Search Results (349)

Serotonergic projections innervate both the dorsal and ventral cochlear nuclei; however, the electrophysiological consequences of serotonergic input in the ventral cochlear nucleus (VCN) remain incompletely understood. This study aimed to identify the serotonin receptor subtypes involved in serotonergic modulation of stellate cells in the mouse anteroventral cochlear nucleus (AVCN) and to determine the underlying ion channel mechanisms. Whole-cell patch-clamp recordings were performed in acute brain slices obtained from postnatal day 12–17 mice. Bath application of serotonin (25 µM) induced membrane depolarization (~5 mV) and increased action potential firing. Pharmacological experiments demonstrated that antagonists of 5-HT1A, 5-HT2A, and 5-HT2C receptors partially reversed the depolarization and reduced serotonin-induced inward currents, indicating that multiple receptor subtypes contribute to serotonergic excitation. Blockade of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with extracellular Cs⁺ suppressed approximately 95% of the serotonin-induced depolarization and inward current, implicating HCN channel-mediated Ih as a principal ionic mechanism. Serotonin significantly increased Ih amplitude. Analysis of steady-state activation revealed no statistically significant shift in V0.5; however, under near-resting membrane potential conditions, serotonin significantly reduced the slope factor of the activation curve, consistent with altered voltage sensitivity of Ih gating. Immunohistochemical analysis confirmed the presence of 5-HT1A, 5-HT2A, and 5-HT2C receptors in the AVCN. Together, these findings indicate that serotonergic excitation of AVCN stellate cells is mediated by coordinated activation of multiple 5-HT receptor subtypes and primarily involves modulation of HCN-dependent subthreshold membrane dynamics. Full article

Arif and colleagues commented on our paper Fleifil et al. “DNAJB1-PKAc is expressed in Young Patients with Pediatric Liver Cancers and Enhances Carcinogenic Pathways” published in Cancers in 2024. In our paper, we examined expression of DNAJB1::PRKACA (DNAJB1-PKAc or J-PKAc) in the Bio Bank of HBL (Hepatoblastoma) and HCN-NOS (Hepatocellular Malignant Neoplasm, Not Otherwise Specified) tissue samples collected at CCHMC during the last five years. Our data demonstrated that DNAJB1::PRKACA was detected in approximately 70% of HBL/HCN-NOS patients, with varying expression levels. In the commentary, the authors reviewed their earlier data and found no evidence of the fusion DNAJB1-PKAc expression within their cohorts of HBL specimens. Based on these data, the authors stated that “…DNAJB1::PRKACA remains specific to fibrolamellar carcinoma among liver tumors and caution against its use as a diagnostic marker for hepatoblastoma without rigorous validation in external cohorts.” After reviewing the commentary, we are offering a response outlined below. Full article

Methanol ammoxidation over FeMo/SiO₂ has emerged as a promising low-temperature route to hydrogen cyanide (HCN). In this work, an eight-parameter Mars–van Krevelen (MvK) kinetic model, previously established from intrinsic fixed-bed experiments, is embedded in a heterogeneous plug-flow description to design an industrial multitubular reactor with a nominal HCN capacity of 10,000 t∙a⁻¹. The reactor is represented by a bank of isothermal tubes that are operated at 420 °C and a mildly elevated pressure, each packed with spherical FeMo/SiO₂ pellets. Detailed simulations for a 30 mm inner tube diameter and 2 mm pellets, including an Ergun pressure drop and intraparticle diffusion with realistic effective diffusivities, show that a 4 m bed at an outlet pressure of 1.5 bar (abs) achieves an essentially complete methanol conversion with a carbon-based HCN yield of ≈0.95 at a space time of ≈160 gcat∙h∙mol⁻¹. Axial effectiveness factors remain above ≈0.6, indicating moderate but manageable diffusion limitations. Comparison with a 35 mm/3 mm geometry reveals a clear trade-off between pressure drop and HCN selectivity. Parametric studies of space time, feed composition and outlet pressure delineate a broad non-flammable operating window with robust HCN yield and moderate compression duty. The results demonstrate how a mechanistic MvK rate expression can be translated into a practical design framework for FeMo-based multitubular HCN reactors. Full article

Flaxseed (Linum usitatissimum L.) is a rich source of α-linolenic acid (ALA) and lignans but contains toxic cyanogenic glycosides (CGs) that limit its application in foods. This study investigated the efficacy of a specialized Lactobacillaceae consortium in detoxifying flaxseed and the subsequent effects of adding this cyanogenic glycoside-depleted flaxseed (CGDF) to a kimchi matrix. Ground flaxseed and CGDF were added to the kimchi seasoning mixture at concentrations of 0.5%, 1.0%, and 2.0% (w/w) and fermented at 4 °C for 8 weeks. Analytical results confirmed that the fermentation process reduced linustatin and neolinustatin to undetectable levels (<500 mg/kg) and reduced total hydrogen cyanide (HCN) to below the Japanese regulatory limit of 10 mg/kg established under the Food Sanitation Act. During fermentation, CGDF-supplemented groups exhibited a delayed decrease in pH and higher retention of free sugars and vitamin C compared to the control and raw flaxseed groups. Notably, the 2.0% CGDF group maintained high oxidative stability of ALA, which we attribute to a putative antioxidant protection mechanism driven by the bioconversion of lignan glycosides into bioactive aglycones. These findings suggest that incorporating biologically detoxified flaxseed into kimchi creates a functional food system that ensures safety while enhancing nutritional stability. Overall, this work provides foundational evidence for developing safe, nutritionally enhanced functional foods within the One Health framework, integrating food safety, microbial ecology, and improved bioactive compound availability. Full article

Achieving efficient and clean use of low-volatile coal is of vital importance to China’s energy system. This study aims to elucidate how the high-concentration-CO₂ atmosphere influences the migration pathways of fuel-bound nitrogen during the pyrolysis of low-volatile coal, thereby providing critical insights for the prediction and control of NO_x emissions under oxy-fuel conditions. A high-temperature drop-tube furnace system capable of high heating rates (up to 10⁴–10⁵ °C/s) was employed to comparatively investigate the pyrolysis behavior of a typical low-volatile coal (volatile matter content of 7.44%) under Ar and pure CO₂ atmospheres at 1000–1400 °C. The outcomes show that the CO₂ atmosphere significantly promoted the release of volatiles, with the volatile release rate at 1400 °C reaching 2.1 times that under the Ar atmosphere. While volatile nitrogen primarily consists of HCN and NH₃ with HCN dominance at lower temperatures, NH₃ release exceeds HCN by more than tenfold at 1400 °C. CO₂ promotes nitrogen release through enhanced gasification reactions, reducing char nitrogen proportion while increasing volatile nitrogen yield approximately fourfold at elevated temperatures. The X-ray photoelectron spectroscopy analysis reveals the transformation pathway of nitrogen functionalities from quaternary nitrogen to pyridine nitrogen and subsequently to pyridine under oxy-fuel conditions. These findings provide fundamental insights into fuel nitrogen evolution mechanisms and offer theoretical support for optimizing oxy-fuel combustion processes toward efficient NO_x control. Full article

This investigation comparatively examined the toxicological, chemical, phytochemical, and antimicrobial characteristics of Paliurus spina-christi Mill. seeds and their oils collected over two consecutive years from four distinct locations in Türkiye. In the seeds, HCN levels ranged from 1.11 to 1.43 g/kg and total phenolics from 6.84 to 15.48 mg GAE/g, while quinic, gallic, protocatechlic, and tannic acids, along with cosmosiin, were identified as the main phenolics in the phenolic profile. In the seed oils, α-tocopherol content ranged from 2178.5 to 2528.4 mg/kg, total phenolics from 96.99 to 118.87 mg GAE/g, and antioxidant activity from 0.147 to 0.150 mg TE/g. β-Sitosterol predominated among sterols (61.51–66.51%). Macrominerals P, S, K, and Ca and microminerals Si, Pt, Pd, Ge, and Sn were present in notable amounts. An antimicrobial activity test revealed the bacteriostatic effects of the seed oils. In conclusion, this study elucidates the toxicological, chemical, phytochemical, and antimicrobial attributes of P. spina-christi seeds and oils, showing that the proportions of the identified bioactive components varied according to harvest year and location. Based on this data, it is recommended that further research is conducted in the future regarding the potential use of P. spina-christi seeds/seed oil for human nutrition, in terms of standardization, bioavailability, and clinical validation. Full article

Glucagon is an endogenous peptide that is produced in the pancreas. Via glucagon receptors, glucagon increases the beating rate in cultured rat neonatal cardiomyocytes and also in isolated right atrial preparations from adult rats. Moreover, in living adult mice, injections of glucagon can elevate the heart rate. It is unknown whether these effects of glucagon in living adult mice are mediated via central glucagon receptors or via a direct effect on cardiac glucagon receptors. Thus, we tested the hypothesis that glucagon can exert a direct positive chronotropic effect in the adult mouse heart. We measured the contractile effects of cumulatively increasing concentrations of glucagon (0.1–100 nM) in isolated paced (1 Hz) left atrial preparations, in isolated spontaneously beating right atrial preparations and in isolated spontaneously beating retrogradely perfused whole hearts. We detected in isolated right atrial preparations time- and concentration-dependent positive chronotropic effects of glucagon that were reversed by the glucagon receptor antagonists SC203972 and desglucagon. The positive chronotropic effects of glucagon were also attenuated by 1 µM of ivabradine, an inhibitor of the hyperpolarization-activated cation channels (HCN), but not by 100 nM rolipram, a phosphodiesterase 4 inhibitor, nor by 10 µM of propranolol, a β-adrenoceptor antagonist. Moreover, the positive chronotropic effects of glucagon were also attenuated by stimulation of the A₁-adenosine receptor or muscarinic receptors. Glucagon decreased the force of contraction in right atrial preparations. In left atrial preparations, glucagon failed to alter the force of contraction. In isolated adult mouse hearts perfused in the Langendorff mode, 10 nM of glucagon increased the beating rate and reduced left ventricular force of contraction. The gene expression of the glucagon receptors was lowest in the left atrium, higher in the ventricle and highest in the right atrium of adult mice. In summary, glucagon exerted a positive chronotropic effect in the mouse heart via glucagon receptors, mediated, at least in part, via HCN channels in the sinus node. Full article

Increased levels of pro-vitamin A carotenoids in cassava (Manihot esculenta Crantz) roots is a valuable contribution toward reducing widely spread vitamin A deficiency in vulnerable human populations worldwide. This study aimed to evaluate five yellow-fleshed cassava genotypes with higher β-carotene contents for fresh consumption in the Cauca River Valley and the Pacific regions of Colombia. Agronomic performance, productivity, and culinary quality were assessed across four locations. The results showed that two yellow-fleshed genotypes had adequate performance in the subregions. SM3677-74 was identified for the Cauca River Valley subregion, and GM3650-51 for the Pacific subregion. These genotypes showed competitive performance compared to the regional checks (often outperforming them) and showed good adaptability to the target environments. The excellent productivity and enhanced nutritional quality (>5 µg/g β-carotene and >11 µg/g total carotenes) of these genotypes make them suitable for potential for release as new varieties in those specific subregions. The experimental genotypes demonstrated acceptable quality for consumption, with low HCN content (less than 50 µg/g) and cooking time was <30 min. The successful adaptation and superiority of improved cassava genotypes ensure the future availability of carotenes-enhanced cassava varieties the Pacific and Andean Regions in Colombia. Full article

Introduction: Clinical variability within families harbouring disease-causing genetic variants hampers clinical care and risk stratification. We studied a multigenerational family presenting with sinus bradycardia and long QT syndrome type 2 (LQTS2). The family harboured a pathogenic variant in KCNH2, which co-segregated with the observed LQTS2. We studied the genetic cause of the high occurrence of sinus bradycardia in this family. Methods: Clinical data was collected, including heart rate, QT-interval, symptoms, and echocardiographic parameters. QTc was calculated using the Bazett and the Fridericia formula. Sanger sequencing of HCN4 was performed, followed by segregation analysis of the identified variant with sinus bradycardia. The biophysiological consequences of two variants, KCNH2-p.L69P (c.206T>C) and HCN4-p.R666W (c.1996C>T), were assessed by patch-clamp experiments. Therefore, a heterologous model was generated by transfection of HEK293A or CHO-k1 cells, respectively. Results: Sanger sequencing of HCN4 identified HCN4-p.R666W (c.1996C>T), which has a stronger segregation with the observed sinus bradycardia than KCNH2-p.L69P. Patch-clamp experiments revealed that KCNH2-p.L69P and HCN4-p.R666W lead to a decrease in the corresponding current densities, which explains the LQTS and sinus bradycardia observed in the patients. Carriers of both genetic variants have a more severe LQTS2 phenotype, reflected in longer QT and higher incidence of syncope. Conclusions: We identified two (likely) pathogenic variants, KCNH2-p.L69P and HCN4-p.R666W, co-segregating with LQTS2 and sinus bradycardia, respectively. Patients carrying both variants showed a more severe phenotype. These findings highlight the importance of additional genetic testing when discordant features are present, thereby enabling more accurate diagnosis, risk prediction, and management. Full article

We investigated the ammoxidation of methanol for the production of hydrogen cyanide. Silica-supported FeMo oxide catalysts achieved above 98% conversion of methanol, with more than 90% selectivity for the ammoxidation reaction product, HCN. The oxidation products, CO and CO₂, were formed with a molar selectivity less than 10%, depending on the operating conditions. The kinetics of the ammoxidation of methanol were investigated in a fixed-bed tubular reactor at 320–445 °C and atmospheric pressure. A Mars–van Krevelen model accounted for the ammoxidation of methanol as well as the formation of CO and CO₂. The Levenberg–Marquardt algorithm was used to estimate the model parameters, which were statistically significant and fit the experimental data well. The model can be used to simulate and guide the operation of the industrial reactor. Full article

Comets are chemically rich and thermally extreme, spanning surface temperatures from ~50 K in the Oort Cloud to >1000 K for sungrazing bodies. These conditions may support key steps of prebiotic chemistry, including the synthesis of nucleic acid precursors. This study present a thermodynamic evaluation of seven candidate reactions, producing nitrogenous bases, sugars, nucleosides, and nucleotides, across the cometary temperature spectrum, 50–1000 K. Purine nucleobase synthesis, including adenine formation via aminoacetonitrile polymerization and HCN polymerization, is strongly exergonic at all temperatures. Sugar formation from formaldehyde is also exergonic, while intermediate pathways, e.g., 2-aminooxazole synthesis, become thermodynamically viable only above ~700 K. Nucleoside formation is thermodynamically neutral at low T but becomes favorable at elevated temperatures, whereas phosphorylation to AMP, i.e., adenosine-monophosphate, a nucleotide serving as a critical regulator of cellular energy status, remains highly endergonic under the entire T range studied. My analysis suggests that, under standard-state assumptions, comets can thermodynamically support formation routes of nitrogenous bases and simple sugars but not a complete nucleotide assembly. This supports a dual-phase origin scenario, where comets act as molecular reservoirs, with further polymerization and biological activation occurring post-delivery on planetary surfaces. Importantly, these findings represent purely thermodynamic assessments under standard-state assumptions and do not address kinetic barriers, catalytic influences, or adsorption effects on ice or mineral surfaces. The results should therefore be viewed as a baseline map of feasibility, subject to modifications in more complex chemical environments. Full article

Ammonia–coal co-combustion has emerged as a promising strategy for reducing carbon emissions from coal utilization, although its underlying reaction mechanisms remain insufficiently understood. The Chemkin simulation of zero-dimensional homogeneous reaction model and entrained flow reaction model was employed here, and the ROP (rate of production) and sensitivity analysis was performed for analyzing in-depth reaction mechanisms. The nitrogen conversion pathways were revealed, and the mechanisms were simplified. Based on simplified mechanisms, molecular-level reaction pathways and thermochemical conversion networks of nitrogen-containing precursors were established. The results indicate that NO emissions peak at a 30% co-firing ratio, while N₂O formation increases steadily. The NH radical facilitates NO reduction to N₂O, with NH + NO → N₂O + H identified as the dominant pathway. Enhancing NNH formation and suppressing NCO intermediates are key to improving nitrogen conversion to N₂. This paper quantifies the correlation between NO_x precursors such as HCN and NH₃ and intermediates such as NCO and NNH during ammonia–coal co-firing and emphasizes the important role of N₂O. These insights offer a molecular-level foundation for designing advanced ammonia–coal co-combustion systems aimed at minimizing NO_x emissions. Full article

Background: Developmental and Epileptic Encephalopathy (DEE) is a severe and heterogeneous neurological disorder in infancy/early childhood. DEE’s genetic and phenotypic variability complicates diagnosis and treatment. This retrospective study aimed to identify genetic variants and explore genotype–phenotype correlations in children with DEE using a targeted epilepsy gene panel (TGP) and Whole Exome Sequencing (WES). Patients and Methods: Medical records of children who underwent custom-designed 55-gene TGP and WES were reviewed. The diagnostic yield of each method was determined based on the detection of pathogenic (P) and likely pathogenic (LP) variants. Results: A total of 129 patients (66 males, 63 females) underwent TGP, which identified P/LP variants in 29 cases (22.48%). Variants were detected in SCN1A, KCNQ2, STXBP1, CDKL5, PCDH19, PLCB1, WWOX, SCN2A, FGF12, HCN1, SCN8A, and SLC35A2. WES further identified several variants in children with West syndrome. A TSC1 variant was detected in a patient without cutaneous stigmata of tuberous sclerosis complex. The NALCN variant in a patient was linked to Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies 1. A CTBP1 variant associated with extremely rare Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome was detected in another patient. A PIEZO2 variant—associated with Marden–Walker syndrome—was found in a child with Early Infantile Developmental and Epileptic Encephalopathy. Conclusions: These findings highlight the extensive genetic heterogeneity and phenotypic variability of DEE. WES demonstrates substantial value in identifying novel gene-disease associations and may be considered as a first-tier diagnostic tool in epilepsy and DEE. Full article

In this work, the gas sensing properties and adsorption mechanisms of Ag- and Au-doped SnSe₂ monolayers toward NO, NO₂, SO₂, H₂S, and HCN were systematically investigated via first-principles calculations. The results demonstrate that NO₂ exhibits the strongest interaction and the highest charge transfer in both doped systems, indicating superior sensing selectivity. Biaxial strain (ranging from −8% to 6%) was further applied to modulate adsorption behavior. By evaluating changes in equilibrium height, adsorption energy, charge transfer, and recovery time across ten representative adsorption systems, it was found that both compressive and tensile strains enhance the interaction between gas molecules and doped SnSe₂ monolayers. Specifically, H₂S/Au–SnSe₂ and HCN/Au–SnSe₂ are highly sensitive to tensile strain, while NO/Au–SnSe₂, H₂S/Ag–SnSe₂, NO/Ag–SnSe₂, and NO₂/Ag–SnSe₂ respond more strongly to compressive strain. Systems such as NO₂/Au–SnSe₂, SO₂/Au–SnSe₂, and SO₂/Ag–SnSe₂ respond to both types of strain, whereas HCN/Ag–SnSe₂ shows relatively low sensitivity in charge transfer. Recovery time analysis indicates that NO₂ exhibits the slowest desorption kinetics and is most affected by strain modulation. Nevertheless, increasing the operating temperature or applying appropriate strain can significantly shorten recovery times. While other gas systems show smaller variations, strain engineering remains an effective strategy to tune desorption behavior and enhance overall sensor performance. These findings offer valuable insights into strain-tunable gas sensing behavior and provide theoretical guidance for the design of high-performance gas sensors based on two-dimensional SnSe₂ materials. Full article

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the kidney participate in reabsorbing potassium (K⁺) and ammonium (NH₄⁺) in the nephron, contributing to the acid–base balance. Acidosis is a metabolic condition of renal tubular acidosis and chronic kidney disease. Acidosis stimulates the production of mitochondrial reactive oxygen species (mROS), activating protective mechanisms dependent on mitochondrial membrane potential (Δψm) such as autophagy. The HCN3 channel is expressed in the plasma membrane, mitochondria (mitoHCN3), and lysosomes (lysoHCN3) of the rat proximal tubule. In this work we aimed to investigate the role of HCN3 in autophagy, mROS production, and Δψm in cultured rat proximal tubule cells (NRK-52E) exposed to ammonium chloride (NH₄Cl). NH₄Cl arrested autophagic flux and produced extracellular acidosis and, under this condition, mitoHCN3 and lysoHCN3 were up-regulated. NH₄Cl or/and ZD7288, a specific blocker of HCN channels, enhanced mROS. ZD7288 in NH₄Cl conditions at 24 h stimulated autophagy by reducing Beclin1, LC3BII, p62, and Parkin in an mROS- or Δψm independent pathway. Therefore, ZD7288 reverted NH₄Cl inhibited autophagy through lysoHCN3 inhibition. Oxidative stress induced by H₂O₂ up-regulated mitoHCN3 expression, while Tiron had the opposite effect. In conclusion, inhibition of mito- and lysoHCN3 channels by ZD7288 can protect against mitochondrial oxidative stress and stimulate the lysosome–autophagy pathway in response to NH₄Cl treatment. Full article