Search Results (320)

Strong differential privacy often collapses utility in transformer-based time-series forecasting because noise is injected directly into high-dimensional gradients (e.g., DP-SGD), severely corrupting the optimization process. We introduce Low-Dimensional Feature-Path Privacy for Transformers (LDPT), which enforces privacy by routing calibrated perturbations through a low-dimensional feature bottleneck ($D=16$) that is independent of the model parameter count. LDPT implements noise via classically simulated quantum channels (Lindblad/depolarizing dynamics) and finite-shot POVM measurements, providing an auditable mapping from privacy budget $\epsilon$ to perturbation magnitude while keeping the transformer gradients clean. Across the ETT datasets and multiple prediction horizons, LDPT substantially preserves forecasting utility under its native local $\epsilon$-QDP guarantee. At a nominal per-pass $\epsilon =0.1$, LDPT limits MSE degradation to under 6%. In contrast, DP-SGD with global $(\epsilon ,\delta )$-DP applied to the identical transformer architecture suffers over 100% MSE degradation. Because these methods operate under different privacy definitions (local $\epsilon$-QDP vs. global $(\epsilon ,\delta )$-DP), this comparison illustrates the impact of noise placement rather than equivalent privacy protection. To isolate the effect of the calibration mechanism, we further evaluate a classical Gaussian mechanism on the same feature-path bottleneck, which requires orders-of-magnitude larger noise and severely degrades utility. Membership inference attacks confirm that LDPT does not amplify membership leakage beyond the non-private baseline. These results demonstrate that decoupling privacy noise from optimization through low-dimensional feature-path placement and tight channel-based calibration is critical for practical privacy-preserving transformer forecasting. Full article

Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na⁺ current (I_Na) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of I_Na when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the non-inactivating (persistent) I_Na elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of I_Na and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on I_Na in cardiac cells. The molecular docking prediction between TEL and the Na_V1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. In addition to its antagonistic action at the AT1 receptor and its agonistic activation of peroxisome proliferator-activator-γ, TEL may also directly enhance I_Na, thereby modulating AP firing in a variety of excitable cells. Current evidence supports TEL’s modulatory impact on Na_V channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation. Full article

Primary aldosteronism (PA) is the most common cause of secondary hypertension and accounts for 5–15% of hypertensive patients. Familial hyperaldosteronism, a monogenic cause of PA, accounts for ~1–5% of cases. Familial hyperaldosteronism type III results from mutations in the KCNJ5 gene, which lead to excessive aldosterone production and hypertension due to dysfunction of the GIRK4 channel in the adrenal gland. Despite the importance of KCNJ5 in PA pathogenesis, little is known about the molecular mechanisms underlying germline KCNJ5 mutations and their functional consequences. This study explored the structural changes in KCNJ5 pathogenic variant c.452G>A (p.Gly151Glu or GIRK4^G151E). Homology modeling and molecular dynamics simulations of the mutant GIRK4 channel showed that structural rearrangements occur in GIRK4^G151E when compared to GIRK4^WT, displaying higher RMSD and SASA, which may be attributed to differences in residue fluctuations in the cytosolic and extracellular domains, and ligands may bind with a stronger affinity to GIRK4^G151E. Given that the mutation is located within or proximal to the selectivity filter of GIRK4, we expect that the primary mechanism of dysfunction involves altered ion selectivity, leading to membrane depolarization. Our novel findings highlight the importance of understanding the molecular mechanisms underlying KCNJ5 mutations in PA and hypertension pathogenesis. This knowledge could inform the development of more targeted and effective treatments for this condition. Full article

Background: Electromechanical coupling is a fundamental process in the regulation of vascular smooth muscle contraction. It is characterized by changes in electrical potential membrane (depolarization). Voltage-gated calcium channels (VGCCs) play a central role in this process by mediating calcium influx necessary for vascular contraction. As highly conserved macromolecules in mammals, VGCCs represent translationally relevant targets for the development of vasorelaxant agents. Inhibition of these channels reduces calcium influx and attenuates the tonic smooth muscle contraction, making them strategic targets for novel therapeutic approaches. This is particularly important given the high prevalence of cardiovascular diseases, which remain the leading cause of global mortality. Methods: The aim of this study is to investigate the mechanism of action of terpenes in VGCCs. Terpenes are phytochemicals that have been widely studied as drug candidates. To this end, the oil from Hyptis crenata was extracted and characterized, revealing monoterpenes and sesquiterpenes as its main constituents. Results: In vitro assays on isolated aortic rings, with and without endothelium, demonstrated that these compounds reverse and block KCl (80 mM)-induced contractions in an endothelium-independent manner. Conclusions: Analyses of the ionic influx of calcium and barium indicated a progressive blockade of contraction, reinforcing the hypothesis of a direct interaction with the macromolecules of the VGCCs. Computational analyses, for the first time, suggest a potential synergistic interaction among terpenes in their binding to these macromolecules. Full article

This paper intends to go through the medical history of a new syndrome, beginning from its incidental observation to the nowadays ongoing reports quickly approaching 7000 published papers. This large number makes it difficult for the researcher to correctly quote the previous significant published data, and the usual strategy is to copy and paste the last articles references. This review is mainly detailed historical research of the step-by-step journey mainly of the first three decades, with less attention to the ongoing and late scientific controversies that are indeed quoted. The new syndrome was early named “precordial early repolarization (PER) syndrome” but became popular after being renamed “Brugada syndrome” (BS). Nowadays it is classified as one of the “J wave syndromes” (JWSs). The main characteristic of this new entity was an unusual astonishing precordial coved ST segment elevation that gave rise since its first descriptions to two different pathophysiological theories, one organic and the second functional. The first theory ascribed the ST elevation to an unusual pattern of depolarization at the right ventricular outflow tract (RVOT), while the second favored an abnormal dynamic repolarization pattern. Both phenomena were sometimes linked to an ion channel genetic abnormality. In the following decades, many eminent scientists and also some excellent humble cardiologists made significant observations regarding epidemiology, laboratory, diagnostic techniques, genetic, clinical findings, histology, embryology, therapeutic approaches, and risk stratification. This rush “to be the first who” has created more confusion than certainty, and only in this last decade a more scientific and less emotional approach has led to a common acceptance of an underlying organic background that causes a strange conduction delay mainly at the epicardial level of the RVOT. “Next generation” cardiologists are in charge of further elucidating the genetic, the structural, and electrical pathophysiology, and the correct risk stratification needed to correctly identify the true patients who need a therapy and avoid unusual and dangerous treatments to healthy people with a benign strange ECG. Full article

Background and Objectives: Sevoflurane, a widely used volatile anesthetic, can induce oxidative stress and apoptosis, but the underlying mechanisms in human cardiomyocytes remain unclear. This study investigated the role of transient receptor potential vanilloid 1 (TRPV1) channels in sevoflurane-induced cardiotoxicity and the potential mitigating effect of ascorbic acid. Materials and Methods: Human cardiomyocytes were exposed to sevoflurane (5.1%, 6 h) and/or ascorbic acid (1 mM, 30 min), with or without the TRPV1 channel antagonist capsazepine and with the TRPV1 channel agonist Capsaicin. Intracellular calcium, reactive oxygen species (ROS), apoptosis, mitochondrial membrane potential, and caspase-3/9 activities were assessed. Results: Sevoflurane significantly increased intracellular calcium levels, ROS production, mitochondrial depolarization, apoptosis, and caspase-3/9 activity compared with controls (p < 0.001). These effects were attenuated by capsazepine, suggesting a role for TRPV1 involvement. Ascorbic acid pretreatment significantly reduced sevoflurane-induced elevations in all parameters (p < 0.001). Combined ascorbic acid and capsazepine treatment yielded further reductions in calcium, ROS, apoptosis, and caspase activities compared to ascorbic acid alone (p < 0.05). Conclusions: Sevoflurane induces apoptosis in human cardiomyocytes via ROS-mediated activation of the TRPV1 channel, leading to calcium overload, mitochondrial dysfunction, and caspase-dependent cell death. Ascorbic acid exerts mitigating effects by reducing oxidative stress and modulating TRPV1 channel activity, suggesting a potential therapeutic strategy for myocardial protection during sevoflurane anesthesia. Full article

Grape pomace extract (GPE) from Vitis vinifera L. cv. Aglianico is rich in polyphenols with recognized cardioprotective properties, yet its direct electrophysiological effects on spontaneous cardiac activity have not been previously investigated. Here, we examined the chronotropic effects of GPE using two complementary models: HL-1 cardiomyocytes, assessed by whole-cell patch-clamp and intracellular Ca²⁺ imaging, and the Drosophila melanogaster larval heart tube, evaluated by optical recording. In HL-1 cells, chronic treatment with 25 µg/mL GPE for 48 h significantly reduced potential spontaneous action frequency and selectively prolonged the diastolic depolarization phase without altering action potential morphology, depolarization-activated currents, or cytosolic Ca²⁺ homeostasis. GPE reduced the hyperpolarization-activated funny current (I_f) density without shifting its voltage dependence. GPE-treated cells retained cAMP sensitivity, as both isoproterenol and intracellular 8-Br-cAMP significantly increased I_f amplitude, while ELISA quantification confirmed that global cAMP levels were unaffected by GPE. In Drosophila larvae, a cAMP-independent myogenic preparation, GPE administered in the diet significantly reduced heart rate. These findings demonstrate that Aglianico GPE exerts a negative chronotropic effect through a mechanism that reduces functional I_f density without altering cAMP availability or HCN channel voltage dependence, and reveal a cAMP-independent component of action conserved across phylogenetically distant species. Full article

Human endometrial mesenchymal stem/stromal cells (eMSCs) are widely used in laboratories and clinical applications to study various aspects of tissue engineering and regenerative medicine. Three-dimensional (3D) cultivated MSCs have a higher therapeutic efficacy compared to 2D culture. Ion channels are involved in maintaining many physiological cell functions, including proliferation, differentiation, apoptosis, and migration. This study describes the functional expression of voltage-gated sodium channels (NaV) in eMSCs and the role of these channels in cell migration. Using RT-PCR analysis and immunofluorescent microscopy, we identified the expression of almost all pore-forming alpha (NaV 1.1, 1.2, 1.4–1.9) and channel-modulating beta-NaV subunits (except beta2) in eMSCs. In the whole-cell patch-clamp configuration, channels activated by membrane depolarization of eMSC were detected. The channels were blocked by the selective NaV antagonist TTX in nanomolar concentrations. The NaV agonist veratridine at a concentration of less than 40 μM inhibited voltage-gated sodium currents, while 100 μM and above prevented channel inactivation. The wound healing assay showed that both TTX (10 μM) and veratridine (100 μM) reduced the migration properties (the wound healing rate) of eMSCs cultivated in 2D conditions compared to the control. An opposite effect by both agents was shown on the motility of eMSCs cultivated in 3D conditions, increasing the cell spreading rate from spheroids. Our data suggest that NaV channels are expressed in human eMSCs and play an important role in the regulation of stem cell migration; this regulatory mechanism significantly depends on the culture conditions of MSCs. Full article

De novo variants in CACNA1E, the gene encoding the Cav2.3 voltage-gated calcium channel, are often associated with severe neurodevelopmental disorders, including developmental and epileptic encephalopathy. All reported variants up to date have exhibited gain-of-function effects on their biophysical properties. Here, we functionally characterize three pathogenic CACNA1E variants: H151L, M163T, and R1182C, using electrophysiology and structural modeling. M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation. Our findings provide the first mechanistic evidence linking loss-of-function Cav2.3 pathogenic variants to variable neurological phenotypes, expanding the clinical spectrum of CACNA1E channelopathies. Full article

Background: Corylin (3-(2,2-dimethylchromen-6-yl)-7-hydroxychromen-4-one), a bioactive flavonoid, has been reported to exercise anti-inflammatory, antineoplastic, and antioxidant effects, and may also possess lifespan-extending properties. Objectives: Any modifications of transmembrane ionic currents produced by corylin remain largely unknown. Methods: The patch-clamp technique and docking prediction were used in this study. Results: In pituitary GH₃ somatolactotrophs, corylin concentration-dependently increased the magnitude of the M-type K⁺ current (I_K(M)), with an EC₅₀ of 3.8 μM. Concurrently, the activation time constant of I_K(M) was shortened. The addition of linopirdine (10 μM), an I_K(M) inhibitor, suppressed the current amplitude. Corylin also induced a leftward shift in the steady-state activation curve and enhanced I_K(M) during pulse-train stimulation. Moreover, corylin increases the hysteretic strength of I_K(M) evoked by a long-lasting triangular ramp pulse; this effect was attenuated by linopirdine. The stimulatory effect of corylin on I_K(M) was not altered by carvedilol or iberiotoxin but was reduced by dapagliflozin. In contrast, depolarization-activated I_K(M) was not affected by 17β-estradiol alone. In cell-attached recordings, corylin increased M-type K⁺ (K_M)-channel activity with minimal change in single-channel amplitude, while prolonging the mean open time. This stimulatory effect was reversed by linopirdine or dapagliflozin. Additionally, corylin slightly inhibited the erg-mediated current. Docking analysis further suggested that corylin potentially interacts with residues in KCNQ2 or KCNH2 channels via hydrogen bonding and hydrophobic interactions. Conclusions: These findings suggest that corylin modulates ionic currents, primarily through K_M (KCNQ/K_V7) channels, which may underlie its in vivo actions and those of related flavonoids. These effects may contribute to the regulation of functional activities of neuronal, neuroendocrine, and endocrine cells. Full article

The hERG potassium channel is critical for cardiac ventricular repolarization and a core target in pre-clinical drug safety screening. A robust, stable cell line with uniform, high hERG expression is essential for high-throughput assessments. In this study, we established a functional stable HEK293T cell line with high hERG expression. The hERG gene was subcloned into Lenti-HA-hERG-P2A-EGFP plasmid, in which GFP serves as a selection marker via a P2A self-cleaving peptide. GFP-positive monoclonal cells were isolated by fluorescence-activated cell sorting (FACS). Confocal imaging confirmed that hERG localized predominantly to the cell membrane, consistent with its physiological role. Manual patch-clamp revealed canonical hERG current properties: a small, stable current during depolarization to 20 mV, followed by a large outward tail current upon repolarization to −40 mV-a hallmark of hERG channel gating. Automated patch-clamp (APC)-based current profiling showed 93.5% of stable hERG cells exhibited peak tail currents > 50 pA (87% > 100 pA, with 49.5% > 400 pA), whereas 100% of blank HEK293T cells showed peak tail currents < 50 pA. Pharmacological validation with E-4031 demonstrated concentration-dependent inhibition of hERG currents, with an IC₅₀ of 29.8 nM, which is consistent with literature-reported values. The stable hERG-expressing HEK293T cell line developed here exhibits consistent hERG expression, canonical channel function, and physiological sensitivity to hERG blockers. When paired with high-throughput APC systems, this cell model provides a robust, standardized platform for pre-clinical drug-induced hERG inhibition evaluation, aiding early detection of long QT syndrome risks and safer drug development. Full article

Optogenetic modulation employs light-sensitive proteins known as opsins to regulate cellular activity. A unique therapeutic application of this technique involves modulating pain perception by selectively targeting neural pathways within the spinal cord. Multi-Characteristic Opsin (MCO) represents an innovative optogenetic actuator capable of activation across a broad spectrum of light wavelengths, exhibiting a slow depolarizing phase that resembles natural photoreceptors. This study examines the current advancements in spinal optogenetic modulation utilizing MCO for pain management. Due to its high sensitivity, MCO facilitates minimally invasive, remotely controlled optogenetic modulation of spinal neurons. This approach enables the regulation of extensive spatial regions, provided the MCO channel receives sufficient light intensity to surpass the activation threshold. Nano-enhanced optical delivery (NOD) successfully transfected spinal neurons with the GAD67-MCO2-mCherry construct, as confirmed by membrane-localized mCherry fluorescence with DAPI-labeled nuclei. Using this platform, 5 Hz spinal optogenetic stimulation produced a significant reduction in formalin-evoked pain behaviors, demonstrating frequency-specific modulation of spinal pain circuits. Neither 2 Hz nor 10 Hz stimulation yielded comparable analgesic effects, underscoring the importance of precise stimulation parameters. The therapeutic impact also depended on transfection efficiency: reducing the fGNR–plasmid concentration diminished MCO expression and weakened the analgesic response. Together, these results show that effective spinal optogenetic pain modulation requires both optimal stimulation frequency and robust gene delivery. Full article

Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood–brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries—including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury—as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial–neuronal communication and cognitive–emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood–brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx—particularly Cx43—occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation. Full article

Skeletal muscle differentiation is tightly regulated by membrane potential dynamics and voltage-dependent ion channel activity. Potassium (K⁺) and calcium (Ca²⁺) currents cooperate to orchestrate the transition of myoblasts into fusion-competent myotubes, and alterations in this process are associated with dystrophic phenotypes. Here, we investigated the electrophysiological remodeling accompanying C2C12 myogenesis and the modulatory effects of the polyphenol resveratrol (RES) on calcium voltage-gated channel subunit alpha 1 S (CACNA1S, Cav1.1, L-type) currents. Whole-cell patch-clamp recordings were performed in proliferating and differentiating C2C12 cells to characterize the temporal expression of K⁺ currents and voltage-dependent Ca²⁺ channels (VDCCs). During differentiation, three electrophysiological subpopulations were identified according to K⁺ current profiles: SK4+/EAG−/Kir−, SK4−/EAG+/Kir−, and SK4−/EAG+/Kir+. This sequence paralleled a progressive membrane hyperpolarization from −20 mV to −70 mV, consistent with the physiological maturation of myogenic cells. In C2C12 myocytes, nimodipine-sensitive L-type currents were the only Ca²⁺ conductance observed. Their activation threshold (~−30 mV) and half-activation voltage (V/2 ≈ −12 mV) indicated the co-expression of embryonic and adult Cav1.1 isoforms. Exposure to RES (30 µM, 48 h) produced a depolarizing shift in activation (ΔV/2 ≈ +9 mV) and a reduction in current amplitude across all voltages, consistent with a transition toward the adult splice variant of Cav1.1. These findings suggest that RES promotes electrophysiological maturation of skeletal muscle cells by modulating calcium channel expression and gating behavior. Given its known ability to correct splicing abnormalities in CACNA1S and related genes, resveratrol emerges as a promising pharmacological agent for restoring calcium homeostasis in neuromuscular disorders such as myotonic dystrophy type 1 (DM1). Full article

The discovery of the glymphatic system (GS) transformed understanding of central nervous system homeostasis by revealing a brain-wide network that facilitates cerebrospinal and interstitial fluid exchange along perivascular pathways. This system clears metabolic waste and maintains the precise ionic environment required for neuronal function through the coordinated action of astrocytic aquaporin-4 channels and intact perivascular architecture. Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, alters physiological barriers through pathological angiogenesis, compression of perivascular spaces, depolarization of aquaporin-4 at astrocytic endfeet, and obstruction of venous and lymphatic drainage. This narrative review synthesizes current experimental and clinical literature identified through targeted searches of PubMed and Scopus to examine interactions between glioblastoma, glymphatic system dysfunction, and tumor microenvironmental changes. To minimize selection bias, studies were categorized according to evidence source and experimental design. Evidence from rodent models and advanced imaging demonstrates as tumor growth impairs glymphatic function, the resulting dysfunction promotes tumor progression by enabling accumulation of pro-tumorigenic growth factors, inflammatory mediators, and acidic metabolites, while elevated interstitial fluid pressure limits drug delivery. Impaired antigen drainage further diminishes immune surveillance, contributing to the immunosuppressive microenvironment that limits immunotherapy efficacy. A critical evaluation of these mechanisms highlights how the glymphatic system influences disease progression and suggests novel avenues for diagnostic imaging and therapeutic intervention. Although significant challenges remain in modeling human fluid dynamics, understanding these hidden networks offers a promising frontier for strategies aimed at restoring cerebral clearance and improving clinical outcomes. Full article