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At least 19 recordsLinked to original sources

PubMed2025

TrkA of Streptococcus mitis CCUG31611 binds cyclic di-adenosine monophosphate and is required for growth in low potassium conditions.

Cyclic di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger regulating many physiological processes in bacteria. In the oral commensal species Streptococcus mitis, c-di-AMP is involved in regulating metabolism, growth, colony morphology, chain length, biofilm formation and DNA stress tolerance. However, no c-di-AMP-regulated effector proteins have yet been characterized in S. mitis. In this study, we first show that a ΔcdaA mutant, unable to produce c-di-AMP, grows slowly under low environmental potassium conditions. Growth of the cdaA mutant was not restored by reintroducing cdaA in the original locus (KBcdaA). Whole-genome sequencing of multiple KBcdaA isolates revealed secondary mutations in a putative potassium transporter. The mutations were predicted to result in the truncation of the protein or the alteration of a conserved glycine residue essential for selective potassium uptake, disrupting protein function. A Δpde2 mutant overproducing c-di-AMP survived poorly under high environmental sodium concentrations. We then characterized the potassium transporter regulator protein TrkA. Biochemical analyses of the purified recombinant TrkA protein revealed that it specifically binds c-di-AMP with high affinity in vitro. Using deletion mutants of trkA, we demonstrate that TrkA is essential for growth under low environmental potassium conditions. Ultra-high-performance liquid chromatography coupled to tandem mass spectrometry revealed lower c-di-AMP concentration in the ΔtrkA mutant compared to the WT. This was not due to transcriptional regulation of the expression of the c-di-AMP turnover proteins CdaA, Pde1 or Pde2. C-di-AMP production is not affected by the extracellular potassium concentrations under the conditions tested. We also demonstrate a potential role of TrkA in UV stress tolerance but do not characterize the mechanism in this study.

Potassium↗

PubMed2025

In silico prediction of the impact of genomic variations in the small conductance calcium activated potassium channel SK3 structure and function.

The small-conductance calcium-activated potassium channel SK3, encoded by the KCNN3 gene, plays a critical role in regulating dopaminergic neuron (DN) firing patterns by modulating after hyperpolarization currents. SK3 dysfunction has been implicated in neuropsychiatric and neurodegenerative disorders. We analyzed structural and functional consequences of KCNN3 splicing and genetic variation. Alternative splicing variants of the KCNN3 gene were retrieved from the Ensembl database and aligned using T-Coffee, manually inspected and curated. Protein domains were identified with Pfam 35.0, SMART 9.0, and InterPro 98.0, and visualized. An AlphaFold2 model of SK3 full-length protein (UniProt: Q9UGI6) used as reference and structural models of its splicing variants were predicted with ColabFold. Functional domains (S1-S6 transmembrane helices, H5 pore loop, and calmodulin-binding) were defined and superimposed onto the AlphaFold2 reference. Domain integrity was assessed based on completeness of all expected residue indices within each functional region. SNPs and CNVs across all coding KCNN3 splicing variants were analyzed, classified, and filtered to isolate pathogenic variants prioritizing non-synonymous amino acid substitutions. Differential variant impacts across splicing isoforms were assessed by mapping variant positions to individual transcript protein sequences and used to predict functional consequences. Two long and two short splicing variants are known. Short variants lack the motif required for potassium channels. Pathogenic variants result from missense mutations resulting in amino acid substitutions. In all cases, the consequential effects depend on the specific location and role of the amino acid being changed.

SK3 channels↗

PubMed2025

Genome-wide identification of potassium transporters and channels in Malus domestica genome.

Potassium (K+) is an essential nutrient for plants. It contributes to most physiological and biochemical pathways for plant metabolism, growth, and development. It is the most available plant nutrient, comprising 10–15% of plant weight. Plants have a sophisticated system of K+ transporters and channels for distribution in plant body. Apple is one of the most consumed fruits in the world. Its fruit quality and yield are positively affected by K+. However, limited information is available about K+ transport systems in Apple. In this study, 47 candidate genes (26 K+ transporters and 21 K+ channels) have been identified in Apple (Malus domestica) genome. The phylogenetic comparisons with other plants (Glycine max, Arabidopsis thaliana, and Oryza sativa) indicated that the K+ transport system is much conserved among different plants. The analysis of Gene structure showed the presence of specific introns and exon patterns for these gene families. Transcriptomic data analysis and RT-qPCR demonstrated significant variations in the transcript abundance of these genes in response to abiotic stresses. The current project represents the first report about the K+ transport system in Apple. Therefore, it may act as a starting point for further functional characterizations.

Malus↗

PubMed2026

Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and KV4.3 Functional Loss.

BACKGROUND: Spinocerebellar ataxia type 19/22 (SCA19/22) is a rare autosomal dominant neurodegenerative disorder caused by KCND3 variants encoding the KV4.3 potassium channel. While most pathogenic variants result in loss-of-function (LOF), no pathogenic variants were previously identified in the channel's selectivity filter, a critical domain for ion selectivity. OBJECTIVES: To elucidate the genetic cause and functional LOF mechanisms underlying severe early-onset cerebellar ataxia and neurodevelopmental impairment in monozygotic twins. METHODS: We evaluated twins presenting with early-onset cerebellar ataxia, developmental delay, and cognitive impairment. Whole-exome sequencing (WES) identified a KCND3 c.1103T>C (p.L368P) variant. Functional impacts were assessed through HEK293T cell protein expression, Xenopus oocyte electrophysiology, and structural homology modeling. RESULTS: WES identified a heterozygous de novo p.L368P variant in the "TLGYG" selectivity filter sequence. Modeling predicted a pore radius reduction, blocking potassium permeation. Biochemical analyses revealed markedly reduced protein expression and impaired trafficking. Electrophysiological recordings confirmed complete potassium current loss and a strong dominant-negative effect on wild-type KV4.3 currents. Clinically, the twins exhibited severe intellectual disability, developmental delay, and cerebellar atrophy with pontine flattening, without epilepsy. CONCLUSIONS: Identifying the first pathogenic variant in the KV4.3 selectivity filter highlights its critical role in channel proteostasis and ion conductance. The p.L368P variant produces a pronounced LOF phenotype and broadens the SCA19/22 clinical spectrum, indicating the filter's structural integrity is a key determinant of disease severity. © 2026 International Parkinson and Movement Disorder Society.

KCND3↗

PubMed2026

Sulfide-oxidizing potential and hypersalinity tolerance strategies in salt-crust covered coastal microbial mats.

Hypersaline microbial mats are dense microbial ecosystems capable of performing nearly complete element cycling under harsh conditions including near-saturation salinity. Our previous study of salt-crust-covered microbial mats showed that oxygenic photosynthesis was inhibited at salt saturation, while phototrophic sulfide oxidation persisted despite well-known sulfide-oxidizing taxa being undetectable. In this study, we analyzed metagenome-assembled genomes (MAGs) from the same mats to identify sulfide-oxidizing taxa and adaptations enabling oxygenic phototrophs to survive salt saturation. We extended the dataset by including morphologically identical mats exposed to lower salinity regimes to identify metabolic capabilities specifically selected for by saturation-level salinity. The phototrophic sulfide oxidation capability was found in nearly all cyanobacterial MAGs, in some Chloroflexota, and in abundant Rhodovibrio populations previously not known to oxidize sulfide. Furthermore, we found clear indications of Haloarchaea-like potassium-based osmoregulation in Bradymonadaceae (Myxococcota) adding another taxon to the few known potassium-accumulating bacteria. Despite lower oxygen concentrations, salt-crust-covered mats showed smaller proportions of fermenters and higher proportions of aerobic microorganisms than lower-salinity mats. We compared the genetic signatures of hypersalinity and desiccation tolerance in cyanobacterial MAGs from this study to genomes from desiccation-prone environments such as desert soils and small freshwater streams. Genomes of hyperhalophilic cyanobacteria were characterized by lack of certain potassium transporters and catalase genes and presence of additional osmolyte transporter subunits and sulfide-oxidation genes. We hypothesize that during salt saturation the oxidative stress for mat dwelling cyanobacteria is lowered, while the ability to oxidize sulfide provides them with energy when oxygenic photosynthesis is inhibited.

Oxidation-Reduction↗

PubMed2026

The effect of nutrition education interventions on dialysis patients' outcomes: a systematic review and meta-analysis.

BACKGROUND: Non-adherence to dietary and fluid restrictions among dialysis patients is associated with adverse clinical outcomes. Quantifying the effectiveness of nutrition education interventions can inform practice and policy. METHODS: We searched MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO, Web of Science, and Scopus up to 15 July 2025, supplemented by trial registries and Google Scholar, with an updated search through 8 April 2026. Eligible studies included randomized and non-randomized trials evaluating nutritional education interventions in adult dialysis populations. Risk of bias was assessed using RoB-2 and ROBINS-I, certainty graded using GRADE, and random-effects meta-analyses conducted alongside subgroup, sensitivity, and meta-regression analyses. Publication bias was assessed with Egger and Begg tests and trim-and-fill where applicable. RESULTS: Forty-four studies comprising 4,106 participants were included. Nutrition education significantly improved knowledge (SMD = 1.09; 95% CI: 0.67-1.51) and health-related quality of life (SMD = 1.43; 95% CI: 0.86-2.00; I² = 0%), and reduced serum potassium (SMD = -0.52; 95% CI: -0.91 to -0.14; I² = 92%) and serum phosphate (SMD = -0.35; 95% CI: -0.56 to -0.15; I² = 81%). Results for albumin, creatinine, sodium, calcium, and BUN were inconsistent and non-significant. Most outcomes were rated low or very low certainty by GRADE, reflecting inconsistency, indirectness, and imprecision. Potential publication bias was identified for certain outcomes. CONCLUSIONS: Nutrition education consistently improves knowledge and quality of life and may modestly reduce serum phosphate and potassium in dialysis patients. High-quality registered trials with standardized outcomes and longer follow-up are needed to establish effectiveness and sustainability. PROSPERO REGISTRATION: CRD420251119567.

Humans↗

PubMed2025

Common food preservatives induce an oxidative stress response in Salmonella enterica serovar Typhimurium.

Despite their frequent use, the mechanisms of action of common food preservatives are poorly understood. As there is a drive to develop alternative preservatives, understanding the mechanisms of action of current preservatives can inform the development of novel food preservatives to ensure their efficacy. Here, we used TraDIS-Xpress, a large-scale, genome-wide unbiased screen to determine the mechanisms of action of common food preservatives by determining the genes that affect preservative susceptibility in Salmonella enterica serovar Typhimurium. We identified genes associated with central metabolism and oxidative stress responses that were important for all four preservatives. Formate dehydrogenase activity and synthesis was crucial for survival in the presence of both sodium chloride and potassium chloride. We found some preservative-specific effects on pathogen susceptibility, for example, LPS synthesis which improved survival upon exposure to sodium nitrite but harmed survival when exposed to sodium chloride or potassium chloride. This research expands our understanding of how some current preservatives act and can inform the effective use of preservatives in current and emerging food products to ensure high standards of food safety.

Salmonella typhimurium↗

PubMed2026

Low-burden metrics for monitoring healthy diets among nonpregnant females aged 15 to 49 years: a multicountry validation analysis using quantitative 24-hour dietary intake data.

BACKGROUND: Limited nationally representative quantitative dietary intake data and a lack of consensus on lower-burden tools and metrics hinder high-frequency monitoring of healthy diets globally. OBJECTIVES: This study aimed to evaluate the comparative construct validity and potential complementarity of low-burden metrics of a healthy diet among nonpregnant females aged 15 to 49 y. METHODS: Quantitative 24-h dietary intake data collected from 77,118 adolescent and adult females across 27 countries were used to construct low-burden metrics and reference metrics of dietary intake. Associations between mean-standardized low-burden measures or indicators and reference metrics were assessed using linear and logistic mixed-effect models, with Spearman's ρ used for survey-level rank correlations. Test characteristics identified low-burden indicators best differentiated adherence to reference indicators. RESULTS: An indicator reflecting nonconsumption of sweet foods and/or sweet beverages was most robustly associated with greater adherence to <10% energy from free sugars in upper-middle-income countries {odds ratio [OR] [95% confidence interval (CI)]: 5.35 [5.05, 5.66]}. Food group diversity score (FGDS) was most strongly associated with and differentiated higher mean adequacy ratio of micronutrients [β of 1-standard deviation (SD) change: ∼11 percentage points (9, 12); ρ: 0.79], whereas noncommunicable disease-Protect score best reflected consumption of ≥400 g/d of fruits and vegetables [range OR of 1-SD changes (95% CI): 2.56-3.01 (2.40, 3.13) in lower-middle and high-income countries, respectively; ρ: 0.56]. FGDS and Global Diet Quality Score Positive were most consistently associated with achieving ≥25 g/d of fiber and ≥3510 mg/d of potassium across contexts. CONCLUSIONS: Low-burden data collection tools yield valid metrics, enabling high-frequency monitoring of healthy diets across contexts. Specifically, avoiding sweet foods and/or sweet beverages is an indicator for adherence to WHO free sugar guidelines among nonpregnant females in upper-middle-income countries, whereas metrics reflecting nutritious food group diversity strongly reflect better micronutrient adequacy and adherence to WHO guidelines for fruits and vegetables, fiber, and potassium intakes within and across contexts.

Humans↗

PubMed2026

Low-salinity stress alters growth, histology, physiology, and transcriptomic profiles of the gills and antennal glands in Macrobrachium rosenbergii.

Salinity is a major abiotic constraint in freshwater aquaculture of the giant freshwater prawn Macrobrachium rosenbergii, yet the coordinated roles of the gills and antennal glands, the two primary osmoregulatory organs in decapod crustaceans, under low-salinity stress remain poorly characterized. Here, we integrated histological, physiological, and transcriptomic analyses to characterize the adaptive responses of M. rosenbergii to acute (96 h) and chronic (8 weeks) exposure to salinity 5. Chronic low-salinity stress significantly impaired growth performance and decreased the survival rate. Acute stress induced thinning of the gill filaments, partial disorganization of pillar cells, and dilation of the intermicrovillar space in the antennal glands, whereas chronic stress caused gill vacuolization, cuticle thinning, and adaptive folding of antennal gland microvilli. In parallel, acute exposure significantly decreased hemolymph sodium and potassium ion concentrations but increased magnesium ion concentration, whereas chronic exposure increased hemolymph sodium and potassium ion concentrations, upregulated gill Na+/K+-ATPase activity, and enhanced hepatopancreatic antioxidant capacity. Transcriptomic analyses revealed distinct tissue-specific responses. Under acute stress, the gills preferentially activated pathways associated with cytoskeletal remodeling, motor proteins, and tight junctions, whereas chronic acclimation shifted the transcriptional response toward the renin-angiotensin system and glutathione metabolism. In the antennal glands, acute stress rapidly activated the renin secretion pathway, whereas chronic exposure promoted membrane remodeling by enriching pathways related to lipid and glycan metabolism. These findings reveal tissue-specific functional differentiation and synergistic coordination between the gills and antennal glands that underpin M. rosenbergii's adaptive response to low-salinity stress.

Animals↗

PubMed2026

Safety of insulin eye drops in the treatment of open angle glaucoma: a randomized phase I clinical trial.

OBJECTIVE: The progression of glaucoma despite adequate intraocular pressure (IOP) control highlights the need for neuroprotective and neuroregenerative therapies. Preclinical studies suggest insulin promotes retinal ganglion cell survival and regeneration, but its safety in higher concentrations (100 and 500 units/mL), administered topically, has been poorly characterized in humans. We aim to assess the safety and tolerability of these two concentrations of insulin eye drops in patients with open-angle glaucoma (OAG). DESIGN: A phase I, randomized, double-blind, placebo-controlled, single-centre clinical trial. PARTICIPANTS: Patients with mild to moderate OAG were randomized 2:2:1 to receive once-daily topical insulin U-100, U-500, or placebo in 1 eye for 5 days, with follow-up visits at 1, 3, and 6 months. The primary safety outcomes include glycemia, serum potassium, ocular adverse events (AEs), and ocular tolerability scores. Secondary outcomes included IOP, best-corrected visual acuity (BCVA), retinal nerve fibre layer thickness, ganglion cell complex, visual field, and OCT angiography. RESULTS: Eighteen open-angle glaucoma patients were enrolled (mean age: 66.2 ± 10.1 years). No serious AEs related to insulin were observed. One asymptomatic, transient near-hypoglycemia event occurred in a fasting participant (3.9 mmol/L), with no recurrence after dietary adjustment. No significant changes were found in serum potassium, IOP, BCVA, visual fields, or OCT. Ocular symptoms in the insulin groups were limited to transient, mild burning sensation upon application. One participant experienced cystoid macular edema at 3 months, which was attributed to pre-existing ocular pathology. CONCLUSION: Topical insulin at 100 and 500 units/mL concentrations was well tolerated in patients for short-term use and did not result in significant systemic or ocular toxicity.

Aged↗

PubMed2025

Calmodulin D133H Disrupts Cav1.2 and Kv7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome.

Calmodulin (CaM) plays a central role in cardiac excitation-contraction coupling by regulating ion channels, including the L-type calcium (Ca2+) channel Cav1.2 and the voltage-gated potassium (K+) channel Kv7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca2+ binding at the C-terminal lobe of CaM, altering its Ca2+-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca2+-dependent inactivation (CDI) of Cav1.2, prolonging Ca2+ influx, while also reducing activation of Kv7.1, thereby limiting repolarising K+ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca2+ and K+ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability.

Calmodulin↗

PubMed2024

Recurrent ATP1A1 variant Gly903Arg causes developmental delay, intellectual disability, and autism.

ATP1A1 encodes a sodium-potassium ATPase that has been linked to several neurological diseases. Using exome and genome sequencing, we identified the heterozygous ATP1A1 variant NM_000701.8: c.2707G>A;p.(Gly903Arg) in two unrelated children presenting with delayed motor and speech development and autism. While absent in controls, the variant occurred de novo in one proband and co-segregated in two affected half-siblings, with mosaicism in the healthy mother. Using a specific ouabain resistance assay in mutant transfected HEK cells, we found significantly reduced cell viability. Demonstrating loss of ATPase function, we conclude that this novel variant is pathogenic, expanding the phenotype spectrum of ATP1A1.

Child↗

PubMed2026

Efficacy and Safety of the Kidney Function-Based Finerenone Dosing Strategy Used in FINEARTS-HF.

BACKGROUND: Given that mineralocorticoid receptor antagonists have the potential to impair renal function and induce hyperkalemia, close monitoring of estimated glomerular filtration rate (eGFR) and serum potassium levels is essential to ensure the safe administration of this therapy. OBJECTIVES: In this prespecified analysis, the authors evaluated the efficacy and safety of the kidney function-based finerenone dosing strategy used in the FINEARTS-HF trial. METHODS: In FINEARTS-HF, patients with an eGFR of 25 to 60 mL/min/1.73 m2 at baseline were stratified at randomization to the low-dose group and started on 10 mg of finerenone once daily (titrated to a maximum 20 mg/d) or matching placebo, whereas those with an eGFR >60 mL/min/1.73 m2 at baseline were stratified to the high-dose group and started on 20 mg of finerenone once daily (titrated to a maximum 40 mg/d) or matching placebo. The primary outcome was the composite of total (first and recurrent) heart failure events and cardiovascular death. RESULTS: Among 5,986 (99.8%) analyzable patients, 3,159 were assigned to the higher eGFR/high-dose stratum and 2,827 to the lower eGFR/low-dose stratum group. The mean ± SD achieved dose was 32.3 ± 9.1 mg (finerenone) and 34.4 ± 7.8 mg (placebo) in the higher eGFR/high-dose stratum, and 15.6 ± 4.3 mg (finerenone) and 16.7 ± 4.0 mg (placebo) in the lower eGFR/low-dose stratum. The effect of finerenone on the primary outcome was consistent across the 2 dosing strata (higher eGFR/high-dose stratum: rate ratio: 0.77 [95% CI: 0.63-0.94] vs lower eGFR/low-dose stratum: rate ratio: 0.87 [95% CI: 0.74-1.03]; P for interaction = 0.34). Consistent benefits were observed for the components of the primary outcome and all-cause death. Safety was also consistent between dosing strata, except for hypokalemia, where the reduction in the odds of hypokalemia with finerenone compared to placebo was greater in the higher eGFR/high-dose stratum (P-interaction < 0.01). CONCLUSIONS: In FINEARTS-HF, an eGFR-based dosing strategy allowed effective and safe use of finerenone in patients with heart failure with mildly reduced ejection fraction/ heart failure with preserved ejection fraction with a baseline eGFR as low as 25 mL/min/1.73 m2. We recommend that clinicians implement the trial-validated dosing strategy and incorporate appropriate uptitration to the target dose to ensure optimal therapeutic outcomes. (FINEARTS-HF [Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone in Participants With Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40%; NCT04435626).

Aged↗

PubMed2026

Epilepsy of infancy with migrating focal seizures: A scoping review of clinical features, diagnostic testing including genetics, long-term outcomes, mortality, and current and emerging therapeutic strategies.

BACKGROUND: Epilepsy of infancy with migrating focal seizures (EIMFS) is among the most severe developmental and epileptic encephalopathies (DEEs), marked by intractable multifocal seizures migrating across both hemispheres, profound developmental arrest, and high early mortality. Advances in next-generation sequencing have revealed a heterogeneous genetic architecture dominated by KCNT1 gain-of-function variants across more than 30 implicated genes, creating opportunities for precision therapeutics. OBJECTIVE: To systematically map published evidence on the clinical, electrophysiological, neuroimaging, genetic, and therapeutic landscape of EIMFS, and to delineate critical knowledge gaps and future research priorities. METHODS: A scoping review was conducted following the Arksey and O'Malley framework, searching PubMed, Ovid MEDLINE, Embase, Cochrane Library/CENTRAL, and ClinicalTrials.gov. RESULTS: Of 643 articles screened, 89 met inclusion criteria. Beyond confirmation of the canonical electroclinical phenotype, several gaps emerged: neonatal versus post-neonatal onset stratification by genetic etiology remains largely uncharacterized; genotype-specific EEG biomarkers are lacking except for a single small KCNT1 study; and the clinical significance of atypical EEG features-including burst suppression and hypsarrhythmia-is undefined. Neuroimaging literature documents progressive cerebral atrophy and myelination abnormalities without quantitative volumetry, diffusion tractography markers, or attribution to seizure burden, medication effects, or underlying etiology. Genetic diagnostic yield was 70-80%, with KCNT1 accounting for 30-50% of solved cases; however, genotype-outcome stratification is limited. Seizures were broadly refractory; potassium bromide, ketogenic diet, cannabidiol, and quinidine (in KCNT1-confirmed cases) showed partial efficacy. Emerging precision approaches include sodium channel blockers for SCN2A gain-of-function variants, novel small molecules, fluoxetine, antisense oligonucleotides, and divalent siRNA targeting KCNT1. Systemic-to-pulmonary collateral circulation causing severe cardiopulmonary complications was reported across multiple cases, yet no consensus screening protocol exists. CONCLUSIONS: EIMFS remains one of the most refractory epilepsy syndromes of infancy. Precision genetic diagnosis is essential to guide targeted therapy. International collaborative registries, standardized outcome measures, genotype-stratified biomarker studies, and rapid point-of-care genomic testing are urgently needed to advance evidence-based care for this highly vulnerable population.

Humans↗

PubMed2025

Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice.

Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while minimizing systemic exposure and side effects. In model systems, replication-defective, disease-free, herpes simplex virus (rdHSV) gene therapy expressing an analgesic carbonic anhydrase-8 (CA8∗) peptide variant corrects somatosensory hyperexcitability by activating Kv7 voltage-gated potassium channels, produces profound, long-lasting analgesia and treats chronic pain from knee osteoarthritis (OA). In these studies, we provide the first non-glucagon-like peptide (GLP) biosafety, efficacy, biodistribution, shedding, and histopathology examination of this rdHSV-CA8∗. Naive mice were examined for clinical safety, biodistribution across all major tissues, knee histopathology, and analgesic efficacy via the intra-articular knee route of administration. We observed no signs of persistent toxicity, viral genomes remained where they were injected, and there was no evidence of shedding. Profound analgesia persisted for 6 months without functional impairments. These initial biosafety and efficacy data support further development of rdHSV-CA8∗ for treating chronic knee pain due to moderate to severe OA.

Animals↗

PubMed2024

The effect of fampridine on working memory: a randomized controlled trial based on a genome-guided repurposing approach.

Working memory (WM), a key component of cognitive functions, is often impaired in psychiatric disorders such as schizophrenia. Through a genome-guided drug repurposing approach, we identified fampridine, a potassium channel blocker used to improve walking in multiple sclerosis, as a candidate for modulating WM. In a subsequent double-blind, randomized, placebo-controlled, crossover trial in 43 healthy young adults (ClinicalTrials.gov, NCT04652557), we assessed fampridine's impact on WM (3-back d-prime, primary outcome) after 3.5 days of repeated administration (10 mg twice daily). Independently of baseline cognitive performance, no significant main effect was observed (Wilcoxon P = 0.87, r = 0.026). However, lower baseline performance was associated with higher working memory performance after repeated intake of fampridine compared to placebo (rs = -0.37, P = 0.014, n = 43). Additionally, repeated intake of fampridine lowered resting motor threshold (F(1,37) = 5.31, P = 0.027, R2β = 0.01), the non-behavioral secondary outcome, indicating increased cortical excitability linked to cognitive function. Fampridine's capacity to enhance WM in low-performing individuals and to increase brain excitability points to its potential value for treating WM deficits.

Adult↗

PubMed2026

Randomized controlled trial comparing 7-day fexuprazan-based and 14-day rabeprazole-based triple therapies for Helicobacter pylori eradication.

BACKGROUND: Fexuprazan is a newly developed potassium-competitive acid blocker used for the treatment of acid-related gastrointestinal diseases; however, clinical data regarding its efficacy in Helicobacter pylori eradication are lacking. This study evaluated the efficacy and safety of a 7-day fexuprazan-based triple therapy regimen compared with a 14-day rabeprazole-based triple therapy regimen for H. pylori infection in Korean patients. METHODS: A randomized controlled single-center study was conducted to compare the eradication rates between 7-day fexuprazan (40 mg)-based triple therapy (with 1 g amoxicillin and clarithromycin 500 mg administered twice daily) and 14-day rabeprazole (20 mg)-based triple therapy for H. pylori eradication. The primary endpoint was the success rate of H. pylori eradication, determined using the 13C-urea breath test. Safety outcomes were also evaluated. RESULTS: A total of 79 patients were randomly assigned to the fexuprazan and rabeprazole groups. In the full analysis set, eradication rates were 80.00% (32/40) in the fexuprazan group and 82.05% (32/39) in the rabeprazole group. In the per-protocol set, eradication rates were 83.78% (31/37) and 88.89% (32/36), respectively (P = 1.000 and P =.737). The overall incidence of treatment-emergent adverse events was 70.00% (28/40) in the fexuprazan group and 66.67% (26/39) in the rabeprazole group, with no significant difference between groups (P =.812); both regimens were well tolerated. Among patients with clarithromycin-susceptible strains in full analysis set, eradication rates were 93.10% (27/29) in the fexuprazan group and 87.09% (27/31) in the rabeprazole group (P =.672). In the per-protocol set, eradication rates for susceptible strains were 96.42% (27/28) in the fexuprazan group and 93.10% (27/29) in the rabeprazole group (P = 1.000). CONCLUSION: Seven-day fexuprazan-based triple therapy demonstrated eradication efficacy comparable with that of 14-day rabeprazole-based therapy in treatment-naïve Korean patients with H. pylori infection. The fexuprazan-based regimen showed a similar safety profile and comparable incidence of adverse events with that of the rabeprazole-based regimen.

Humans↗

PubMed2026

GIRK Channels Regulate Circadian Rhythms of Excitability in Prokineticin 2 Neurons of the Suprachiasmatic Nucleus and Modulate Behavioral Circadian Rhythms.

The suprachiasmatic nucleus (SCN), the central circadian clock in mammals, generates robust yet adaptable circadian rhythms through electrically mediated coordination among heterogeneous peptidergic neuronal populations with presumed cell type-specific roles. Previous studies have proposed that circadian changes in membrane excitability of individual SCN neurons arise from time-of-day-dependent shifts in the relative balance of subthreshold Na+ and K+ conductances. Although multiple channels have been implicated in these processes, how nocturnally dominant K+ conductances are implemented in a cell type-specific manner remains poorly understood. Prokineticin 2 (Prok2) has been identified as a SCN signaling peptide essential for behavioral circadian regulation; however, the electrophysiological properties of Prok2-expressing neurons and the mechanisms underlying their diurnal rhythmicity remain largely unexplored. Here, using electrophysiological approaches in mice of either sex, we show that Prok2 neurons exhibit diurnal variations in electrical properties, with higher excitability during the day and reduced excitability at night, and that G-protein-coupled inwardly rectifying potassium (GIRK) channel-mediated basal current contributes to nighttime hyperpolarization. Immunofluorescence and single-cell RT-PCR analyses revealed that GIRK1 and GIRK3 are the predominant GIRK subunits expressed in Prok2 neurons. Moreover, Prok2 neuron-specific deletion of GIRK3 using in vivo genome editing resulted in significant nocturnal depolarization and induced abnormalities in behavioral rhythms, including delayed activity onset and circadian period lengthening, with altered SCN network activity. Together, these findings suggest that tonic, G-protein-dependent regulation of GIRK channels provides a night-specific inhibitory mechanism that contributes to intrinsic diurnal neuronal excitability in Prok2 neurons and supports the regulation of behavioral circadian rhythms.

Animals↗