Are SCN2A-related BFNISs also responsible for seizures in adulthood? A case report opens new scenarios.

Large cohort studies and variant-specific electrophysiology have enabled the delineation of different SCN2A-epilepsy phenotypes, phenotype-genotype correlations, prediction of pharmacosensitivity to sodium channel blockers, and long-term prognostication for clinicians and families. One of the most common clinical presentations of SCN2A pathological variants is benign familial neonatal-infantile seizures (BFNIS), which are characterized by seizure onset between the first day of life and 23 months of age and typically resolve, either spontaneously or with the aid of sodium channel blockers, within the first 2 years of life. In 2004, Berkovic et al. reported the case of a young boy affected by SCN2A-related BFNIS whose mother, who carried the same pathological variant, had also presented with BFNIS in infancy. Our case report focuses on the aforementioned woman who, more than 40 years later, presented two additional seizures, therefore opening the possibility of a role for SCN2A-related seizures in adulthood.

Inhibitory Effect of Evodiamine on Psoriasis Lesions and Itching in Mice.

Purpose: This study seeks to investigate the effect of evodiamine on psoriasis and psoriatic pruritus. Methods: Imiquimod-induced psoriasiform dermatitis in mice was used as a model, and evodiamine was topically applied for seven days. The mice were observed daily for skin damage on the back, clinical score and their scratching behavior was recorded. Blood samples were collected on the final day of the experiment, and the serum levels of pruritus-associated inflammatory cytokines tumor necrosis factor (TNF) -α, interleukin (IL) -23, and IL-17A were measured using enzyme-linked immunosorbent assay. Histopathological changes were observed in Hematoxylin and Eosin-stained skin specimens. The expression levels of transient receptor potential vanilloid (TRPV) 1, TRPV3, TRPV4, and the pruritus-related mediators Substance P (SP), nerve growth factor (NGF), and calcitonin gene-related peptide (CGRP) in the skin lesions were analyzed using Western blot and qRT-PCR. The effect of evodiamine on the exploratory behavior, motor, and coordination abilities of mice was assessed using open field, suspension, and Rota-Rod experiments. Molecular docking was utilized to verify the binding of evodiamine to the residues of TRPV1, TRPV3, and TRPV4. Results: Evodiamine reduced pruritus and inhibited inflammation by decreasing the levels of inflammatory mediators TNF-α, IL-23, and IL-17A in the serum of Imiquimod-induced mice and attenuated the mRNA and protein expression levels of SP, NGF, CGRP, TRPV1, TRPV3, and TRPV4 in the skin. Conclusion: Evodiamine is an effective treatment for psoriasis and pruritus, due to its ability to inhibit immune inflammation and pruritic mediators.

Human Transient Receptor Potential Ankyrin 1 Channel: Structure, Function, and Physiology.

The transient receptor potential ion channel TRPA1 is a Ca2+-permeable nonselective cation channel widely expressed in sensory neurons, but also in many nonneuronal tissues typically possessing barrier functions, such as the skin, joint synoviocytes, cornea, and the respiratory and intestinal tracts. Here, the primary role of TRPA1 is to detect potential danger stimuli that may threaten the tissue homeostasis and the health of the organism. The ability to directly recognize signals of different modalities, including chemical irritants, extreme temperatures, or osmotic changes resides in the characteristic properties of the ion channel protein complex. Recent advances in cryo-electron microscopy have provided an important framework for understanding the molecular basis of TRPA1 function and have suggested novel directions in the search for its pharmacological regulation. This chapter summarizes the current knowledge of human TRPA1 from a structural and functional perspective and discusses the complex allosteric mechanisms of activation and modulation that play important roles under physiological or pathophysiological conditions. In this context, major challenges for future research on TRPA1 are outlined.

Frontiers in Acute Pain Management: Emerging Concepts in Pain Pathways and the Role of VX-548 as a Novel NaV1.8 Inhibitor: A Narrative Review.

PURPOSE OF REVIEW: Despite ongoing research into alternative postsurgical pain treatments, opioids remain widely used analgesics regardless of associated adverse effects, including dependence and overdose, as demonstrated throughout the current opioid crisis. This is likely related to a failure in proving the efficacy of alternative analgesics in clinical trials, despite strong evidence supporting the potential for effective analgesia through in vitro studies. While NaV1.7 and NaV1.8 channels have shown to be key components of pain perception, studies regarding pharmacological agents utilizing these channels as targets have largely failed to demonstrate the efficacy of these proposed analgesics when compared to current multimodal pain treatment regimens. RECENT FINDINGS: However, the novel NaV1.8 channel inhibitor, VX-548 has surpassed previously studied NaV1.8 inhibitors in clinical trials and continues to hold promise of a novel efficacious analgesic to potentially be utilized in multimodal pain treatment on postsurgical patients. Additionally, NaV1.8 is encoded by the SCN10A, which has been shown to be minimally expressed in the brain, suggesting a lower likelihood of adverse effects in the CNS, including dependence and abuse. Novel pharmacologic analgesics that are efficacious without the significant side effects associated with opioids have lacked meaningful development. However, recent clinical trials have shown promising results in the safety and efficacy of the pharmacological agent VX-548. Still, more clinical trials directly comparing the efficacy of VX-548 to standard of care post-surgical drugs, including opioids like morphine and hydromorphone are needed to demonstrate the long-term viability of the agent replacing current opioids with an unfavorable side effect profile.

HCN channels in the lateral habenula regulate pain and comorbid depressive-like behaviors in mice.

AIMS: Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain. METHODS: After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open-field test, and elevated plus maze test to evaluate their anxiodepressive-like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms. RESULTS: Evident anxiodepressive-like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive-like behaviors. CONCLUSION: Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up-regulation of HCN2 isoforms.

Involvement of TRPV4 in temperature-dependent perspiration in mice.

Reports indicate that an interaction between TRPV4 and anoctamin 1 (ANO1) could be widely involved in water efflux of exocrine glands, suggesting that the interaction could play a role in perspiration. In secretory cells of sweat glands present in mouse foot pads, TRPV4 clearly colocalized with cytokeratin 8, ANO1, and aquaporin-5 (AQP5). Mouse sweat glands showed TRPV4-dependent cytosolic Ca2+ increases that were inhibited by menthol. Acetylcholine-stimulated sweating in foot pads was temperature-dependent in wild-type, but not in TRPV4-deficient mice and was inhibited by menthol both in wild-type and TRPM8KO mice. The basal sweating without acetylcholine stimulation was inhibited by an ANO1 inhibitor. Sweating could be important for maintaining friction forces in mouse foot pads, and this possibility is supported by the finding that wild-type mice climbed up a slippery slope more easily than TRPV4-deficient mice. Furthermore, TRPV4 expression was significantly higher in controls and normohidrotic skin from patients with acquired idiopathic generalized anhidrosis (AIGA) compared to anhidrotic skin from patients with AIGA. Collectively, TRPV4 is likely involved in temperature-dependent perspiration via interactions with ANO1, and TRPV4 itself or the TRPV4/ANO 1 complex would be targeted to develop agents that regulate perspiration.

Stress, spicy foods and elevated temperatures can all trigger specialized gland cells to move water to the skin ­ in other words, they can make us sweat. This process is one of the most important ways by which our bodies regulate their temperature and avoid life-threatening conditions such as heatstroke. Disorders in which this function is impaired, such as AIGA (acquired idiopathic generalized anhidrosis), pose significant health risks. Finding treatments for sweat-related diseases requires a detailed understanding of the molecular mechanisms behind sweating, which has yet to be achieved. Recent research has highlighted the role of two ion channels, TRPV4 and ANO1, in regulating fluid secretion in glands that produce tears and saliva. These gate-like proteins control how certain ions move in or out of cells, which also influences water movement. Once activated by external stimuli, TRPV4 allows calcium ions to enter the cell, causing ANO1 to open and chloride ions to leave. This results in water also exiting the cell through dedicated channels, before being collected in ducts connected to the outside of the body. TRPV4, which is activated by heat, is also present in human sweat gland cells. This prompted Kashio et al. to examine the role of these channels in sweat production, focusing on mice as well as AIGA patients. Probing TRPV4, ANO1 and AQP5 (a type of water channel) levels using fluorescent antibodies confirmed that these channels are all found in the same sweat gland cells in the foot pads of mice. Further experiments highlighted that TRPV4 mediates sweat production in these animals via ANO1 activation. As rodents do not regulate their body temperature by sweating, Kashio et al. explored the biological benefits of having sweaty paws. Mice lacking TRPV4 had reduced sweating and were less able to climb a slippery slope, suggesting that a layer of sweat helps improve traction. Finally, Kashio et al. compared samples obtained from healthy volunteers with those from AIGA patients and found that TRPV4 levels are lower in individuals affected by the disease. Overall, these findings reveal new insights into the underlying mechanisms of sweating, with TRPV4 a potential therapeutic target for conditions like AIGA. The results also suggest that sweating could be controlled by local changes in temperature detected by heat-sensing channels such as TRPV4. This would depart from our current understanding that sweating is solely controlled by the autonomic nervous system, which regulates involuntary bodily functions such as saliva and tear production.

Aqp4a and Trpv4 mediate regulatory cell volume increase for swimming maintenance of marine fish spermatozoa.

Volume regulation is essential for cell homeostasis and physiological function. Amongst the sensory molecules that have been associated with volume regulation is the transient receptor potential vanilloid 4 (TRPV4), which is a non-selective cation channel that in conjunction with aquaporins, typically controls regulatory volume decrease (RVD). Here we show that the interaction between orthologous AQP4 (Aqp4a) and TRPV4 (Trpv4) is important for regulatory volume increase (RVI) in post-activated marine fish spermatozoa under high osmotic stress. Based upon electrophysiological, volumetric, and in vivo and ex vivo functional experiments using the pharmacological and immunological inhibition of Aqp4a and Trpv4 our model suggests that upon ejaculation and exposure to the hypertonic seawater, spermatozoon shrinkage is initially mediated by water efflux through Aqp1aa in the flagellar tail. The shrinkage results in an increase in intracellular Ca2+ concentration, and the activation of sperm motility and a Na+/K+/2Cl- (NKCC1) cotransporter. The activity of NKCC1 is required for the initiation of cell swelling, which secondarily activates the Aqp4a-Trpv4 complex to facilitate the influx of water via Aqp4a-M43 and Ca2+ via Trpv4 and L-type channels for the mediation of RVI. The inhibitory experiments show that blocking of each of these events prevents either shrinkage or RVI. Our data thus reveal that post-activated marine fish spermatozoa are capable of initiating RVI under a high hypertonic stress, which is essential for the maintenance of sperm motility.

Mechanistic insights into phosphoactivation of SLAC1 in guard cell signaling.

Stomata in leaves regulate gas (carbon dioxide and water vapor) exchange and water transpiration between plants and the atmosphere. SLow Anion Channel 1 (SLAC1) mediates anion efflux from guard cells and plays a crucial role in controlling stomatal aperture. It serves as a central hub for multiple signaling pathways in response to environmental stimuli, with its activity regulated through phosphorylation via various plant protein kinases. However, the molecular mechanism underlying SLAC1 phosphoactivation has remained elusive. Through a combination of protein sequence analyses, AlphaFold-based modeling and electrophysiological studies, we unveiled that the highly conserved motifs on the N- and C-terminal segments of SLAC1 form a cytosolic regulatory domain (CRD) that interacts with the transmembrane domain(TMD), thereby maintaining the channel in an autoinhibited state. Mutations in these conserved motifs destabilize the CRD, releasing autoinhibition in SLAC1 and enabling its transition into an activated state. Our further studies demonstrated that SLAC1 activation undergoes an autoinhibition-release process and subsequent structural changes in the pore helices. These findings provide mechanistic insights into the activation mechanism of SLAC1 and shed light on understanding how SLAC1 controls stomatal closure in response to environmental stimuli.

Effects of pulse shape on pitch sensitivity of cochlear implant users.

Contemporary cochlear implants (CIs) use cathodic-leading symmetric biphasic (C-BP) pulses for electrical stimulation. It remains unclear whether asymmetric pulses emphasizing the anodic or cathodic phase may improve spectral and temporal coding with CIs. This study tested place- and temporal-pitch sensitivity with C-BP, anodic-centered triphasic (A-TP), and cathodic-centered triphasic (C-TP) pulse trains on apical, middle, and basal electrodes in 10 implanted ears. Virtual channel ranking (VCR) thresholds (for place-pitch sensitivity) were measured at both a low and a high pulse rate of 99 (Experiment 1) and 1000 (Experiment 2) pulses per second (pps), and amplitude modulation frequency ranking (AMFR) thresholds (for temporal-pitch sensitivity) were measured at a 1000-pps pulse rate in Experiment 3. All stimuli were presented in monopolar mode. Results of all experiments showed that detection thresholds, most comfortable levels (MCLs), VCR thresholds, and AMFR thresholds were higher on more basal electrodes. C-BP pulses had longer active phase duration and thus lower detection thresholds and MCLs than A-TP and C-TP pulses. Compared to C-TP pulses, A-TP pulses had lower detection thresholds at the 99-pps but not the 1000-pps pulse rate, and had lower MCLs at both pulse rates. A-TP pulses led to lower VCR thresholds than C-BP pulses, and in turn than C-TP pulses, at the 1000-pps pulse rate. However, pulse shape did not affect VCR thresholds at the 99-pps pulse rate (possibly due to the fixed temporal pitch) or AMFR thresholds at the 1000-pps pulse rate (where the overall high performance may have reduced the changes with different pulse shapes). Notably, stronger polarity effect on VCR thresholds (or more improvement in VCR with A-TP than with C-TP pulses) at the 1000-pps pulse rate was associated with stronger polarity effect on detection thresholds at the 99-pps pulse rate (consistent with more degeneration of auditory nerve peripheral processes). The results suggest that A-TP pulses may improve place-pitch sensitivity or spectral coding for CI users, especially in situations with peripheral process degeneration.

Recycling channel strategy in the presence of free-riding in the carbon neutrality era.

Recycling has become a critical response to the goals of reaching a carbon peak and achieving carbon neutrality. This study explores the effects of consumer free-riding behavior, the quality of recycling services, and the costs of channel transfers on the profitability of manufacturers and retailers in a dual-channel closed-loop supply chain (CLSC), focusing on the importance of recycling practices for carbon neutrality. Using consumer utility theory and a Stackelberg game model, we analyze the dynamics among these factors. Our results show that: (i) Consumer free-riding behavior slightly increases market demand and recycling volumes, enhancing profitability for both manufacturers and retailers in the dual-channel CLSC. (ii) The quality of recycling services and the transfer costs associated with retailer free-riding behavior jointly influence the profits of manufacturers and retailers. (iii) The effect of free-riding behavior on recycling services affects both forward sales and reverse recycling channels equally. This study provides valuable insights for decision-making in sustainable development practices in the recycling sector, significantly contributing to the goal of achieving carbon neutrality.

Recent advancement of sonogenetics: A promising noninvasive cellular manipulation by ultrasound.

Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques. Sonogenetics, a method that uses genetic engineering to produce ultrasound-sensitive proteins in target cells, is gaining prominence along with optogenetics, electrogenetics, and magnetogenetics. Upon stimulation with ultrasound, these proteins trigger a cascade of cellular activities and functions. Unlike traditional ultrasound modalities, sonogenetics offers enhanced spatial selectivity, improving precision and safety in disease treatment. This technology broadens the scope of non-surgical interventions across a wide range of clinical research and therapeutic applications, including neuromodulation, oncologic treatments, stem cell therapy, and beyond. Although current literature predominantly emphasizes ultrasonic neuromodulation, this review offers a comprehensive exploration of sonogenetics. We discuss ultrasound properties, the specific ultrasound-sensitive proteins employed in sonogenetics, and the technique's potential in managing conditions such as neurological disorders, cancer, and ophthalmic diseases, and in stem cell therapies. Our objective is to stimulate fresh perspectives for further research in this promising field.

Current status of the biliary tract malformation.

The choledochal cyst (CC) can be better termed as biliary tract malformation because of the close association of embryology and etiology in the causation of CC. Contrary to Babbitt's postulation of reflux, damage and dilatation, reflux was not demonstrable as the causative factor in all varieties of CC. High pressure in the biliary system, otherwise termed ductal hypertension, is put forth as an alternative to explain the evolution of CC. The forme fruste type, which does not find a place in the standard classification, typifies the ductal hypertension hypothesis. Hence a closer, in-depth review would be able to highlight this apt terminology of biliary tract malformation.

Expression levels of KATP channel subunits and morphological changes in the mouse liver after exposure to radiation.

BACKGROUND: ATP sensitive K+ (KATP) channels are ubiquitously distributed in various of cells and tissues, including the liver. They play a role in the pathogenesis of myocardial and liver ischemia. AIM: To evaluate the radiation-induced changes in the expression of KATP channel subunits in the mouse liver to understand the potential role of KATP channels in radiation injury. METHODS: Adult C57BL/6 mice were randomly exposed to γ-rays at 0 Gy (control, n = 2), 0.2 Gy (n = 6), 1 Gy (n = 6), or 5 Gy (n = 6). The livers were removed 3 and 24 h after radiation exposure. Hematoxylin and eosin staining was used for morphological observation; immunohistochemical staining was applied to determine the expression of KATP channel subunits in the liver tissue. RESULTS: Compared with the control group, the livers exposed to 0.2 Gy γ-ray showed an initial increase in the expression of Kir6.1 at 3 h, followed by recovery at 24 h after exposure. Exposure to a high dose of 5.0 Gy resulted in decreased expression of Kir6.1 and increased expression of SUR2B at 24 h. However, the expression of Kir6.2, SUR1, or SUR2A had no remarkable changes at 3 and 24 h after exposure to any of these doses. CONCLUSION: The expression levels of Kir6.1 and SUR2B in mouse liver changed differently in response to different radiation doses, suggesting a potential role for them in radiation-induced liver injury.

Acclimatize experimental approach to adjudicate hydraulic coefficients under different bed material configurations and slopes with and without weir.

The primary purpose of this study was to evaluate the hydraulic coefficient of coarse aggregate grain size beds and hydraulic parameters under random and perpendicular bed configurations, as well as to explore the discharge coefficient for rectangular weirs. The research objectives were to compare flow resistance coefficients, evaluate the discharge coefficient for rectangular weirs, investigate the relationship between roughness coefficient and hydraulic parameters, and validate the theoretical hydraulic equation for the rectangular weir. This was achieved by analysing different bed configurations, bed slopes, and 20 and 30-mm bed materials. Sieve analysis was conducted on bed materials using American-standard sieves to determine their particle size distribution. The experiment was performed in a rectangular flume measuring 12 m in length, 0.31 m in width, and 0.45 m in depth. In a laboratory experiment, water was pumped into a flume using centrifugal pumps, and a rectangular weir was attached downstream for discharge measurement. The experiment investigated factors such as Manning roughness coefficient, bed material geometry, bed slope, and weir shapes. Approximately 1680 tests were conducted to analysed the impact of these factors on discharge and the coefficient of discharge. The average Manning's roughness coefficients for a grain size of 20 mm were 0.019 (with weir) and 0.019 (without weir) in a random bed configuration, and 0.028 (with weir) and 0.027 (without weir) in a perpendicular flow bed configuration. For a grain size of 30 mm, the coefficients were 0.023 (with weir) and 0.022 (without weir) in a random bed configuration, and 0.033 (with weir) and 0.026 (without weir) in a perpendicular flow bed configuration. The presence of a weir has affected Manning's roughness coefficients and discharge coefficients. With a weir, the roughness coefficients have generally been higher compared to without a weir, indicating increased roughness in the channel. The discharge coefficient for a rectangular weir with a grain size of 20 mm ranged from 0.39 to 0.84 (random bed) and 0.27 to 0.68 (perpendicular flow bed), while for a grain size of 30 mm it ranged from 0.31 to 0.81 (random bed) and 0.23 to 0.48 (perpendicular flow bed). The discharge coefficients have varied depending on the grain size and bed configuration, reflecting different flow efficiencies over the weir. Rough particles influenced flow and Manning's roughness coefficient value, then reduced discharge and velocity values. Under two bed configurations and slopes, beds with a grain size of 30 mm have higher roughness coefficients compared to those with a grain size of 20 mm. The models have shown that the roughness coefficient is inversely proportional to the discharge and directly proportional to the tailgate water levels. The coefficient of roughness and discharge coefficient are mainly influenced by the channel slopes, bed roughness, bed grain size, and bed configuration. A randomly configured bed with a 20 mm grain size gravel bed is preferred over a perpendicular bed configuration to handle high discharges. Using a 20 mm grain-size gravel bed in open-channel flow is more suitable than a 30 mm grain-size bed. Relying on the constant friction factor, Manning's n, is not recommended as it may result in design errors. These findings have the potential to improve hydraulic engineering design practices, enhancing the accuracy and efficiency of open-channel flow systems.

Improved YOLO-FastestV2 wheat spike detection model based on a multi-stage attention mechanism with a LightFPN detection head.

The number of wheat spikes has an important influence on wheat yield, and the rapid and accurate detection of wheat spike numbers is of great significance for wheat yield estimation and food security. Computer vision and machine learning have been widely studied as potential alternatives to human detection. However, models with high accuracy are computationally intensive and time consuming, and lightweight models tend to have lower precision. To address these concerns, YOLO-FastestV2 was selected as the base model for the comprehensive study and analysis of wheat sheaf detection. In this study, we constructed a wheat target detection dataset comprising 11,451 images and 496,974 bounding boxes. The dataset for this study was constructed based on the Global Wheat Detection Dataset and the Wheat Sheaf Detection Dataset, which was published by PP Flying Paddle. We selected three attention mechanisms, Large Separable Kernel Attention (LSKA), Efficient Channel Attention (ECA), and Efficient Multi-Scale Attention (EMA), to enhance the feature extraction capability of the backbone network and improve the accuracy of the underlying model. First, the attention mechanism was added after the base and output phases of the backbone network. Second, the attention mechanism that further improved the model accuracy after the base and output phases was selected to construct the model with a two-phase added attention mechanism. On the other hand, we constructed SimLightFPN to improve the model accuracy by introducing SimConv to improve the LightFPN module. The results of the study showed that the YOLO-FastestV2-SimLightFPN-ECA-EMA hybrid model, which incorporates the ECA attention mechanism in the base stage and introduces the EMA attention mechanism and the combination of SimLightFPN modules in the output stage, has the best overall performance. The accuracy of the model was P=83.91%, R=78.35%, AP= 81.52%, and F1 = 81.03%, and it ranked first in the GPI (0.84) in the overall evaluation. The research examines the deployment of wheat ear detection and counting models on devices with constrained resources, delivering novel solutions for the evolution of agricultural automation and precision agriculture.

Alignment of lyotropic liquid crystals using magnetic nanoparticles improves ionic transport through built-in peptide ion channels.

HYPOTHESIS: We hypothesize that simultaneous incorporation of ion channel peptides (in this case, potassium channel as a model) and hydrophobic magnetite Fe3O4 nanoparticles (hFe3O4NPs) within lipidic hexagonal mesophases, and aligning them using an external magnetic field can significantly enhance ion transport through lipid membranes. EXPERIMENTS: In this study, we successfully characterized the incorporation of gramicidin membrane ion channels and hFe3O4NPs in the lipidic hexagonal structure using SAXS and cryo-TEM methods. Additionally, we thoroughly investigated the conductive characteristics of freestanding films of lipidic hexagonal mesophases, both with and without gramicidin potassium channels, utilizing a range of electrochemical techniques, including impedance spectroscopy, normal pulse voltammetry, and chronoamperometry. FINDINGS: Our research reveals a state-of-the-art breakthrough in enhancing ion transport in lyotropic liquid crystals as matrices for integral proteins and peptides. We demonstrate the remarkable efficacy of membranes composed of hexagonal lipid mesophases embedded with K+ transporting peptides. This enhancement is achieved through doping with hFe3O4NPs and exposure to a magnetic field. We investigate the intricate interplay between the conductive properties of the lipidic hexagonal structure, hFe3O4NPs, gramicidin incorporation, and the influence of Ca2+ on K+ channels. Furthermore, our study unveils a new direction in ion channel studies and biomimetic membrane investigations, presenting a versatile model for biomimetic membranes with unprecedented ion transport capabilities under an appropriately oriented magnetic field. These findings hold promise for advancing membrane technology and various biotechnological and biomedical applications of membrane proteins.

Voltage-gated sodium channel epilepsies in a tertiary care center: Phenotypic spectrum with correlation to predicted functional effects.

BACKGROUND: Variants in sodium channel genes (SCN) are strongly associated with epilepsy phenotypes. Our aim in this study to evaluate the genotype and phenotype correlation of patients with SCN variants in our tertiary care center. METHODS: In this retrospective study, patients with SCN variants and epilepsy who were followed up at our clinic between 2018 and 2022 were evaluated. Our study discussed the demographics of the patients, the seizure types, the age of seizure onset, the SCN variants, the domains and the functions of the variants, the magnetic resonance imaging findings, the motor, cognitive, and psychiatric comorbidities, and the response to anti-seizure medication. Genetic testing was conducted using a next-generation sequencing gene panel (epilepsy panel) or a whole-exome sequencing. For evaluating variant function, we used a prediction tool (https://funnc.shinyapps.io/shinyappweb/ site). To assess protein domains, we used the PER viewer (http://per.broadinstitute.org/). RESULTS: Twenty-three patients with SCN variants and epilepsy have been identified. Sixteen patients had variants in the SCN1A, six patients had variants in the SCN2A, and one patient had a variant in the SCN3A. Two novel SCN1A variants and two novel SCN2A variants were identified. The analysis revealed 14/23 missense, 6/23 nonsense, 2/23 frameshift, and 1/23 splice site variants in the SCN. There are seven variants predicted to be gain-of-function and 13 predicted to be loss-of-function. Among 23 patients; 11 had Dravet Syndrome, 6 had early infantile developmental and epileptic encephalopathy, three had genetic epilepsy with febrile seizures plus spectrum disorder, one had self-limited familial neonatal-infantile epilepsy, one had self-limited infantile epilepsy and one had infantile childhood development epileptic encephalopathy. CONCLUSION: Our cohort consists of mainly SCN1 variants, most of them were predicted to be loss of function. Dravet syndrome was the most common phenotype. The prediction tool used in our study demonstrated overall compatibility with clinical findings. Due to the diverse clinical manifestations of variant functions, it may assist in guiding medication selection and predicting outcomes. We believe that such a tool will help the clinician in both prognosis prediction and solving therapeutic challenges in this group where refractory seizures are common.

Efficient pyramid channel attention network for pathological myopia recognition with pretraining-and-finetuning.

Pathological myopia (PM) is the leading ocular disease for impaired vision worldwide. Clinically, the characteristics of pathology distribution in PM are global-local on the fundus image, which plays a significant role in assisting clinicians in diagnosing PM. However, most existing deep neural networks focused on designing complex architectures but rarely explored the pathology distribution prior of PM. To tackle this issue, we propose an efficient pyramid channel attention (EPCA) module, which fully leverages the potential of the clinical pathology prior of PM with pyramid pooling and multi-scale context fusion. Then, we construct EPCA-Net for automatic PM recognition based on fundus images by stacking a sequence of EPCA modules. Moreover, motivated by the recent pretraining-and-finetuning paradigm, we attempt to adapt pre-trained natural image models for PM recognition by freezing them and treating the EPCA and other attention modules as adapters. In addition, we construct a PM recognition benchmark termed PM-fundus by collecting fundus images of PM from publicly available datasets. The comprehensive experiments demonstrate the superiority of EPCA-Net over state-of-the-art methods in the PM recognition task. For example, EPCA-Net achieves 97.56% accuracy and outperforms ViT by 2.85% accuracy on the PM-fundus dataset. The results also show that our method based on the pretraining-and-finetuning paradigm achieves competitive performance through comparisons to part of previous methods based on traditional fine-tuning paradigm with fewer tunable parameters, which has the potential to leverage more natural image foundation models to address the PM recognition task in limited medical data regime.

Voltage-dependent anion channel 1 mediates mitochondrial fission and glucose metabolic reprogramming in response to ionizing radiation.

The ionizing radiation (IR) represents a formidable challenge as an environmental factor to mitochondria, leading to disrupt cellular energy metabolism and posing health risks. Although the deleterious impacts of IR on mitochondrial function are recognized, the specific molecular targets remain incompletely elucidated. In this study, HeLa cells subjected to γ-rays exhibited concomitant oxidative stress, mitochondrial structural alterations, and diminished ATP production capacity. The γ-rays induced a dose-dependent induction of mitochondrial fission, simultaneously manifested by an elevated S616/S637 phosphorylation ratio of the dynamin-related protein 1 (DRP1) and a reduction in the expression of the mitochondrial fusion protein mitofusin 2 (MFN2). Knockdown of DRP1 effectively mitigated γ-rays-induced mitochondrial network damage, implying that DRP1 phosphorylation may act as an effector of radiation-induced mitochondrial damage. The mitochondrial outer membrane protein voltage-dependent anion channel 1 (VDAC1) was identified as a crucial player in IR-induced mitochondrial damage. The VDAC1 inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), counteracts the excessive mitochondrial fission induced by γ-rays, consequently rebalancing the glycolytic and oxidative phosphorylation equilibrium. This metabolic shift was uncovered to enhance glycolytic capacity, thus fortifying cellular resilience and elevating the radiosensitivity of cancer cells. These findings elucidate the intricate regulatory mechanisms governing mitochondrial morphology under radiation response. It is anticipated that the development of targeted drugs directed against VDAC1 may hold promise in augmenting the sensitivity of tumor cells to radiotherapy and chemotherapy.