression, and inhibited AKT phosphorylation in MSCs. A cycloheximide-chase assay showed that SCN1A-silencing induced CDK2 but not AKT protein degradation in MSCs. A proteolysis inhibition assay using epoxomicin, bafilomycin A1 and NH4 Cl revealed that both the ubiquitin–proteasome system and the autophagy and endo- lysosome system were irrelevant to CDK2 and AKT protein reduction in SCN1A-silenced MSCs. The AKT inhibitor LY294002 did not affect the degradation and nuclear localization of CDK2 in MSCs. Likewise, the AKT activator SC79 did not attenuate the SCN1A-silencing effects on CDK2 in MSCs. These results suggest that NaV 1.1 contributes to the cell cycle of MSCs by regulating the post-translational control of AKT and CDK2. [ABSTRACT FROM AUTHOR]

Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na+ conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing. The authors here present a high-resolution structure of riluzole bound to a voltage-gated sodium channel. This identifies an intramembranous drug-binding site allowing the potent riluzole-induced enhancement of channel inactivation, normalising the hyperexcitable cellular states found in ALS models. This supports riluzole repurposing and aids future drug design efforts. [ABSTRACT FROM AUTHOR]

The δ‐conotoxins, a class of peptides produced in the venom of cone snails, are of interest due to their ability to inhibit the inactivation of voltage‐gated sodium channels causing paralysis and other neurological responses, but difficulties in their isolation and synthesis have made structural characterization challenging. Taking advantage of recent breakthroughs in computational algorithms for structure prediction that have made modeling especially useful when experimental data is sparse, this work uses both the deep‐learning‐based algorithm AlphaFold and comparative modeling method RosettaCM to model and analyze 18 previously uncharacterized δ‐conotoxins derived from piscivorous, vermivorous, and molluscivorous cone snails. The models provide useful insights into the structural aspects of these peptides and suggest features likely to be significant in influencing their binding and different pharmacological activities against their targets, with implications for drug development. Additionally, the described protocol provides a roadmap for the modeling of similar disulfide‐rich peptides by these complementary methods. [ABSTRACT FROM AUTHOR]

Background: Intensive deployment of insecticide based malaria vector control tools resulted in the rapid evolution of phenotypes resistant to these chemicals. Understanding this process at the genomic level is important for the deployment of successful vector control interventions. Therefore, longitudinal sampling followed by whole genome sequencing (WGS) is necessary to understand how these evolutionary processes evolve over time. This study investigated the change in genetic structure and the evolution of the insecticide resistance variants in natural populations of Anopheles gambiae over time and space from 2012 to 2017 in Burkina Faso. Methods: New genomic data have been generated from An. gambiae mosquitoes collected from three villages in the western part of Burkina Faso between 2012 and 2017. The samples were whole-genome sequenced and the data used in the An. gambiae 1000 genomes (Ag1000G) project as part of the Vector Observatory. Genomic data were analysed using the analysis pipeline previously designed by the Ag1000G project. Results: The results showed similar and consistent nucleotide diversity and negative Tajima's D between An. gambiae sensu stricto (s.s.) and Anopheles coluzzii. Principal component analysis (PCA) and the fixation index (FST) showed a clear genetic structure in the An. gambiae sensu lato (s.l.) species. Genome-wide FST and H12 scans identified genomic regions under divergent selection that may have implications in the adaptation to ecological changes. Novel voltage-gated sodium channel pyrethroid resistance target-site alleles (V402L, I1527T) were identified at increasing frequencies alongside the established alleles (Vgsc-L995F, Vgsc-L995S and N1570Y) within the An. gambiae s.l. populations. Organophosphate metabolic resistance markers were also identified, at increasing frequencies, within the An. gambiae s.s. populations from 2012 to 2017, including the SNP Ace1-G280S and its associated duplication. Variants simultaneously identified in the same vector populations raise concerns about the long-term efficacy of new generation bed nets and the recently organophosphate pirimiphos-methyl indoor residual spraying in Burkina Faso. Conclusion: These findings highlighted the benefit of genomic surveillance of malaria vectors for the detection of new insecticide resistance variants, the monitoring of the existing resistance variants, and also to get insights into the evolutionary processes driving insecticide resistance. [ABSTRACT FROM AUTHOR]

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs. [ABSTRACT FROM AUTHOR]

Background/Objectives: Epilepsy is a brain disease with both environmental and genetic inputs. Ion channel dysfunction seems to be of great significance for abnormal neuronal behavior during epileptic seizures. Within neurons, the voltage-gated sodium channels are crucial proteins contributing to the initiation and propagation of action potentials. The voltage-gated sodium channel α subunit 1 (SCN1A) gene encodes for the α subunit of a voltage-gated ion channel. The aim of the study was to investigate the relation of two common SCN1A variants, i.e., rs3812718 and rs2298771, with distinct epileptic phenotypes in a South-Eastern European population. Methods: DNA was extracted from 214 unrelated participants with focal onset, focal to bilateral tonic–clonic, or generalized onset epileptic seizures and genotyped using real-time PCR (LightSNiP assays) followed by melting curve analysis. Statistical analysis of the results was performed using IBM SPSS Statistics software (version 29.0 for Windows). Results: Genotype frequency distribution analysis indicated an association for the A-allele-containing genotypes of both rs3812718 and rs2298771 polymorphisms of SCN1A with generalized onset seizures and focal to bilateral tonic–clonic seizures versus focal onset seizures. Conclusions: Consequently, the study provides evidence that supports a potential association of the investigated SCN1A polymorphisms with distinct seizure subtype susceptibility in South-Eastern Europeans. [ABSTRACT FROM AUTHOR]

Tetrodotoxin (TTX) is a potent neurotoxin firstly discovered in the ovary of pufferfish. The genetic basis of voltage-gated sodium channel resistance to TTX has been widely studied, but it remains unclear in the evolution history of voltage-gated sodium channel resistance to TTX in pufferfish with different TTX concentrations. In this study, six scn4aa coding sequences of pufferfish were firstly cloned and sequenced, then used to investigate the adaptive evolution of scn4aa associated with TTX concentration and reconstruct ancestral sequences with seven scn4aa of other fishes. The result of CODEML (codon substitution model) program from the PAML (phylogenetic analysis by maximum likelihood) package shows only in the genus of Takifugu, which contains TTX highly in the liver, under positive selection. The result also indicates that three of four positively selected sites are located in the intracellular regions, which may compensate for normal function. The ancestral sequence reconstruction may suggest that the replacements providing weak toxin resistance might have appeared first in scn4aa, then the genus Takifugu evolved stronger resistance to TTX later. These results contribute to the explanation of the evolutional history of voltage-gated sodium channel resistance to TTX in pufferfish. [ABSTRACT FROM AUTHOR]

Resistance to insecticides is one of the great challenges that vector control programs must face. The constant use of pyrethroid-type insecticides worldwide has caused selection pressure in populations of the Aedes aegypti vector, which has promoted the emergence of resistant populations. The resistance mechanism to pyrethroid insecticides most studied to date is target-site mutations that desensitize the voltage-gated sodium channel (VGSC) of the insect to the action of pyrethroids. In the present study, susceptibility to the pyrethroid insecticides permethrin, lambda-cyhalothrin, and deltamethrin was evaluated in fourteen populations from the department of Córdoba, Colombia. The CDC bottle bioassay and WHO tube methods were used. Additionally, the frequencies of the F1534C, V1016I, and V410L mutations were determined, and the association of resistance with the tri-locus haplotypes was examined. The results varied between the two techniques used, with resistance to permethrin observed in thirteen of the fourteen populations, resistance to lambda-cyhalothrin in two populations, and susceptibility to deltamethrin in all the populations under study with the CDC method. In contrast, the WHO method showed resistance to the three insecticides evaluated in all populations. The frequencies of the mutated alleles ranged from 0.05–0.43 for 1016I, 0.94–1.0 for 1534C, and 0.01–0.59 for 410L. The triple homozygous mutant CIL haplotype was associated with resistance to all three pyrethroids evaluated with the WHO bioassay, while with the CDC bioassay, it was only associated with resistance to permethrin. This study highlights the importance of implementing systematic monitoring of kdr mutations, allowing resistance management strategies to be dynamically adjusted to achieve effective control of Aedes aegypti. [ABSTRACT FROM AUTHOR]

Background: Pyrethroid chemicals are one of the main acaricides used against ticks. Resistance to these chemicals has been reported to be associated with mutations in the voltage-gated sodium channel (VGSC) gene of the Rhipicephalus microplus. This study investigates R. microplus resistance to pyrethroids in Guangxi region of China, marking one of the first research efforts in this area. The findings are intended to provide vital baseline for the effective implementation of localized tick control strategies. Methods: From March to July 2021, 447 R. microplus tick samples were collected from five prefecture-level cities in Guangxi. Allele-specific polymerase chain reaction (AS-PCR) was used to amplify segments C190A and G215T of the domain II S4-5 linker and T2134A of domain III S6 in the VGSC, to detect nucleotide mutations associated with resistance to pyrethroid acaricides. Subsequent analyses were conducted to ascertain the prevalence, types of mutations, and genotypic distributions within the sampled populations. Results: Mutations within VGSC gene were identified across all five studied populations of R. microplus, although the mutation rates remained generally low. Specifically, the most prevalent mutation was C190A, observed in 4.9% of the samples (22/447), followed by G215T at 4.0% (18/447), and T2134A at 1.3% (6/447). The distribution of mutations across three critical sites of the VGSC gene revealed four distinct mutation types: C190A, G215T, C190A + G215T, and T2134A. Notably, the single mutation C190A had the highest mutation frequency, accounting for 4.3%, and the C190A + G215T combination had the lowest, at only 0.7%. The analysis further identified seven genotypic combinations, with the wild-type combination C/C + G/G + T/T predominating at a frequency of 90.4%. Subsequently, the C/A + G/G + T/T combination was observed at a frequency of 4.3%, whereas the C/C + T/T + T/T combination exhibited the lowest frequency (0.2%). Additionally, no instances of simultaneous mutations at all three sites were detected. Geographical differences in mutation types were apparent. Both samples from Hechi to Chongzuo cities exhibited the same three mutation types; however, C190A was the most prevalent in Hechi, while G215T dominated in Chongzuo. In contrast, samples from Beihai to Guilin each exhibited only one mutation type: G215T occurred in 12.5% (4/32) of Beihai samples, and C190A in 7.5% (4/53) of Guilin samples. Conclusions: These findings underscore the relatively low frequency of VGSC gene mutations in R. microplus associated with pyrethroid resistance in the Guangxi, China. Moreover, the variation in mutation types and genotypic distributions across different locales highlights the need for regionalized strategies in monitoring and managing pyrethroid resistance in tick populations. This molecular surveillance is crucial for informing targeted control measures and mitigating the risk of widespread resistance emergence. [ABSTRACT FROM AUTHOR]

Slow brain rhythms, for example during slow-wave sleep or pathological conditions like seizures and spreading depolarization, can be accompanied by oscillations in extracellular potassium concentration. Such slow brain rhythms typically have a lower frequency than tonic action-potential firing. They are assumed to arise from network-level mechanisms, involving synaptic interactions and delays, or from intrinsically bursting neurons. Neuronal burst generation is commonly attributed to ion channels with slow kinetics. Here, we explore an alternative mechanism generically available to all neurons with class I excitability. It is based on the interplay of fast-spiking voltage dynamics with a one-dimensional slow dynamics of the extracellular potassium concentration, mediated by the activity of the Na+/K+-ATPase. We use bifurcation analysis of the complete system as well as the slow-fast method to reveal that this coupling suffices to generate a hysteresis loop organized around a bistable region that emerges from a saddle-node loop bifurcation–a common feature of class I excitable neurons. Depending on the strength of the Na+/K+-ATPase, bursts are generated from pump-induced shearing the bifurcation structure, spiking is tonic, or cells are silenced via depolarization block. We suggest that transitions between these dynamics can result from disturbances in extracellular potassium regulation, such as glial malfunction or hypoxia affecting the Na+/K+-ATPase activity. The identified minimal mechanistic model outlining the sodium-potassium pump's generic contribution to burst dynamics can, therefore, contribute to a better mechanistic understanding of pathologies such as epilepsy syndromes and, potentially, inform therapeutic strategies. Author summary: The brain can produce slow rhythms, such as those observed during sleep or epilepsy. These rhythms are much slower than the neuronal electrical signals, and their origins are still under debate. Mechanisms discussed so far are often based on the connection delays in neural networks or on neuronal ion channels with particularly slow kinetics. We show that neurons with specific spiking dynamics–allowing them to fire at arbitrarily low frequencies (so-called class I neurons) can produce slow rhythmic patterns without requiring synaptic connectivity or special ion channels. In these cells, slow rhythmic activity arises from the interplay of slow changes in extracellular potassium concentration and the cell's voltage dynamics, mediated by the Na+/K+-ATPase pump. The latter, found in all neurons, regulates the concentrations of sodium and potassium ions across the cell membrane. The core mechanism is not idiosyncratic, rather mathematical analysis shows under which conditions slow rhythmic activity can arise generically from the pump-based coupling in a broad class of neurons. We demonstrate that the pump is relevant for the creation of different firing patterns, some of which have been associated with pathologies of the brain. A better mechanistic understanding of these complex, concentration-dependent dynamics can therefore be relevant for therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Vector control based on indoor residual spraying (IRS) is one of the main components of the visceral leishmaniasis (VL) elimination programme in India. Dichlorodiphenyltrichloroethane (DDT) was used for IRS until 2015 and was later replaced by the synthetic pyrethroid alpha-cypermethrin. Both classes of insecticides share the same target site, the voltage-gated sodium channel (Vgsc). As high levels of resistance to DDT have been documented in the local sand fly vector, Phlebotomus argentipes, it is possible that mutations in the Vgsc gene could provide resistance to alpha-cypermethrin, affecting current IRS pyrethroid-based vector control. Methods: This study aimed to compare frequencies of knockdown resistance (kdr) mutations in Vgsc between two sprayed and two unsprayed villages in Bihar state, India, which had the highest VL burden of the four endemic states. Across four villages, 350 female P. argentipes were collected as part of a 2019 molecular xenomonitoring study. DNA was extracted and used for sequence analysis of the IIS6 fragment of the Vgsc gene to assess the presence of kdr mutations. Results: Mutations were identified at various positions, most frequently at codon 1014, a common site known to be associated with insecticide resistance in mosquitoes and sand flies. Significant inter-village variation was observed, with sand flies from Dharampur, an unsprayed village, showing a significantly higher proportion of wild-type alleles (55.8%) compared with the three other villages (8.5–14.3%). The allele differences observed across the four villages may result from selection pressure caused by previous exposure to DDT. Conclusions: While DDT resistance has been reported in Bihar, P. argentipes is still susceptible to pyrethroids. However, the presence of kdr mutations in sand flies could present a threat to IRS used for VL control in endemic villages in India. Continuous surveillance of vector bionomics and insecticide resistance, using bioassays and target genotyping, is required to inform India's vector control strategies and to ensure the VL elimination target is reached and sustained. [ABSTRACT FROM AUTHOR]

Loss-, gain-of-function and mixed variants in SCN1A (Nav1.1 voltage-gated sodium channel) have been associated with a spectrum of neurologic disorders with different severity and drug-responsiveness. Most SCN1A variants are heterozygous changes occurring de novo or dominantly inherited; recessive inheritance has been reported in a few cases. Here, we report a family in which the biallelic inheritance of two novel SCN1A variants, N935Y and H1393Q, occurs in two siblings presenting with drug-responsive developmental and epileptic encephalopathy and born to heterozygous asymptomatic parents. To assess the genotype–phenotype correlation and support the treatment choice, HEK 293 cells were transfected with different combinations of the SCN1A WT and mutant cDNAs, and the resulting sodium currents were recorded through whole-cell patch-clamp. Functional studies showed that the N935Y and H1393Q channels and their combinations with the WT (WT + N935Y and WT + H1393Q) had current densities and biophysical properties comparable with those of their respective control conditions. This explains the asymptomatic condition of the probands' parents. The co-expression of the N935Y + H1393Q channels, mimicking the recessive inheritance of the two variants in siblings, showed ~20% reduced current amplitude compared with WT and with parental channels. This mild loss of Nav1.1 function may contribute in part to the disease pathogenesis, although other mechanisms may be involved. [ABSTRACT FROM AUTHOR]

The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause–effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion. The methodology used here consisted of an initial assessment of a single chemical hazard using the Integrated Approach to Testing and Assessment (IATA) framework. An evidence‐based approach was then used to gather empirical evidence combining systematic literature review methods with expert knowledge to ensure the effectiveness of the AOP development methodology. The structured framework used assured transparency, objectivity and comprehensiveness, and included expert knowledge elicitation for the evaluation of key event relationships (KERs). This stepwise approach led to the development of an AOP that begins with binding of chemicals to Voltage Gate Sodium Channels (VGSC/Nav) during mammalian development leading to adverse consequences in neurodevelopment evidenced as deficits in cognitive functions. Disruption of the formation of precise neural circuits by alterations in VGSC kinetics during the perinatal stages of brain development may also underlie neurodevelopmental disorders. Gaps in our understanding include the specific critical developmental windows and the quantitative relationship of binding to VGSC and subsequent disruption and cognitive function. Despite the limited quantitative information at all KER levels, regulatory applications of this AOP for DNT assessment have been identified. [ABSTRACT FROM AUTHOR]

Dynamic wrinkle reduction continues to challenge aesthetic dermatology, predominantly addressed through Botulinumtoxin (Botox) injections. Despite Botox's robust efficacy with up to an 80% reduction in wrinkle visibility within just one week, its invasive administration and specific mechanism of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex inhibition prompt the exploration of safer, non-invasive alternatives. This review critically assesses recent innovations in non-invasive effects, with a focus on peptides and botanical extracts that exhibit a diverse array of mechanisms including SNARE complex inhibition, modulation of calcium and sodium channels, and interactions with acetylcholine receptors, contributing to their effectiveness in muscle relaxation on dynamic wrinkle approaches. Noteworthy peptides such as Argireline and SYN-Ake replicate the neuromodulatory effects of Botox, achieving up to a 52% reduction in wrinkles within four weeks without injections. Moreover, botanical extracts meet the rising demand for clean beauty solutions by enhancing skin elasticity and health through gentle yet potent mechanisms. However, the main concern with peptides is their low absorption rate, with only six clinical validations regarding Botox-like peptide anti-wrinkle efficacy available. These advancements not only deepen our understanding of cosmetic dermatology but also significantly influence market dynamics and consumer behavior, underscoring their pivotal role in redefining the future landscape of anti-aging effects. [ABSTRACT FROM AUTHOR]

Background: The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold. Results: Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib1 and xib13 with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib1 and xib13 increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib13 either originates from the common ancestor of pancrustaceans or earlier while xib1 is more restricted to remipedes. The ten-cysteine scaffolded xib2 emerged from xib1, a result that is supported by our phylogenetic and machine learning-based analyses. Conclusions: Our functional characterization of synthesized variants of xib1, xib2, and xib13 elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib2 with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib1 and xib13 activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib1, xib2, and xib13 requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib2 from xib1. Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms. [ABSTRACT FROM AUTHOR]

Constructing powerful anode/cathode interphases by modulate ion solvation structure is the principle of electrolyte design. However, the methodological and theoretical design principles of electrolyte/solvation structure and their effect on electrochemical performance are still vague. Here, we propose a cationic weakly coordinating-intervention strategy for modulating the Na+ solvation sheathes and constructing robust anode/cathode interphases in sodium-metal batteries. Unlike the local highly concentrated electrolytes, 1,2-difluorobenzene can weakly coordinate with Na+ thus transforming the solvation structure into Na+-anion-incorporated structures and strengthening anode/cathode interphases formation by combining with salt decomposition. Furthermore, the correlations between the electrode interface properties and solvation structure are revealed, which can be tuned by the weakly coordination. Ultimately, the modulated electrolyte achieves 97.5% Coulombic efficiency for 600 cycles in Na‖Cu cells at 1 mA cm−2 and a beneficial lifetime (2500 h) in Na‖Na cells. Meanwhile, Na‖PB cells have achieved long-term operation at 4.8 V, along with operation at wide temperatures. Here, authors propose a weakly coordinating-intervention strategy to modulate the Na+ solvation sheath and construct a robust interphase in sodium-metal batteries. Correlation between electrode interface properties and solvation structure is also stated. [ABSTRACT FROM AUTHOR]

SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. This hyper-proinflammatory state involves activation of signaling by NFκB, and unexpectedly, ENaC, the epithelial sodium channel. Post-infection inflammation may also contribute to "Long COVID"/PASC. Enhanced signaling by NFκB and ENaC also marks the airway of patients suffering from cystic fibrosis, a life-limiting proinflammatory genetic disease due to inactivating mutations in the CFTR gene. We therefore hypothesized that inflammation in the COVID-19 airway might similarly be due to inhibition of CFTR signaling by SARS-CoV-2 spike protein, and therefore activation of both NFκB and ENaC signaling. We used western blot and electrophysiological techniques, and an organoid model of normal airway epithelia, differentiated on an air–liquid-interface (ALI). We found that CFTR protein expression and CFTR cAMP-activated chloride channel activity were lost when the model epithelium was exposed to SARS-CoV-2 spike proteins. As hypothesized, the absence of CFTR led to activation of both TNFα/NFκB signaling and α and γ ENaC. We had previously shown that the cardiac glycoside drugs digoxin, digitoxin and ouabain blocked interaction of spike protein and ACE2. Consistently, addition of 30 nM concentrations of the cardiac glycoside drugs, prevented loss of both CFTR protein and CFTR channel activity. ACE2 and CFTR were found to co-immunoprecipitate in both basal cells and differentiated epithelia. Thus spike-dependent CFTR loss might involve ACE2 as a bridge between Spike and CFTR. In addition, spike exposure to the epithelia resulted in failure of endosomal recycling to return CFTR to the plasma membrane. Thus, failure of CFTR recovery from endosomal recycling might be a mechanism for spike-dependent loss of CFTR. Finally, we found that authentic SARS-CoV-2 virus infection induced loss of CFTR protein, which was rescued by the cardiac glycoside drugs digitoxin and ouabain. Based on experiments with this organoid model of small airway epithelia, and comparisons with 16HBE14o- and other cell types expressing normal CFTR, we predict that inflammation in the COVID-19 airway may be mediated by inhibition of CFTR signaling by the SARS-CoV-2 spike protein, thus inducing a cystic fibrosis-like clinical phenotype. To our knowledge this is the first time COVID-19 airway inflammation has been experimentally traced in normal subjects to a contribution from SARS-CoV-2 spike-dependent inhibition of CFTR signaling. [ABSTRACT FROM AUTHOR]

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or noninactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow-inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506), are commonly used immunosuppressants for preserving transplanted organs and tissues. However, these drugs can cause severe and persistent pain. GluA2-lacking, calcium-permeable AMPA receptors (CP-AMPARs) are implicated in various neurological disorders, including neuropathic pain. It is unclear whether and how constitutive calcineurin, a Ca2+/calmodulin protein phosphatase, controls synaptic CP-AMPARs. In this study, we found that blocking CP-AMPARs with IEM-1460 markedly reduced the amplitude of AMPAR-EPSCs in excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2), but not in inhibitory neurons expressing vesicular GABA transporter, in the spinal cord of FK506-treated male and female mice. FK506 treatment also caused an inward rectification in the current–voltage relationship of AMPAR-EPSCs specifically in VGluT2 neurons. Intrathecal injection of IEM-1460 rapidly alleviated pain hypersensitivity in FK506-treated mice. Furthermore, FK506 treatment substantially increased physical interaction of α2δ-1 with GluA1 and GluA2 in the spinal cord and reduced GluA1/GluA2 heteromers in endoplasmic reticulum-enriched fractions of spinal cords. Correspondingly, inhibiting α2δ-1 with pregabalin, Cacna2d1 genetic knock-out, or disrupting α2δ-1–AMPAR interactions with an α2δ-1 C terminus peptide reversed inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons caused by FK506 treatment. In addition, CK2 inhibition reversed FK506 treatment–induced pain hypersensitivity, α2δ-1 interactions with GluA1 and GluA2, and inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons. Thus, the increased prevalence of synaptic CP-AMPARs in spinal excitatory neurons plays a major role in calcineurin inhibitor-induced pain hypersensitivity. Calcineurin and CK2 antagonistically regulate postsynaptic CP-AMPARs through α2δ-1—mediated GluA1/GluA2 heteromeric assembly in the spinal dorsal horn. [ABSTRACT FROM AUTHOR]

Objective(s): Amiloride is a pyrazine compound that inhibits the reabsorption of sodium by blocking sodium channels in the cells of the renal cortex. It has demonstrated promising efficacy in the treatment of cancer in recent times. This study assessed the in vivo biodistribution of amiloride conjugated to dendrimer as a targeted agent utilizing SPECT imaging. Materials and Methods: The dendrimer was synthesised using polyethylene glycol and citric acid as precursors, and dicyclohexyl carbodiimide as a zero-order crosslinker. Amiloride was then conjugated to the dendrimer through the terminal amine group, forming an amide bond with the acidic group of the dendrimer. The synthetic particles were assessed by characterization techniques including FTIR, TEM, LC-Mass, and MAP. The response surface optimization method based on the core chemical was employed to achieve maximum labelling efficiency. The ideal circumstances and biodistribution in the in vivo environment were assessed. Results: TThe characterization findings demonstrated the effective formation and linkage of the nanoconjugate. The Radiochemical purity (RCP) of the dendrimer-amiloride complexes with Technetium- 99m, achieved under ideal conditions (28 minutes of incubation, 1.4 units of reduced agent, and 17.5 mg of dendrimer-amiloride), exceeds 90%. This demonstrates the considerable potential of dendrimer-amiloride in forming complexes with Technetium-99m. The results from imaging and biodistribution tests showed that 99mTc-dendrimer-amiloride had a high level of activity (7.8 %ID/g) at the tumor site. This was due to the increased expression of sodium channel. Conclusion: The favorable characteristics and conduct of the produced nanoprobe indicate its potential as an innovative tool for the advancement of radiopharmaceutical-based medication. Furthermore, it has the capacity to envision a broad spectrum of malignancies. [ABSTRACT FROM AUTHOR]

In silico modeling offers an opportunity to supplement and accelerate cardiac safety testing. With in silico modeling, computational simulation methods are used to predict electrophysiological interactions and pharmacological effects of novel drugs on critical physiological processes. The O'Hara-Rudy's model was developed to predict the response to different ion channel inhibition levels on cardiac action potential duration (APD) which is known to directly correlate with the QT interval. APD data at 30% 60% and 90% inhibition were derived from the model to delineate possible ventricular arrhythmia scenarios and the marginal contribution of each ion channel to the model. Action potential values were calculated for epicardial, myocardial, and endocardial cells, with action potential curve modeling. This study assessed cardiac ion channel inhibition data combinations to consider when undertaking in silico modeling of proarrhythmic effects as stipulated in the Comprehensive in Vitro Proarrhythmia Assay (CiPA). As expected, our data highlight the importance of the delayed rectifier potassium channel (IKr) as the most impactful channel for APD prolongation. The impact of the transient outward potassium channel (Ito) inhibition on APD was minimal while the inward rectifier (IK1) and slow component of the delayed rectifier potassium channel (IKs) also had limited APD effects. In contrast, the contribution of fast sodium channel (INa) and/or L-type calcium channel (ICa) inhibition resulted in substantial APD alterations supporting the pharmacological relevance of in silico modeling using input from a limited number of cardiac ion channels including IKr, INa, and ICa, at least at an early stage of drug development. [ABSTRACT FROM AUTHOR]

Myelinated axons conduct action potentials, or spikes, in a saltatory manner. Inward current caused by a spike occurring at one node of Ranvier spreads axially to the next node, which regenerates the spike when depolarized enough for voltage-gated sodium channels to activate, and so on. The rate at which this process progresses dictates the velocity at which the spike is conducted and depends on several factors including axial resistivity and axon diameter that directly affect axial current. Here we show through computational simulations in modified double-cable axon models that conduction velocity also depends on extracellular factors whose effects can be explained by their indirect influence on axial current. Specifically, we show that a conventional double-cable model, with its outside layer connected to ground, transmits less axial current than a model whose outside layer is less absorptive. A more resistive barrier exists when an axon is packed tightly between other myelinated fibers, for example. We show that realistically resistive boundary conditions can significantly increase the velocity and energy efficiency of spike propagation, while also protecting against propagation failure. Certain factors like myelin thickness may be less important than typically thought if extracellular conditions are more resistive than normally considered. We also show how realistically resistive boundary conditions affect ephaptic interactions. Overall, these results highlight the unappreciated importance of extracellular conditions for axon function. [ABSTRACT FROM AUTHOR]

Highlights: MXene sediments is innovatively used as photothermal material for seawater desalination. Inspired by the natural wood transpiration process, a 3D MXene sediment-based aerogel with vertically aligned channels is innovatively prepared as solar evaporator. With unique structure and composition, excellent photothermal conversion efficiency, evaporation rate, salt resistance, and resistance to biological/oil/special environments are achieved in practical desalination. Solar-driven interfacial evaporation from seawater is considered an effective way to alleviate the emerging freshwater crisis because of its green and environmentally friendly characteristics. However, developing an evaporator with high efficiency, stability, and salt resistance remains a key challenge. MXene, with an internal photothermal conversion efficiency of 100%, has received tremendous research interest as a photothermal material. However, the process to prepare the MXene with monolayer is inefficient and generates a large amount of "waste" MXene sediments (MS). Here, MXene sediments is selected as the photothermal material, and a three-dimensional MXene sediments/poly(vinyl alcohol)/sodium alginate aerogel evaporator with vertically aligned pores by directional freezing method is innovatively designed. The vertical porous structure enables the evaporator to improve water transport, light capture, and high evaporation rate. Cotton swabs and polypropylene are used as the water channel and support, respectively, thus fabricating a self-floating evaporator. The evaporator exhibits an evaporation rate of 3.6 kg m−2 h−1 under one-sun illumination, and 18.37 kg m−2 of freshwater is collected in the condensation collection device after 7 h of outdoor sun irradiation. The evaporator also displays excellent oil and salt resistance. This research fully utilizes "waste" MS, enabling a self-floating evaporation device for freshwater collection. [ABSTRACT FROM AUTHOR]

The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily accessible library (OREAL), which is characterized by readily accessibility, unique chemical space, ideal drug-like properties, and structural diversity. We used a scaffold-based approach to screen the OREAL and discovered compound C4 as a potent Nav1.7 inhibitor. The bioactivity characterization of C4 reveals that it is a selective Nav1.7 inhibitor and effectively reverses Paclitaxel-induced neuropathic pain (PINP) in rodent models. Preliminary toxicology study shows C4 is negative to hERG. The consistent results of molecular docking and molecular simulations further support the reasonability of the in-silico screening and show the insight of the binding mode of C4. Our discovery of C4 paves the way for pushing the Nav1.7-based anti-nociceptive drugs forward to the clinic. Voltage-gated sodium channel subtype Nav1.7 is a promising drug target associated with neuropathic pain disorder, however, the current Nav1.7 inhibitors show limited efficacy in clinical trials. More new molecular entities need to be discovered. Here, the authors report a selective Nav1.7 inhibitor by using carbenoid-involved reactions to construct an oxindole-based library, applying it to the scaffold-oriented virtual screening, and validating the hit compound in a clinically relevant model. [ABSTRACT FROM AUTHOR]

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in Scn1a+/- and Scn1aRH/+ DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single-unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients' EEG, which are consistent with the dysfunctions that we observed in single neurons and that allowed seizure prediction. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Preictal spectral features may be used as predictive seizure biomarkers. [ABSTRACT FROM AUTHOR]

SCN1A, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel's function affect the initiation and propagation of action potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation of SCN1A channelopathy, is characterized by severe myoclonic epilepsy in infancy (SMEI). Variants' characteristics and other genetic or epigenetic factors lead to extreme clinical heterogeneity, ranging from non-epileptic conditions to developmental and epileptic encephalopathy (DEE). This current study reports on findings from 343 patients referred by physicians in hospitals and tertiary care centers in Greece between 2017 and 2023. Positive family history for specific neurologic disorders was disclosed in 89 cases and the one common clinical feature was the onset of seizures, at a mean age of 17 months (range from birth to 15 years old). Most patients were specifically referred for SCN1A investigation (Sanger Sequencing and MLPA) and only five for next generation sequencing. Twenty-six SCN1A variants were detected, including nine novel causative variants (c.4567A>Τ, c.5564C>A, c.2176+2T>C, c.3646G>C, c.4331C>A, c.1130_1131delGAinsAC, c.1574_1580delCTGAGGA, c.4620A>G and c.5462A>C), and are herein presented, along with subsequent genotype–phenotype associations. The identification of novel variants complements SCN1A databases extending our expertise on genetic counseling and patient and family management including gene-based personalized interventions. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease that affects approximately 50 million people worldwide. Despite an existing abundance of antiepileptic drugs, lifelong disease treatment is often required but could be improved with alternative drugs that have fewer side effects. Given that epileptic seizures stem from abnormal neuronal discharges predominately modulated by the human sodium channel Nav1.2, the quest for novel and potent Nav1.2 blockers holds promise for epilepsy management. Herein, an in vivo approach was used to detect new antiepileptic compounds using the maximum electroshock test on mice. Pre-treatment of mice with extracts from the Ficus religiosa plant ameliorated the tonic hind limb extensor phase of induced convulsions. Subsequently, an in silico approach identified potential Nav1.2 blocking compounds from F. religiosa using a combination of computational techniques, including molecular docking, prime molecular mechanics/generalized Born surface area (MM/GBSA) analysis, and molecular dynamics (MD) simulation studies. The molecular docking and MM/GBSA analysis indicated that out of 82 compounds known to be present in F. religiosa, seven exhibited relatively strong binding affinities to Nav1.2 that ranged from −6.555 to −13.476 kcal/mol; similar or with higher affinity than phenytoin (−6.660 kcal/mol), a known Na+-channel blocking antiepileptic drug. Furthermore, MD simulations revealed that two compounds: 6-C-glucosyl-8-C-arabinosyl apigenin and pelargonidin-3-rhamnoside could form stable complexes with Nav1.2 at 300 K, indicating their potential as lead antiepileptic agents. In summary, the combination of in vivo and in silico approaches supports the potential of F. religiosa phytochemicals as natural antiepileptic therapeutic agents. [ABSTRACT FROM AUTHOR]

Studies on the interaction sites of peptide toxins and ion channels typically involve site-directed mutations in toxins. However, natural mutant toxins exist among them, offering insights into how the evolutionary process has conserved crucial sequences for activities and molecular target selection. In this study, we present a comparative investigation using electrophysiological approaches and computational analysis between two alpha toxins from evolutionarily close scorpion species of the genus Tityus, namely, Tst3 and Ts3 from T. stigmurus and T. serrulatus, respectively. These toxins exhibit three natural substitutions near the C-terminal region, which is directly involved in the interaction between alpha toxins and Nav channels. Additionally, we characterized the activity of the Tst3 toxin on Nav1.1-Nav1.7 channels. The three natural changes between the toxins did not alter sensitivity to Nav1.4, maintaining similar intensities regarding their ability to alter opening probabilities, delay fast inactivation, and induce persistent currents. Computational analysis demonstrated a preference for the down conformation of VSD4 and a shift in the conformational equilibrium towards this state. This illustrates that the sequence of these toxins retained the necessary information, even with alterations in the interaction site region. Through electrophysiological and computational analyses, screening of the Tst3 toxin on sodium isoform revealed its classification as a classic α-NaTx with a broad spectrum of activity. It effectively delays fast inactivation across all tested isoforms. Structural analysis of molecular energetics at the interface of the VSD4-Tst3 complex further confirmed this effect. [ABSTRACT FROM AUTHOR]

This document is an editorial from the journal "Life" titled "Ion Channels and Neurological Disease." It discusses the role of ion channels in neurological disorders and their potential as drug targets for treatment. The editorial introduces a special issue of the journal that includes ten peer-reviewed articles covering various types of ion channels and their dysfunctions in neurological diseases such as Alzheimer's disease, Parkinson's disease, and cerebellar ataxias. The articles provide updates on research and present new findings on the structure-function relationships of ion channels and their impact on the pathophysiology of neurological diseases. The editorial concludes by highlighting the importance of understanding ion channels in developing new therapeutic interventions for these diseases. [Extracted from the article]

Na 3 V 2 (PO 4) 2 F 3–2y O 2y (0 ≤ y ≤ 1, NVPOF) as a polyanionic compounds cathode material of sodium ion batteries (SIBs), features the excellent intrinsic advantages of high average operating voltage, high reversible capacity and faint structural volume change. Whereas, the intrinsically low Na+/electronic conductivity of sodium vanadium fluorophosphate leads to the unreliable electrochemical performance of the battery, thus reducing the possibility of practical application. This paper puts forward the method of hydrothermal synthesis, and carries out a series of studies on modification methods such as Al doping and composite with carbonaceous materials. The high conductivity carbon coated sodium vanadium fluorophosphate particles with high purity and crystallinity are realized, and a double carbon network is formed with carbon nanotubes with large aspect ratio, which signally enhances the kinetic and electrochemical properties of the materials. Na 3 V 1.94 Al 0.06 (PO 4) 2 F 1.06 O 1.94 /C/CNTs with the optimum Al doping amount can obviously decrease the band gap energy and enhance the Na+/electronic dynamic transportation. At the same time, it shows the best electrochemical performance at room temperature, with an excellent specific discharge capacity of 127.4 mAh g−1 at 0.5 C, and the capacity retention rate can achieve 93% after long lifespan 700 cycles, showing unexpected cycle stability. [Display omitted] • The excellent morphology of cross-linked double carbon skeleton composed of carbon layers and CNTs was prepared. • The optimum Al doping ratio of NaV 1.94 Al 0.06 POF/C/CNTs shows excellent rate capability and ultralong lifespan. • The MoSe 2 @C//NV 1.94 Al 0.06 POF/C/CNTs full cells revealed outstanding performance beyond expectations. [ABSTRACT FROM AUTHOR]

The sodium (Na+) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (NaVs and CaVs, respectively). Unlike NaVs and CaVs, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145, and Y1436) that block these openings. Structural data suggest that occluded fenestrations underlie the pharmacological resistance of NALCN, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned residues with alanine (AAAA) and compared the effects of NaV, CaV, and NALCN blockers on both wild-type (WT) and AAAA channels. Most compounds behaved in a similar manner on both channels, but phenytoin and 2-aminoethoxydiphenyl borate (2-APB) elicited additional, distinct responses on AAAA channels. Further experiments using single alanine mutants revealed that phenytoin and 2-APB enter the inner cavity through distinct fenestrations, implying structural specificity to their modes of access. Using a combination of computational and functional approaches, we identified amino acid residues critical for 2-APB activity, supporting the existence of drug binding site(s) within the pore region. Intrigued by the activity of 2-APB and its analogues, we tested compounds containing the diphenylmethane/amine moiety on WT channels. We identified clinically used drugs that exhibited diverse activity, thus expanding the pharmacological toolbox for NALCN. While the low potencies of active compounds reiterate the pharmacological resistance of NALCN, our findings lay the foundation for rational drug design to develop NALCN modulators with refined properties. [ABSTRACT FROM AUTHOR]

Background: Mexico has experienced a significant reduction in malaria cases over the past two decades. Certification of localities as malaria-free areas (MFAs) has been proposed as a steppingstone before elimination is achieved throughout the country. The Mexican state of Quintana Roo is a candidate for MFA certification. Monitoring the status of insecticide susceptibility of major vectors is crucial for MFA certification. This study describes the susceptibility status of Anopheles albimanus, main malaria vector, from historically important malaria foci in Quintana Roo, using both phenotypic and genotypic approaches. Methods: Adult mosquito collections were carried out at three localities: Palmar (Municipality of Othon P. Blanco), Buenavista (Bacalar) and Puerto Morelos (Puerto Morelos). Outdoor human-landing catches were performed by pairs of trained staff from 18:00 to 22:00 during 3-night periods at each locality during the rainy season of 2022. Wild-caught female mosquitoes were exposed to diagnostic doses of deltamethrin, permethrin, malathion, pirimiphos-methyl or bendiocarb using CDC bottle bioassays. Mortality was registered at the diagnostic time and recovery was assessed 24 h after exposure. Molecular analyses targeting the Voltage-Gated Sodium Channel (vgsc) gene and acetylcholinesterase (ace-1) gene were used to screen for target site polymorphisms. An SNP analysis was carried out to identify mutations at position 995 in the vgsc gene and at position 280 in the ace-1 gene. Results: A total of 2828 anophelines were collected. The main species identified were Anopheles albimanus (82%) and Anopheles vestitipennis (16%). Mortalities in the CDC bottle bioassay ranged from 99% to 100% for all the insecticides and mosquito species. Sequence analysis was performed on 35 An. albimanus across the three localities; of those, 25 were analysed for vgsc and 10 for ace-1 mutations. All individuals showed wild type alleles. Conclusion: The results demonstrated that An. albimanus populations from historical malaria foci in Quintana Roo are susceptible to the main insecticides used by the Ministry of Health. [ABSTRACT FROM AUTHOR]

Simple Summary: The tiger mosquito, Aedes albopictus, spreads the virus causing dengue fever, notably in Southeast Asian countries. To stop the spread of this disease, the Aedes mosquitoes are killed with chemicals known as pyrethroids. However, despite pyrethroids being highly effective insecticides, tiger mosquitoes are becoming resistant and surviving exposure to these chemicals. We have measured that tiger mosquitoes from two regions in Cambodia (the capital, Phnom Penh, and rural Pailin province) are highly resistant to pyrethroids. To determine what causes resistance, we have implicated unusually high activity of enzymes, known as P450 monooxygenases, which break down pyrethroids and thus render them harmless in the resistant mosquitoes. We have ruled out another common mechanism of pyrethroid resistance, which is changes in the mosquitoes' DNA sequence, which prevents pyrethroids from binding to a protein known as the voltage-gated sodium channel, thereby disrupting signals being sent throughout the nervous system. Overall, our findings describe an important survey monitoring the prevalence of insecticide resistance in disease-spreading mosquitoes in Cambodia, and with the increased understanding of what causes resistance, we are in a strong position to advise that mosquito control methods alternative to pyrethroids should be implemented as soon as possible to ensure continuing management of dengue fever. (1) Background: In Cambodia, Aedes albopictus is an important vector of the dengue virus. Vector control using insecticides is a major strategy implemented in managing mosquito-borne diseases. Resistance, however, threatens to undermine the use of insecticides. In this study, we present the levels of insecticide resistance of Ae. albopictus in Cambodia and the mechanisms involved. (2) Methods: Two Ae. albopictus populations were collected from the capital, Phnom Penh city, and from rural Pailin province. Adults were tested with diagnostic doses of malathion (0.8%), deltamethrin (0.03%), permethrin (0.25%), and DDT (4%) using WHO tube assays. Synergist assays using piperonyl butoxide (PBO) were implemented before the pyrethroid assays to detect the potential involvement of metabolic resistance mechanisms. Adult female mosquitoes collected from Phnom Penh and Pailin were tested for voltage-gated sodium channel (VGSC) kdr (knockdown resistance) mutations commonly found in Aedes sp.-resistant populations throughout Asia (S989P, V1016G, and F1534C), as well as for other mutations (V410L, L982W, A1007G, I1011M, T1520I, and D1763Y). (3) Results: The two populations showed resistance against all the insecticides tested (<90% mortality). The use of PBO (an inhibitor of P450s) strongly restored the efficacy of deltamethrin and permethrin against the two resistant populations. Sequences of regions of the vgsc gene showed a lack of kdr mutations known to be associated with pyrethroid resistance. However, four novel non-synonymous mutations (L412P/S, C983S, Q1554STOP, and R1718L) and twenty-nine synonymous mutations were detected. It remains to be determined whether these mutations contribute to pyrethroid resistance. (4) Conclusions: Pyrethroid resistance is occurring in two Ae. albopictus populations originating from urban and rural areas of Cambodia. The resistance is likely due to metabolic resistance specifically involving P450s monooxygenases. The levels of resistance against different insecticide classes are a cause for concern in Cambodia. Alternative tools and insecticides for controlling dengue vectors should be used to minimize disease prevalence in the country. [ABSTRACT FROM AUTHOR]

Severe cases of COVID-19 are characterized by development of acute respiratory distress syndrome (ARDS). Water accumulation in the lungs is thought to occur as consequence of an exaggerated inflammatory response. A possible mechanism could involve decreased activity of the epithelial Na+ channel, ENaC, expressed in type II pneumocytes. Reduced transepithelial Na+ reabsorption could contribute to lung edema due to reduced alveolar fluid clearance. This hypothesis is based on the observation of the presence of a novel furin cleavage site in the S protein of SARS-CoV-2 that is identical to the furin cleavage site present in the alpha subunit of ENaC. Proteolytic processing of αENaC by furin-like proteases is essential for channel activity. Thus, competition between S protein and αENaC for furin-mediated cleavage in SARS-CoV-2-infected cells may negatively affect channel activity. Here we present experimental evidence showing that coexpression of the S protein with ENaC in a cellular model reduces channel activity. In addition, we show that bidirectional competition for cleavage by furin-like proteases occurs between 〈ENaC and S protein. In transgenic mice sensitive to lethal SARS-CoV-2, however, a significant decrease in gamma ENaC expression was not observed by immunostaining of lungs infected as shown by SARS-CoV2 nucleoprotein staining. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is a neurodevelopmental disorder characterized by epilepsy, developmental delay/intellectual disability, and features of autism spectrum disorder, caused by heterozygous loss-of-function variants in SCN1A encoding the voltage-gated sodium channel α subunit Nav1.1. The dominant model of DS pathogenesis is the "interneuron hypothesis," whereby GABAergic interneurons (INs) express and preferentially rely on Nav1.1-containing sodium channels for action potential (AP) generation. This has been shown for three of the major subclasses of cerebral cortex GABAergic INs: those expressing parvalbumin (PV), somatostatin, and vasoactive intestinal peptide. Here, we define the function of a fourth major subclass of INs expressing neuron-derived neurotrophic factor (Ndnf) in male and female DS (Scn1a+/-) mice. Patch-clamp electrophysiological recordings of Ndnf-INs in brain slices from Scn1a+/â mice and WT controls reveal normal intrinsic membrane properties, properties of AP generation and repetitive firing, and synaptic transmission across development. Immunohistochemistry shows that Nav1.1 is strongly expressed at the axon initial segment (AIS) of PV-expressing INs but is absent at the Ndnf-IN AIS. In vivo two-photon calcium imaging demonstrates that Ndnf-INs in Scn1a+/â mice are recruited similarly to WT controls during arousal. These results suggest that Ndnf-INs are the only major IN subclass that does not prominently rely on Nav1.1 for AP generation and thus retain their excitability in DS. The discovery of amajor IN subclass with preserved function in the Scn1a+/â mouse model adds further complexity to the "interneuron hypothesis" and highlights the importance of considering cell-type heterogeneity when investigating mechanisms underlying neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ/KV7 potassium channel cause gating pore currents (Igp) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A/NaV1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of NaV1.2 caused Igp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective Igp. These potentially pathogenic Igp were exacerbated by the absence of the extracellular Mg2+ and Ca2+. In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward Igp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD. [ABSTRACT FROM AUTHOR]