Search Results (599)

In this study, we propose a bidirectional chemical sensor platform based on a reconfigurable ion-sensitive field-effect transistor (R-ISFET) architecture. The device incorporates Ni-silicide Schottky barrier source/drain (S/D) contacts, enabling ambipolar conduction and bidirectional turn-on behavior for both p-type and n-type configurations. Channel polarity is dynamically controlled via the program gate (PG), while the control gate (CG) suppresses leakage current, enhancing operational stability and energy efficiency. A dual-control-gate (DCG) structure enhances capacitive coupling, enabling sensitivity beyond the Nernst limit without external amplification. The extended-gate (EG) architecture physically separates the transistor and sensing regions, improving durability and long-term reliability. Electrical characteristics were evaluated through transfer and output curves, and carrier transport mechanisms were analyzed using band diagrams. Sensor performance—including sensitivity, hysteresis, and drift—was assessed under various pH conditions and external noise up to 5 V_pp (i.e., peak-to-peak voltage). The n-type configuration exhibited high mobility and fast response, while the p-type configuration demonstrated excellent noise immunity and low drift. Both modes showed consistent sensitivity trends, confirming the feasibility of complementary sensing. These results indicate that the proposed R-ISFET sensor enables selective mode switching for high sensitivity and robust operation, offering strong potential for next-generation biosensing and chemical detection. Full article

Membrane transporters play a crucial role in any cell. Identifying the substrates they translocate across membranes is important for many fields of research, such as metabolomics, pharmacology, and biotechnology. In this study, we leverage recent advances in deep learning, such as amino acid sequence embeddings with protein language models (pLMs), highly accurate 3D structure predictions with AlphaFold 2, and structure-encoding 3Di sequences from FoldSeek, for predicting substrates of membrane transporters. We test new deep learning features derived from both sequence and structure, and compare them to the previously best-performing protein encodings, which were made up of amino acid k-mer frequencies and evolutionary information from PSSMs. Furthermore, we compare the performance of these features either using a previously developed SVM model, or with a regularized feedforward neural network (FNN). When evaluating these models on sugar and amino acid carriers in A. thaliana, as well as on three types of ion channels in human, we found that both the DL-based features and the FNN model led to a better and more consistent classification performance compared to previous methods. Direct encodings of 3D structures with Foldseek, as well as structural embeddings with ProstT5, matched the performance of state-of-the-art amino acid sequence embeddings calculated with the ProtT5-XL model when used as input for the FNN classifier. Full article

Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca²⁺ dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective M₁R antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca²⁺-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including M₁R. TRPM3 activation enhanced mitochondrial Ca²⁺ uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca²⁺ signaling imbalances in DSPN and presents M₁R antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies. Full article

Background: The reproducibility of research findings continues to be a challenge in many fields, including neurosciences. It is now required that biological variables such as sex and age be considered in preclinical and clinical research. Rodents are frequently used to model clinical conditions; however, litter information is rarely presented. Some studies utilize entire litters with each animal treated as an independent sample, while others equally assign animals from each litter to different groups/treatments, and others use averaged data. These methods can yield different results. Methods: This study used different analysis methods to evaluate embryo and placenta weights from E17.5 acid-sensing ion channel 2a (ASIC2a) mice with or without seizure exposure. Results: When each embryo was treated as an individual sample, fetal and placental weight significantly differed following seizures in the ASIC2a heterozygous (+/−) and homozygous (−/−) groups. Differences in fetal weight were driven by females in the ASIC2a+/− group and both sexes in the ASIC2a−/− group. These differences were lost when an average per sex/genotype/litter was used. There was no difference in placental weight when treated individually; however, female ASIC2a−/− placentas weighed less following seizures. This difference was lost with averaged data. ASIC2a−/− fetuses from −/− dams had reduced weights post-seizure exposure. Position on the uterine horn influenced embryo and placental weight. Conclusions: Our results indicate that using full litters analyzed as individual data points should be avoided, as it can lead to Type I errors. Furthermore, studies should account for litter effects and be transparent in their methods and results. Full article

Oxidative stress is a key mediator of physiological dysfunction in aquatic organisms under environmental challenges, yet its comprehensive impacts on gill physiology require further clarification. This study investigated the molecular and cellular responses of Eriocheir sinensis gills to hydrogen peroxide (H₂O₂)-induced oxidative stress, integrating antioxidant defense, ion transport regulation, and stress-induced cell apoptosis and autophagy. Morphological alterations in the gill filaments were observed, characterized by septum degeneration, accumulation of haemolymph cells, and pronounced swelling. For antioxidant enzymes like catalase (CAT) and glutathione peroxidase (GPx), activities were enhanced, while superoxide dismutase (SOD) activity was reduced following 48 h of exposure. Overall, the total antioxidant capacity (T-AOC) showed a significant increase. The elevated concentrations of malondialdehyde (MDA) and H₂O₂ indicated oxidative stress. Ion transport genes displayed distinct transcription patterns: Na⁺-K⁺-2Cl⁻ co-transporter-1 (NKCC1), Na⁺/H⁺ exchanger 3 (NHE3), aquaporin 7 (AQP7), and chloride channel protein 2 (CLC2) were significantly upregulated; the α-subunit of Na⁺/K⁺-ATPase (NKAα) and carbonic anhydrase (CA) displayed an initial increase followed by decline; whereas vacuolar-type ATPase (VATP) consistently decreased, suggesting compensatory mechanisms to maintain osmotic balance. Concurrently, H₂O₂ triggered apoptosis (Bcl2, Caspase-3/8) and autophagy (beclin-1, ATG7), likely mediated by MAPK and AMPK signaling pathways. These findings reveal a coordinated yet adaptive response of crab gills to oxidative stress, providing new insights into the mechanistic basis of environmental stress tolerance in crustaceans. Full article

Cardiomyocytes, similarly to cells in various tissues, are responsive to mechanical stress of all types, which is reflected in the significant alterations to their electrophysiological characteristics. This phenomenon, known as mechanoelectric feedback, is based on the work of mechanically gated channels (MGCs) and mechano-sensitive channels (MSCs). Since microgravity (MG) in space, as well as simulated microgravity (SMG), changes the morphological and physiological properties of the heart, it was assumed that this result would be associated with a change in the expression of genes encoding MGCs and MSCs, leading to a change in the synthesis of channel proteins and, ultimately, a change in channel currents during cell stretching. In isolated ventricular cardiomyocytes of rats exposed to SMG for 14 days, the amount of MGCs and MSCs gene transcripts was studied using the RNA sequencing method by normalizing the amount of “raw” reads using the Transcripts Per Kilobase Million (TPM) method. Changes in the level of channel protein, using the example of the MGCs TRPM7, were assessed by the Western blot method, and changes in membrane ion currents in the control and during cardiomyocyte stretching were assessed by the patch-clamp method in the whole-cell configuration. The data obtained demonstrate that SMG results in a multidirectional change in the expression of genes encoding various MGCs and MSCs. At the same time, a decrease in the TPM of the MGCs TRPM7 gene leads to a decrease in the amount of TRPM7 protein. The resulting redistribution in the synthesis of most channel proteins leads to a marked decrease in the sensitivity of the current through MGCs to cell stretching and, ultimately, to a change in the functioning of the heart. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and is often diagnosed at advanced stages. PIEZO1, a mechanosensitive ion channel, has been implicated in cancer progression, but its prognostic relevance in ccRCC remains unclear. This study aimed to evaluate the expression pattern of PIEZO1 in ccRCC and its association with clinicopathological characteristics and patient survival. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tumor tissues from 111 patients with ccRCC, along with 23 matched peritumoral non-cancerous tissues. Protein expression was quantified using the H-score system. Associations with tumor grade, staging, and overall survival (OS) were analyzed. mRNA expression data were retrieved from The Cancer Genome Atlas (TCGA) to validate the protein-level findings. Functional enrichment and pathway analyses were conducted to explore the biological context of PIEZO1-related gene expression. PIEZO1 showed predominantly cytoplasmic localization, with significantly lower expression in tumor tissues compared to adjacent non-malignant tissue (p < 0.0001). High PIEZO1 expression was correlated with higher tumor grade (p = 0.0147) and shorter OS (p = 0.0047). These findings were confirmed at the mRNA level in the TCGA cohort. Multivariate Cox regression analysis identified PIEZO1 as an independent prognostic factor for OS. In conclusion, PIEZO1 may serve as a clinically relevant biomarker in ccRCC. Its overexpression is associated with more aggressive tumor characteristics and poor prognosis, underscoring the need for further investigation into its functional role and potential as a therapeutic target. Full article

Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase the risk of arrhythmias and sudden cardiac death (SCD). Understanding genotype–phenotype correlations is key, given the variability of clinical manifestations even within families sharing the same variant. We aimed to evaluate new pathogenic variants by analyzing genotype–phenotype correlations in informative families. Methods: Genetic and clinical assessments were performed on index cases and family members carrying KCNH2 pathogenic variants, referred for genetic testing between 2010 and June 2023. The next-generation sequencing (NGS) of 210 cardiovascular-related genes was conducted. Clinical data, including demographic details, family history, arrhythmic events, electrocardiographic parameters, and treatments, were collected. Results: Among 390 patients (152 probands) tested for LQTS, only 2 KCNH2 variants had over 5 carriers. The detailed clinical information of 22 carriers of this KCNH2 p.Ser261fs. has already been reported by our research group. Moreover, we identified 12 carriers of the KCNH2 c.77-2del variant, predicted to disrupt a splice site and not previously reported. Segregation analysis showed its high penetrance, supporting its classification as pathogenic. Conclusions: The newly identified KCNH2 c.77-2del variant is a pathogenic, as strongly supported by the segregation analysis. Our findings underscore the importance of further research into splice site variants to enhance clinical management and genetic counseling for affected families. Full article

Background/Objectives: Dimethyl trisulfide (DMTS) is a naturally occurring polysulfide with known antioxidant and neuroprotective properties. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression-like behaviour, has yet to be explored. This study investigates the influence of DMTS on stress responses and whether this effect is mediated through the TRPA1 ion channel, known for its role in stress adaptation. Using a mouse model involving three-week exposure, we examined the impact of DMTS on depression-like behaviour and anxiety and identified the involved brain regions. Methods: Our methods involved testing both Trpa1-wild-type and gene-knockout mice under CUMS conditions and DMTS treatment. DMTS was administered intraperitoneally at a dose of 30 mg/kg on days 16 and 20 of the 21-day CUMS protocol—in hourly injections seven times to ensure sustained exposure. Various behavioural assessments—including the open field, marble burying, tail suspension, forced swim, and sucrose preference tests—were performed to evaluate anxiety and depression-like behaviour. Additionally, we measured body weight changes and the relative weights of the thymus and adrenal glands, while serum levels of corticosterone and adrenocorticotropic hormone were quantified via ELISA. FOSB (FBJ murine osteosarcoma viral oncogene homolog B) immunohistochemistry was utilised to assess chronic neuronal activation in stress-relevant brain areas. Results: Results showed that CUMS induces depression-like behaviour, with the response being modulated by the TRPA1 status and that DMTS treatment significantly reduced these effects when TRPA1 channels were functional. DMTS also mitigated thymus involution due to hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Conclusions: Overall, DMTS appears to relieve depressive and anxiety symptoms through TRPA1-mediated pathways, suggesting its potential as a dietary supplement or adjunct therapy for depression and anxiety. Full article

Purinergic P2X receptors (P2X) are ATP-gated ion channels that are broadly expressed in the brain, particularly in the hypothalamus. As ionic channels with high permeability to calcium, P2X play an important and active role in neural functions. The hypothalamus contains a number of small nuclei with many molecularly defined types of peptidergic neurons that affect a wide range of physiological functions, including water balance, blood pressure, metabolism, food intake, circadian rhythm, childbirth and breastfeeding, growth, stress, body temperature, and multiple behaviors. P2X are expressed in hypothalamic neurons, astrocytes, tanycytes, and microvessels. This review focuses on cell-type specific expression of P2X in the most important hypothalamic nuclei, such as the supraoptic nucleus (SON), paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN), anteroventral periventricular nucleus (AVPV), anterior hypothalamic nucleus (AHN), arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus (DMH), tuberomammillary nucleus (TMN), and lateral hypothalamic area (LHA).> The review also notes the possible role of P2X and extracellular ATP in specific hypothalamic functions. The literature summarized here shows that purinergic signaling is involved in the control of the hypothalamic-pituitary endocrine system, the hypothalamic–neurohypophysial system, the circadian systems and nonendocrine hypothalamic functions. Full article

Objectives: Comparative analyses of anesthetic agents on mutants with altered anesthetic sensitivity remain limited in the current literature. This study examines the sensitivity of various Drosophila melanogaster wild-type strains and mutants to the volatile anesthetics chloroform and isoflurane. We utilized recently identified mutants in ion channel-encoding genes and others historically selected for anesthetic resistance, such as AGAR (autosomal general anesthesia resistant) and har (halothane-resistant). Method: Based on the principles of the conventional inebriometer assay used to isolate these mutants, we developed a new, simpler method to measure the anesthetic response in these flies. Results: Interestingly, we discovered that wild-type flies exhibit varying levels of anesthetic resistance. Contrary to previous reports, AGAR and har mutants showed little resistance to anesthesia using our method. Several ion channel mutants displayed increased resistance or sensitivity. Across all strains, isoflurane was more potent than chloroform. To ensure objectivity, all experiments were conducted double-blind. These findings highlight the variability in anesthetic sensitivity among both wild-type and mutant flies and underscore the importance of assay design in assessing resistance. Full article

Sleep deprivation is a prevalent issue that disrupts the circadian rhythm of estrogen, particularly estradiol, thereby significantly affecting women’s skin health and appearance. These disruptions can impair skin barrier functionality and decrease dermal collagen synthesis. In this study, our results demonstrate that topical taurine supplementation promotes the expression of tight junction (TJ)-related proteins and enhances collagen production, effectively restoring skin homeostasis in sleep-deprived female mice. Mechanistically, taurine upregulates the expression of TMEM38B, a gene encoding the TRIC-B trimeric cation channel, resulting in increased intracellular calcium ion levels. This, in turn, promotes the upregulation of TJ-related proteins, such as ZO-1, occludin, and claudin-11 in epidermal cells, while also enhancing the expression of type III collagen in fibroblasts, thus restoring skin homeostasis. These findings suggest that taurine may serve as an alternative to estradiol, effectively improving skin homeostasis disrupted by sleep deprivation while mitigating the potential risks associated with exogenous estrogen supplementation. Collectively, these results provide preliminary insights into the protective mechanisms of taurine against sleep deprivation-induced skin impairments and establish a foundation for its potential application in treating skin conditions related to estrogen imbalances, such as skin aging in menopausal women. Full article

Understanding how past factors influence ion channel kinetics is essential for understanding complex phenomena in cardiac electrophysiology, such as early afterdepolarizations (EADs), which are abnormal depolarizations during the action potential plateau associated with life-threatening arrhythmias. We developed a mathematical framework that extends Hodgkin-Huxley type equations with gamma Mittag-Leffler distributed delays, using tools from Fractional Calculus. Traditional memoryless two-variable models fail to reproduce EADs. Our approach modifies FitzHugh-Nagumo, Mitchell-Schaeffer, and Karma cardiac models, enabling the generation of EADs in each of them. We analyze the emergence of these oscillations by discussing the fractional parameters and the mean and variance of the memory kernels. Stability observations are also presented. Full article

Ion channels are proteins that regulate the flow of ions across cell membranes, playing a vital role in cervical cancer development and progression. These channels serve as both potential diagnostic markers and therapeutic targets, offering new opportunities for cancer treatment. Moreover, ion channels are crucial molecular indicators and possible therapeutic targets due to their role in the development of cervical cancer. Our review focuses on the various types of ion channels which are associated with cervical cancer (CCa), including sodium, calcium, and potassium channels. In our review, we clarify their diagnostic and prognostic value, as well as their relationship to the prognosis and stage of the disease. We also examine how ion channels contribute to the metastasis of cervical cancer, specifically in relation to their influence on cell motility, invasion, and interaction with the tumor microenvironment. By examining preclinical and clinical research involving ion channel blockers and modulators, we also highlight the therapeutic potential of targeting ion channels. We have demonstrated the available assays and imaging methods based on ion channel activity as examples of emerging diagnostic breakthroughs that show promise for enhancing the early detection of cervical cancer. Additionally, the possibility that ion channel modulator-based combination therapy could improve the efficacy of traditional treatments is investigated. To demonstrate the potential of ion channels in cervical cancer diagnosis and treatment, our review highlights the current challenges and the promising role in cervical cancer diagnostics and therapy. Full article

Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce the ion currents that are known to be functionally expressed in pituitary cells. These currents include a voltage-gated Na⁺ current (I_Na), erg-mediated K⁺ current (I_K(erg)), M-type K⁺ current (I_K(M)), hyperpolarization-activated cation current (I_h), and large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel. The biophysical characteristics of the respective ion current were described. Additionally, we also provide explanations for the effect of various drugs or compounds on each of these currents. GH₃-cell exposure to GV-58 can increase the magnitude of I_Na with a concurrent rise in the inactivation time constant of the current. The presence of esaxerenone, an antagonist of the aldosterone receptor, directly suppresses the magnitude of peak and late I_Na. Risperidone, an atypical antipsychotic agent, is effective at suppressing the I_K(erg) amplitude directly, and di(2-ethylhexyl)-phthalate suppressed I_K(erg). Solifenacin and kynurenic acid can interact with the K_M channel to stimulate I_K(M), while carisbamate and cannabidiol inhibit the I_h amplitude activated by sustained hyperpolarization. Moreover, the presence of either rufinamide or QO-40 can enhance the activity of single BK_Ca channels. To summarize, alterations in ion currents within native pituitary cells or pituitary tumor cells can influence their functional activity, particularly in processes like stimulus–secretion coupling. The effects of small-molecule modulators, as demonstrated here, bear significance in clinical, therapeutic, and toxicological contexts. Full article