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As a basic component of batteries, separators are proposed to apart the two electrodes while allowing the transport of ionic charge carriers. Cellulose separators have attracted tremendous attention due to their excellent thermal stability and wettability. In this study, we prepare all-cellulose composite (ACC) separators coated with Zn 5 (OH) 8 Cl 2 ·H 2 O (ZHC) particles. The surface of the cellulose filter paper is partially dissolved by the 65% ZnCl 2 solution, forming a tortuous and porous all-cellulose composite membrane. At the same time, ZHC is generated in situ on the surface during the removal of residual ZnCl 2 from the cellulose, which effectively promotes the passage of a sodium ion (Na+) and substantially improves the cycling performance of the batteries. Density functional theory (DFT) calculations demonstrate that suitable adsorption energy on ZHC is favorable for promoting Na+ transport. The corresponding ACC separator exhibits high ionic conductivity (2.75 mS/cm) and Na+ transference number (0.82), correspondingly the assembled Na/hard carbon half-cells show an excellent reversible specific capacity (315 mA h/g at 25 mA/g) and cycling stability (the retention is 97.77% after 50 cycles at 50 mA/g), outperforming the glass fiber separator in both sodium-ion half-cell and full-cell. [Display omitted] • A novel cellulose-based separator is obtained by a facile sol-gel method. • In situ growth of ZHC on the separator is shown to facilitate Na + transport. • The separator exhibits a high Na + transference number (0.82). • The cells assembled with the composite separator show excellent performance. • The ZHC loading method can be extended to other separator systems. [ABSTRACT FROM AUTHOR]

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]

Acid‐sensing ion channels (ASICs) are members of the diverse family of degenerin/epithelial sodium channels (DEG/ENaCs). They perform a wide range of physiological roles in healthy organisms, including in gut function and synaptic transmission, but also play important roles in disease, as acidosis is a hallmark of painful inflammatory and ischaemic conditions. We performed a screen for acid sensitivity on all 30 subunits of the Caenorhabditis elegans DEG/ENaC family using two‐electrode voltage clamp in Xenopus oocytes. We found two groups of acid‐sensitive DEG/ENaCs characterised by being either inhibited or activated by increasing proton concentrations. Three of these acid‐sensitive C. elegans DEG/ENaCs were activated by acidic pH, making them functionally similar to the vertebrate ASICs. We also identified three new members of the acid‐inhibited DEG/ENaC group, giving a total of seven additional acid‐sensitive channels. We observed sensitivity to the anti‐hypertensive drug amiloride as well as modulation by the trace element zinc. Acid‐sensitive DEG/ENaCs were found to be expressed in both neurons and non‐neuronal tissue, highlighting the likely functional diversity of these channels. Our findings provide a framework to exploit the C. elegans channels as models to study the function of these acid‐sensing channels in vivo, as well as to study them as potential targets for anti‐helminthic drugs. Key points: Acidosis plays many roles in healthy physiology, including synaptic transmission and gut function, but is also a key feature of inflammatory pain, ischaemia and many other conditions. Cells monitor acidosis of their surroundings via pH‐sensing channels, including the acid‐sensing ion channels (ASICs). These are members of the degenerin/epithelial sodium channel (DEG/ENaC) family, along with, as the name suggests, vertebrate ENaCs and degenerins of the roundworm Caenorhabditis elegans.By screening all 30 C. elegans DEG/ENaCs for pH dependence, we describe, for the first time, three acid‐activated members, as well as three additional acid‐inhibited channels.We surveyed both groups for sensitivity to amiloride and zinc; like their mammalian counterparts, their currents can be blocked, enhanced or unaffected by these modulators. Likewise, they exhibit diverse ion selectivity.Our findings underline the diversity of acid‐sensitive DEG/ENaCs across species and provide a comparative resource for better understanding the molecular basis of their function. [ABSTRACT FROM AUTHOR]

A common side effect of pharmaceutical drugs is an increased propensity for cardiac arrhythmias. Many drugs bind to cardiac ion-channels in a state-specific manner, which alters the ionic conductances in complicated ways, making it difficult to identify the mechanisms underlying pro-arrhythmic drug effects. To better understand the fundamental mechanisms underlying the diverse effects of state-dependent sodium (Na + ) channel blockers on cellular excitability, we consider two canonical motifs of drug-ion-channel interactions and compare the effects of Na + channel blockers on the rate-dependence of peak upstroke velocity, conduction velocity, and vulnerable window size. In the literature, both motifs are referred to as "guarded receptor," but here we distinguish between state-specific binding that does not alter channel gating (referred to here as "guarded receptor") and state-specific binding that blocks certain gating transitions ("gate immobilization"). For each drug binding motif, we consider drugs that bind to the inactivated state and drugs that bind to the non-inactivated state of the Na + channel. Exploiting the idealized nature of the canonical binding motifs, we identify the fundamental mechanisms underlying the effects on excitability of the various binding interactions. Specifically, we derive the voltage-dependence of the drug binding time constants and the equilibrium fractions of channels bound to drug, and we then derive a formula that incorporates these time constants and equilibrium fractions to elucidate the fundamental mechanisms. In the case of charged drug, we find that drugs that bind to inactivated channels exhibit greater rate-dependence than drugs that bind to non-inactivated channels. For neutral drugs, the effects of guarded receptor interactions are rate-independent, and we describe a novel mechanism for reverse rate-dependence resulting from neutral drug binding to non-inactivated channels via the gate immobilization motif., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Neuronal networks control motor output through multi-rhythmic electrical activities with different frequencies and amplitudes of different neurons. For example, the pre-Bötzinger complex related to respiratory function exhibits sigh (slow frequency and large amplitude) and eupnea (fast frequency and small amplitude) rhythms. In the present paper, rhythm transitions modulated by several physiological factors are simulated in a coupling model composed of sigh and eupnea compartments, and the roles of ionic currents and the underlying bifurcation mechanism of the rhythm transitions are acquired. The transition from sigh- and eupnea-rhythm to the eupnea rhythm induced by the blockage of calcium or hyperpolarization-activated channels is related to supercritical Hopf bifurcation of the sigh compartment, and to the sigh rhythm caused by the blockage of persistent sodium channel or change of extracellular potassium concentration is associated with subcritical Hopf/fold limit cycle bifurcation of the eupnea compartment. The parameter regions of ionic currents and dynamical mechanism of rhythm transitions in the pre-Bötzinger complex are helpful for the modulation to the respiratory rhythms. [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]

Despite the exemplary efficacy of voltage-gated sodium channel blockers as a first-line treatment of trigeminal neuralgia, the pharmacological management of this excruciating facial pain condition remains a major issue, as these first-line drugs produce intolerable side effects in a significant portion of patients. In addition, in patients with concomitant continuous pain, the efficacy of these drugs may drop, thus suggesting the opportunity to test the efficacy of different drug categories. The aim of this review is to provide current, evidence-based, knowledge about the use of gabapentin and other α 2δ ligands in patients with trigeminal neuralgia. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), considering publications up to April 2023. Two authors independently selected studies for inclusion and data extraction. The efficacy of α 2δ ligands, gabapentin and pregabalin, has been assessed in seven controlled or open-label studies. Despite the low quality of evidence, the favorable tolerability profile and the possible action on concomitant continuous pain make this drug category of interest for future trials in trigeminal neuralgia.Plain Language Summary: Trigeminal neuralgia is a really excruciating neuropathic pain condition. Although sodium channel blockers are efficacious in most of the patients, the poor tolerability profile and the limited efficacy in patients with concomitant continuous pain represent a major issue over the long-term treatment.Gabapentin and other α 2δ ligands, which have been shown to be effective in the treatment of other neuropathic conditions characterized by continuous pain, may be tried as additional agents along with sodium channel blockers.In this review, based on a systematic search of relevant literature, we aim to provide current, evidence-based, knowledge about the use of gabapentin and other α 2δ ligands in patients with trigeminal neuralgia. The favourable tolerability profile and the possible action on concomitant continuous pain make this drug category of interest for future trials in trigeminal neuralgia. [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]

Marinobufagenin (MBG) is a member of the bufadienolide family of compounds, which are natural cardiac glycosides found in a variety of animal species, including man, which have different physiological and biochemical functions but have a common action on the inhibition of the adenosine triphosphatase sodium-potassium pump (Na+/K+-ATPase). MBG acts as an endogenous cardiotonic steroid, and in the last decade, its role as a pathogenic factor in various human diseases has emerged. In this paper, we have collated major evidence regarding the biological characteristics and functions of MBG and its implications in human pathology. This review focused on MBG involvement in chronic kidney disease, including end-stage renal disease, cardiovascular diseases, sex and gender medicine, and its actions on the nervous and immune systems. The role of MBG in pathogenesis and the development of a wide range of pathological conditions indicate that this endogenous peptide could be used in the future as a diagnostic biomarker and/or therapeutic target, opening important avenues of scientific research. [ABSTRACT FROM AUTHOR]

Simple Summary: Brugada syndrome (BrS) has always been considered a purely electrical disease and imaging techniques do not currently play a specific role in the diagnosis of this arrhythmic syndrome. The aim of this review is to identify possible structural abnormalities of BrS and their potential association with symptoms, risk stratification, and prognosis. The aim of this review is to identify possible structural abnormalities of BrS and their potential association with symptoms, risk stratification, and prognosis. (1) Background: BrS has always been considered a purely electrical disease and imaging techniques do not currently play a specific role in the diagnosis of this arrhythmic syndrome. Some authors have recently hypothesized the presence of structural and functional abnormalities. Therefore, several studies investigated the presence of pathological features in echocardiography and cardiac magnetic resonance imaging (MRI) in patients with BrS, but results were controversial. (2) Methods: We performed a systematic review of the literature on the spectrum of features detected by echocardiography and cardiac MRI. Articles were searched in Pubmed, Cochrane Library, and Biomed Central. Only papers published in English and in peer-reviewed journals up to November 2021 were selected. After an initial evaluation, 596 records were screened; the literature search identified 19 relevant articles. (3) Results: The imaging findings associated with BrS were as follows: right ventricular dilation, right ventricular wall motion abnormalities, delayed right ventricular contraction, speckle and feature tracking abnormalities, late gadolinium enhancement, and fat infiltration in the right ventricle. Furthermore, these features emerged more frequently in patients carrying the genetic mutation on the sodium voltage-gated channel α-subunit 5 (SCN5A) gene. (4) Conclusions: Specific imaging features detected by echocardiography and cardiac magnetic resonance are associated with BrS. However, this population appears to be heterogeneous and imaging anomalies emerged to be more frequent in patients carrying genetic mutations of SCN5A. Future studies with an evaluation of BrS patients are needed to identify the specific association linking the Brugada pattern, imaging abnormalities and their possible correlation with prognosis. [ABSTRACT FROM AUTHOR]

Zingiber officinale Roscoe (ginger) has long been used as an herbal medicine to treat various diseases, and its main sub-components, [6]-gingerol and [6]-shogaol, were also reported to have anti-inflammatory, anti-oxidant, and anti-tumor effects. However, their effects on various types of pain and their underlying mechanisms of action have not been clearly analyzed and understood yet. Thus, in this review, by analyzing 16 studies that used Z. officinale, [6]-gingerol, and [6]-shogaol on mechanical, spontaneous and thermal pain, their effects and mechanisms of action have been analyzed. Pain was induced by either nerve injury or chemical injections in rodents. Nine studies analyzed the analgesic effect of Z. officinale, and four and three studies focused on [6]-gingerol and [6]-shogaol, respectively. Seven papers have demonstrated the underlying mechanism of action of their analgesic effects. Studies have focused on the spinal cord and one on the dorsal root ganglion (DRG) neurons. Involvement and change in the function of serotonergic receptors (5-HT1A, B, D, and 5A), transient receptor potential vanilloid 1 (TRPV1), N-methyl-D-aspartate (NMDA) receptors, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), histone deacetylase 1 (HDAC1), voltage-gated sodium channel 1.8 (Nav1.8), substance P (SP), and sciatic nerve's morphology have been observed. [ABSTRACT FROM AUTHOR]

The genetic dissection of autism spectrum disorders (ASD) has uncovered the contribution of de novo mutations in many single genes as well as de novo copy number variants. More recent work also suggests a strong contribution from recessively inherited variants, particularly in populations in which consanguineous marriages are common. What is also becoming more apparent is the degree of pleiotropy, whereby mutations in the same gene may have quite different phenotypic and clinical consequences. We performed whole exome sequencing in a group of 115 trios from countries with a high level of consanguineous marriages. In this paper we report genetic and clinical findings on a proband with ASD, who inherited a biallelic truncating pathogenic/likely pathogenic variant in the gene encoding voltage-gated sodium channel X alpha subunit, SCN10A (NM_006514.2:c.937G>T:(p.Gly313*)). The biallelic pathogenic/likely pathogenic variant in this study have different clinical features than heterozygous mutations in the same gene. The study of consanguineous families for autism spectrum disorder is highly valuable. [ABSTRACT FROM AUTHOR]

Owing to the increased reports in Aedes-borne diseases in the Caribbean and Latin America, the United States Agency for International Development assisted the Jamaican Ministry of Health and Wellness in conducting insecticide susceptibility tests on Aedes aegypti populations. Sentinel sites were established in seven parishes of Jamaica (St. Catherine, Kingston and St. Andrew, St. Thomas, Portland, St. Mary and St. Ann) and Aedes aegypti eggs were collected, reared to adults per collected population and their susceptibility to varying pyrethroids and organophosphates were tested using the World Health Organization paper bioassays for these insecticides. The Centers for Disease Control and Prevention bottle bioassay was used to assess susceptibility to the carbamate, bendiocarb. The voltage gated sodium channel gene mutations V1016I and I1011V, normally associated with pyrethroid resistance, were also analysed. The results showed that Aedes aegypti collected from all parishes exhibited resistance to pyrethroids at the following concentrations, permethrin 0.25–2.5%; deltamethrin 0.03–0.15%; lambda-cyhalothrin 0.03–0.3%; and etofenprox 0.5–2.5%. The insecticide deltamethrin at concentration 0.3% was the only pyrethroid tested that resulted in high mortality, 94.9 ± 0.34% knockdown within 1 hour of exposure and 98.95 ± 0.01% mortality (p <0.01) at 24 hours post exposure. The frequency of the voltage gated sodium channel gene mutation V1016I was high in the tested population, possibly accounting for the reduced sensitivity to pyrethroids. Organophosphate resistance was also observed in all populations tested. Mortality rates for 0.8% Malathion was 0.8 ± 0.02–60.68 ± 0.01% after 24 hour and 0.00–47.10 ± 0.09%, for pirimiphos-methyl 0.21%. Bendiocarb applied as 12.5 μg/ bottle resulted in mortality rates of 76.25 ± 4.30–100 ± 0.00% after 30 minutes of exposure. The results showed that Ae. aegypti from the seven parishes analysed demonstrated resistance to the insecticides tested. Deltamethrin and bendiocarb at concentrations 0.3% and 12.5μg respectively, were considered most effective, causing high mortality in the local populations. Routine monitoring and evaluations of Ae. aegypti populations from the included parishes are recommended. Additionally, the study results represent the most comprehensive testing to date with local Aedes aegypti populations distributed across different parishes of Jamaica and should be useful to guide national and sub national strategies for vector control and surveillance. Author summary: The recent outbreaks of chikungunya, Zika and dengue viruses in the Caribbean and Latin America during 2013–2018, have motivated local health authorities in individual countries to seek international assistance from multiple agencies and adjust their vector management strategies in order to contain the transmission of Aedes-borne diseases. Countries within the region rely mainly on the use of commercially available insecticides to manage the mosquito populations and by extension, reduce the transmission of vector-borne diseases. However, this practice is stymied by the ability of these insects to develop resistance mechanisms to insecticides of frequent use. Many countries in the Caribbean and Latin America regions lack the facilities and supplies to conduct routine insecticide susceptibility testing. In an effort to ascertain knowledge on the presence of insecticide resistance in Aedes aegypti populations, and to determine which insecticide is more effective to reduce vector populations of Jamaica, we conducted an array of bioassays with three different types of insecticides (pyrethroid, organophosphate, carbamate) to use local evidence and inform public health authorities on vector control status and alternatives. [ABSTRACT FROM AUTHOR]

Ion channel proteins have many conformational (metastable) states and, for this reason, they exhibit hysteresis. This fact is responsible for the non-Markovian stochastic nature of single ion channel recordings. It is suggested in the paper that the stochastic single channel recordings can be modeled as the random outputs of rectangular hysteresis loops driven by stochastic processes. The latter problem can be mathematically treated as an exit problem for stochastic processes or by using the theory of stochastic processes on graphs. It is also demonstrated in the paper that the collective action of sodium and potassium channels responsible for the generation and propagation of action potentials exhibit hysteresis. This demonstration is accomplished by using the inverse problem approach to the nonlinear Hodgkin-Huxley diffusion equation. [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]

Novel stimulation protocols for neuromodulation with magnetic fields are explored in clinical and laboratory settings. Recent evidence suggests that the activation state of the nervous system plays a significant role in the outcome of magnetic stimulation, but the underlying cellular and molecular mechanisms of state-dependency have not been completely investigated. We recently reported that high frequency magnetic stimulation could inhibit neural activity when the neuron was in a low active state. In this paper, we investigate state-dependent neural modulation by applying a magnetic field to single neurons, using the novel micro-coil technology. High frequency magnetic stimulation suppressed single neuron activity in a state-dependent manner. It inhibited neurons in slow-firing states, but spared neurons from fast-firing states, when the same magnetic stimuli were applied. Using a multi-compartment NEURON model, we found that dynamics of voltage-dependent sodium and potassium channels were significantly altered by the magnetic stimulation in the slow-firing neurons, but not in the fast-firing neurons. Variability in neural activity should be monitored and explored to optimize the outcome of magnetic stimulation in basic laboratory research and clinical practice. If selective stimulation can be programmed to match the appropriate neural state, prosthetic implants and brain-machine interfaces can be designed based on these concepts to achieve optimal results. [ABSTRACT FROM AUTHOR]

Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel NaV1.5, and machine learning-based structure–activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze Veratrum alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (−10.8 kcal/mol), logP value (4.188), and pKa value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC50. In general, all three analyzed alkaloids show the affinity to NaV1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by Veratrum aqua confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by NaV1.5 inhibition. [ABSTRACT FROM AUTHOR]

Background: Volatile pyrethroid insecticides, such as transfluthrin, have received increasing attention for their potent repellent activities in recent years for controlling human disease vectors. It has been long understood that pyrethroids kill insects by promoting activation and inhibiting inactivation of voltage-gated sodium channels. However, the mechanism of pyrethroid repellency remains poorly understood and controversial., Methodology/principal Findings: Here, we show that transfluthrin repels Aedes aegypti in a hand-in-cage assay at nonlethal concentrations as low as 1 ppm. Contrary to a previous report, transfluthrin does not elicit any electroantennogram (EAG) responses, indicating that it does not activate olfactory receptor neurons (ORNs). The 1S-cis isomer of transfluthrin, which does not activate sodium channels, does not elicit repellency. Mutations in the sodium channel gene that reduce the potency of transfluthrin on sodium channels decrease transfluthrin repellency but do not affect repellency by DEET. Furthermore, transfluthrin enhances DEET repellency., Conclusions/significance: These results provide a surprising example that sodium channel activation alone is sufficient to potently repel mosquitoes. Our findings of sodium channel activation as the principal mechanism of transfluthrin repellency and potentiation of DEET repellency have broad implications in future development of a new generation of dual-target repellent formulations to more effectively repel a variety of human disease vectors., Competing Interests: The authors have declared that no competing interests exist. A patent application (Application Ser. No. 63/040,918) was filed by The Board of Trustees of Michigan State University. The inventors include Ke Dong, Feng Liu, Qiang Wang, Peng Xu, Felipe Andreazza, and Wilson R. Valbon. The status of the patent application is pending. The application covered the finding of enhanced DEET repellency by transfluthrin in Ae. aegypti. However, the patent does not influence the writing of this paper.

Global efforts to control Aedes mosquito-transmitted pathogens still rely heavily on insecticides. However, available information on vector resistance is mainly restricted to mosquito populations located in residential and public areas, whereas commercial settings, such as hotels are overlooked. This may obscure the real magnitude of the insecticide resistance problem and lead to ineffective vector control and resistance management. We investigated the profile of insecticide susceptibility of Aedes aegypti mosquitoes occurring at selected hotel compounds on Zanzibar Island. At least 100 adults Ae. aegypti females from larvae collected at four hotel compounds were exposed to papers impregnated with discriminant concentrations of DDT (4%), permethrin (0.75%), 0.05 deltamethrin (0.05%), propoxur (0.1%) and bendiocarb (0.1%) to determine their susceptibility profile. Allele-specific qPCR and sequencing analysis were applied to determine the possible association between observed resistance and presence of single nucleotide polymorphisms (SNPs) in the voltage-gated sodium channel gene (VGSC) linked to DDT/pyrethroid cross-resistance. Additionally, we explored the possible involvement of Glutathione-S-Transferase gene (GSTe2) mutations for the observed resistance profile. In vivo resistance bioassay indicated that Ae. aegypti at studied sites were highly resistant to DDT, mortality rate ranged from 26.3% to 55.3% and, moderately resistant to deltamethrin with a mortality rate between 79% to and 100%. However, genotyping of kdr mutations affecting the voltage-gated sodium channel only showed a low frequency of the V1016G mutation (n = 5; 0.97%). Moreover, for GSTe2, seven non-synonymous SNPs were detected (L111S, C115F, P117S, E132A, I150V, E178A and A198E) across two distinct haplotypes, but none of these were significantly associated with the observed resistance to DDT. Our findings suggest that cross-resistance to DDT/deltamethrin at hotel compounds in Zanzibar is not primarily mediated by mutations in VGSC. Moreover, the role of identified GSTe2 mutations in the resistance against DDT remains inconclusive. We encourage further studies to investigate the role of other potential insecticide resistance markers. Author summary: Available information on mosquito resistance to insecticides is mainly restricted to residential and public areas, whereas commercial settings, such as hotels are overlooked. This may hide the real size of an insecticide resistance problem and lead to ineffective mosquito control. We investigated insecticide susceptibility of Aedes aegypti mosquitoes occurring at selected hotel compounds on Zanzibar Island. We also looked at whether resistance occurred in mosquitoes with gene mutations for two proteins (voltage-gated sodium channels and glutathione-S-transferase) that are known to cause resistance to insecticides in other parts of the world. The Ae. aegypti mosquitoes collected from hotels were highly resistant to DDT, and moderately and possibly resistant to deltamethrin and propoxur, respectively. However, resistance to these insecticides was not linked to mutations in either of the studied genes. The presence of insecticide resistance in Ae. aegypti in hotel compounds on Zanzibar is concerning and shows that these areas can act as sources of resistant mosquitoes. More needs to be done to establish the underlying causes for insecticide resistance in hotel Ae. aegypti populations, and this information can then be used to design measures that prevent resistance from becoming more widespread on Zanzibar. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) use genetic polymorphism across the genomes of individuals with distinct characteristics to identify genotype-phenotype associations. In mosquitoes, complex traits such as vector competence and insecticide resistance could benefit from GWAS. We used the Aedes aegypti 50k SNP chip to genotype populations with different levels of pyrethroid resistance from Northern Brazil. Pyrethroids are widely used worldwide to control mosquitoes and agricultural pests, and their intensive use led to the selection of resistance phenotypes in many insects including mosquitoes. For Ae. aegypti , resistance phenotypes are mainly associated with several mutations in the voltage-gated sodium channel, known as knockdown resistance (kdr). We phenotyped those populations with the WHO insecticide bioassay using deltamethrin impregnated papers, genotyped the kdr alleles using qPCR, and determined allele frequencies across the genome using the SNP chip. We identified single-nucleotide polymorphisms (SNPs) directly associated with resistance and one epistatic SNP pair. We also observed that the novel SNPs correlated with the known kdr genotypes, although on different chromosomes or not in close physical proximity to the voltage gated sodium channel gene. In addition, pairwise comparison of resistance and susceptible mosquitoes from each population revealed differentiated genomic regions not associated with pyrethroid resistance. These new bi-allelic markers can be used to genotype other populations along with kdr alleles to understand their worldwide distribution. The functional roles of the genes near the newly discovered SNPs require new studies to determine if they act synergistically with kdr alleles or reduce the fitness cost of maintaining resistant alleles. [ABSTRACT FROM AUTHOR]

This paper studies the performance of a scheduled transmit antenna selection (TAS) with maximal ratio combining (MRC) in the presence of non-identically delayed feedback channels. This paper derives the probability density function of the scheduled TAS with MRC under non-identical feedback delay channels. Using the distribution, this paper derives exact closed-form expressions of the scheduled TAS with MRC for the outage probability and symbol error rate (SER) with M-ary phase shift keying and quadrature amplitude modulation as well as the ergodic capacity under the non-identical feedback delay channels. We also quantify the diversity order of the outage probability and SER. The asymptotic results show that the receive antenna diversity is only available under non-identical feedback delay channels, while the multi-user diversity and transmit spatial diversity are diminished compared to the perfect channel environment. Further, the performance of the scheduled TAS with MRC in the presence of non-identical feedback delay is significantly improved by the number of receive antennas, while the impact of the number of transmit antennas or correlation coefficients of feedback delay is insignificant. [ABSTRACT FROM AUTHOR]

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Channel migration becomes the main characteristic of major rivers of Mohana-Macheli watershed of western Nepal. Study of river channel migration of major rivers of watershed using freely available remote sensing show that the channel has shifted to as high as 1000 meters from the original river path over the span of 9 years (2009–2017). The channel migration directly affects the land use and it has direct effect on the flood plain settlements of the study area. Cultivation of sugarcane in sand area is one of the mitigating measures of flood effects and prevent river bank erosion. The study shows that the area of sand is changing disproportionately in the region. This paper presents an enhanced change detection method of river channel migration using remotely sensed images and identification of sand area using classification and interpretation technique. [ABSTRACT FROM AUTHOR]

Virtual screening (VS) procedures have been widely used to accelerate the drug discovery process. These procedures have also been implemented in other fields such as catalysts, energetic materials and more recently, the design of novel insecticides. The latter is an industrial priority to meet current legislation. Particularly challenging are cockroaches as they are associated with a number of diseases, while the available solutions are harmful to humans. Herein, we performed an in silico and in vivo screening of the Drug Bank (DB) database for new potential voltage-dependent sodium channel (VGSC) synergists against the American cockroach (Periplaneta americana). The VS pipeline procedure implements two ligand-based methods, e.g., Glide and METADOCK 2.0, which are further refined by rescoring. The most promising compounds are tested using in vivo models. Our combined computational and theoretical scheme leads to the discovery of miglitol as a new effective synergistic compound when combined with commercial formulations. Miglitol speeds up the overall knockout time by a factor of 12× while providing 100% of mortality after 24 hours. These findings open the door to improved insecticides as well as to a wider use of VS methods. [ABSTRACT FROM AUTHOR]

Introduction: Fibroblast growth factor homologous factors (FHFs), among other fibroblast growth factors, are increasingly found to be important regulators of ion channel functions. Although FHFs have been link to several neuronal diseases and arrhythmia, its role in inflammatory pain still remains unclear., Objectives: This study aimed to investigate the role and mechanism of FGF13 in inflammatory pain., Methods: Fgf13 conditional knockout mice were generated and CFA-induced chronic inflammatory pain model was established to measure the pain threshold. Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of FGF13 in CFA-induced inflammatory pain. Whole-cell patch clamp recording was used to record the action potential firing properties and sodium currents of DRG neurons., Results: Conditional knockout of Fgf13 in dorsal root ganglion (DRG) neurons ( Fgf13 -/Y ) led to attenuated pain responses induced by complete Freund's adjuvant (CFA). FGF13 was expressed predominantly in small-diameter DRG neurons. CFA treatment resulted in an increased expression of FGF13 proteins as well as an increased excitability in nociceptive DRG neurons which was inhibited when FGF13 was absent. The role of FGF13 in neuronal excitability of DRG was linked to its modulation of voltage-gated Na + channels mediated by microtubules. Overexpression of FGF13, but not FGF13 mutant which lacks the ability to bind and stabilize microtubules, rescued the decreased neuronal excitability and Na + current density in DRG neurons of Fgf13 -/Y mice., Conclusion: This study revealed that FGF13 could stabilize microtubules to modulate sodium channel function in DRG neurons and modulate inflammatory pain. This study provides a novel mechanism for FGF13 modulation of sodium channel function and suggests that FGF13 might be a novel target for inflammatory pain treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

Mutation-induced transformations of conductivity and selectivity in NaChBac bacterial channels are studied experimentally and interpreted within the framework of ionic Coulomb blockade (ICB), while also taking account of resonant quantised dehydration (QD) and site protonation. Site-directed mutagenesis and whole-cell patch-clamp experiments are used to investigate how the fixed charge Q f at the selectivity filter (SF) affects both valence selectivity and same-charge selectivity. The new ICB/QD model predicts that increasing ∣Q f ∣ should lead to a shift in selectivity sequences toward larger ion sizes, in agreement with the present experiments and with earlier work. Comparison of the model with experimental data leads to the introduction of an effective charge Q f ∗ at the SF, which was found to differ between Aspartate and Glutamate charged rings, and also to depend on position within the SF. It is suggested that protonation of the residues within the restricted space of the SF is important in significantly reducing the effective charge of the EEEE ring. Values of Q f ∗ derived from experiments on divalent blockade agree well with expectations based on the ICB/QD model and have led to the first demonstration of ICB oscillations in Ca 2+ conduction as a function of the fixed charge. Preliminary studies of the dependence of Ca 2+ conduction on pH are qualitatively consistent with the predictions of the model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pufferfish saxitoxin and tetrodotoxin binding proteins (PSTBPs) play an important role in the toxification of certain species of pufferfish. Recombinant Takifugu rubripes PSTBP1 (rTrub.PSTBP1) is reported to bind to tributyltin, and so it has been suggested that rTrub.PSTBP1 may reduce the toxicity of tributyltin. However, the role of PSTBP1 in vivo remains to be elucidated. Here, we established a transgenic medaka line showing whole-body Renilla reniformis green fluorescent protein and Trub.PSTBP1 expression, as confirmed by real-time polymerase chain reaction and mRNA-Seq analysis. mRNA-Seq analysis also showed that cytochrome P450 superfamily genes and the gene encoding ATP-binding cassette sub-family G member 2 were highly expressed in the transgenic medaka. Using embryos of the transgenic medaka line, we conducted an in ovo nanoinjection test to examine the effect of Trub.PSTBP1 in vivo, and obtained data suggesting that Trub.PSTBP1 expression may have reduced the toxicity of tributyltin in our transgenic medaka line. Our findings will be useful for future functional analyses of Trub.PSTBP1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Theories of pain have traditionally attributed the sensory experience of pain to the brain. We present here a new hypothesis on the origin of pain which is based on a novel approach to the management of persistent pain. We call it the 'pain channel' hypothesis of the origin of pain. There are key components to the development of our hypothesis: [1] Our clinical outcome of a persistently pain-free state, representing a maintained pain score of 0/10 has been achieved in a growing cohort of various presentations of persistent pain now exceeding 130 patients over the course of the last five years. With complete control of pain, the patients rapidly return to their premorbid state and level of function. This result requires careful consideration and explanation. [2] Regional anaesthesia has been used as a diagnostic tool to confirm the clinically suspected source of the persistent pain. The pharmacodynamics of local anaesthetics identify the sodium channel of the primary nociceptive sensory neuron as the critical subcellular structure generating pain. [3] Sodium channel function has been recognised as a bioelectromagnetic phenomenon. [4] Neuromodulation has been used to provide our long-term pain relief result. We understand the neuromodulation unit as producing an electromagnetic field within the super low wavelength range of the electromagnetic spectrum and we have devised a strategy which we believe delivers maximal electromagnetic field effect to the intended sodium channels to create a long-term conduction block. We believe that our clinical outcome challenges the current understanding of the role of the brain in pain. We hypothesise that pain is a peripheral phenomenon rather than being a construct of the brain, as our strategy is peripherally based and completely reverses the presenting clinical profile of persistent pain. More specifically we hypothesise that the sensory phenomenon of pain is a function of specific sodium channels which are coded for pain and which are part of the subcellular structure of peripheral nociceptive sensory nerves. We believe that these hypotheses can lead to a change in focus in the diagnosis and management of pain and drive improvement in current technology and medications to facilitate effective treatment of persistent pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)