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A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer’s disease (AD) risk among African Americans (AAs) and European Americans. Their findings indicated that moderate-to-high TEL exposure was linked to a decreased incidence of AD among AAs. These results suggest a potential association between TEL and a reduced risk of AD specifically within the AA population. Here, we investigated the effects of TEL, either alone or in combination with ranolazine (Ran) or dapagliflozin (Dapa), on voltage-gated Na+ currents (INa) in Neuro-2a cells. TEL, primarily used for treating hypertension and cardiovascular disorders, showed a stimulatory effect on INa, while Ran and Dapa reversed this stimulation. In Neuro-2a cells, we demonstrated that with exposure to TEL, the transient (INa(T)) and late (INa(L)) components of INa were differentially stimulated with effective EC50’s of 16.9 and 3.1 μM, respectively. The research implies that TEL’s impact on INa might be associated with enhanced neuronal excitability. This study highlights the complex interplay between TEL, Ran, and Dapa on INa and their potential implications for AD, emphasizing the need for further investigation to understand the mechanisms involved.

As the need for effective antiviral treatment intensifies, such as with the coronavirus disease 19 (COVID-19) infection, it is crucial to understand that while the mechanisms of action of these drugs or compounds seem apparent, they might also interact with unexplored targets, such as cell membrane ion channels in diverse cell types. In this review paper, we demonstrate that many different drugs or compounds, in addition to their known interference with viral infections, may also directly influence various types of ionic currents on the surface membrane of the host cell. These agents include artemisinin, cannabidiol, memantine, mitoxantrone, molnupiravir, remdesivir, SM-102, and sorafenib. If achievable at low concentrations, these regulatory effects on ion channels are highly likely to synergize with the identified initial mechanisms of viral replication interference. Additionally, the immediate regulatory impact of these agents on the ion-channel function may potentially result in unintended adverse effects, including changes in cardiac electrical activity and the prolongation of the QTc interval. Therefore, it is essential for patients receiving these related agents to exercise additional caution to prevent unnecessary complications.

Dermatophytic pseudomycetoma (DPM) is a rarely reported invasive fungal infection of humans and animals, especially cats. This study aimed to identify dermatophytes, breed associations, and the frequency of extracutaneous (EC) involvement in feline DPM. Electronic records and formalin-fixed paraffin-embedded tissue (FFPET) from 32 suspected DPM cases in 30 cats were retrieved from a diagnostic laboratory between 2018 and 2024. To confirm DPM and molecular identity, DNA was extracted from FFPET for ITS2 sequencing, and immunohistochemistry was performed on PCR-negative cases. All cases were confirmed as DPM. Microsporum canis was the only dermatophyte identified. The sensitivity and specificity of ITS2 sequencing for M. canis identification in FFPET were 22/32 (68.8%) and 21/22 (95.5%), respectively. Exotic (36.7%) and Persian (23.3%) but not British breeds (26.3%) were over-represented compared to feline admissions at an affiliated veterinary hospital (8.5%, p < 0.001; 3%, p < 0.001; 21.6%, p = 0.817, respectively). Five cases (16.7%) had EC lesions; two had intra-abdominal masses; two had oral cavity masses, including one which extended into the cranial vault; and one had superficial cervical lymph node invasion. Exotic and Persian breeds are over-represented for DPM and M. canis is the primary cause. EC lesions of DPM may occur more commonly than previously thought.

This review paper delves into the current body of evidence, offering a thorough analysis of the impact of large-conductance Ca2+-activated K+ (BKCa or BK) channels on the electrical dynamics of the heart. Alterations in the activity of BKCa channels, responsible for the generation of the overall magnitude of Ca2+-activated K+ current at the whole-cell level, occur through allosteric mechanisms. The collaborative interplay between membrane depolarization and heightened intracellular Ca2+ ion concentrations collectively contribute to the activation of BKCa channels. Although fully developed mammalian cardiac cells do not exhibit functional expression of these ion channels, evidence suggests their presence in cardiac fibroblasts that surround and potentially establish close connections with neighboring cardiac cells. When cardiac cells form close associations with fibroblasts, the high single-ion conductance of these channels, approximately ranging from 150 to 250 pS, can result in the random depolarization of the adjacent cardiac cell membranes. While cardiac fibroblasts are typically electrically non-excitable, their prevalence within heart tissue increases, particularly in the context of aging myocardial infarction or atrial fibrillation. This augmented presence of BKCa channels’ conductance holds the potential to amplify the excitability of cardiac cell membranes through effective electrical coupling between fibroblasts and cardiomyocytes. In this scenario, this heightened excitability may contribute to the onset of cardiac arrhythmias. Moreover, it is worth noting that the substances influencing the activity of these BKCa channels might influence cardiac electrical activity as well. Taken together, the BKCa channel activity residing in cardiac fibroblasts may contribute to cardiac electrical function occurring in vivo.

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The IK(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K+ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na+ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (Ih) with an IC50 of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of Ih was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on Ih elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo.

The hyperpolarization-activated cation current (Ih) exhibits a slowly activating time course of the current (Ih) when the cell membrane is hyperpolarized for an extended duration. It is involved in generating electrical activity in various excitable cells. Numerous structurally distinct compounds or herbal drugs have the potential to impact both the magnitude and gating kinetics of this current. Brivaracetam, a chemical analog of levetiracetam known to be a ligand for synaptic vesicle protein 2A, could directly suppress the Ih magnitude. Carisbamate, an anticonvulsant agent, not only inhibited the Ih amplitude but also reduced the strength of voltage-dependent hysteresis (Hys(V)) associated with Ih. Cilobradine, similar to ivabradine, inhibited the amplitude of Ih; however, it also suppressed the amplitude of delayed-rectifier K+ currents. Dexmedetomidine, an agonist of α2-adrenergic receptor, exerted a depressant action on Ih in a concentration-dependent fashion. Suppression of Ih amplitude was observed when GAL-021, a breathing control modulator, was present at a concentration exceeding 30 μM. Lutein, one of the few xanthophyll carotenoids, was able to suppress the Ih amplitude as well as to depress Hys(V)’s strength of Ih. Pirfenidone, a pyridine derivative known to be an anti-fibrotic agent, depressed the Ih magnitude in a concentration- and voltage-dependent fashion. Tramadol, a synthetic centrally active analgesic, was shown to reduce the Ih magnitude, independent of its interaction with opioid receptors. Various herbal drugs, including ent-kaurane-type diterpenoids from Croton tonkinensis, Ganoderma triterpenoids, honokiol, and pterostilbene, demonstrated efficacy in reducing the magnitude of Ih. Conversely, oxaliplatin, a platinum-based chemotherapeutic compound, was observed to effectively increase the Ih amplitude. Collectively, the regulatory effects of these compounds or herbal drugs on cellular function can be partly attributed to their perturbations on Ih.

Summary: Background: This study aims to evaluate the association between thromboembolic events and hemorrhagic stroke following BNT162b2 and CoronaVac vaccination. Methods: Patients with incident thromboembolic events or hemorrhagic stroke within 28 days of covid-19 vaccination or SARS-CoV-2 positive test during 23 February to 30 September 2021 were included. The incidence per 100,000 covid-19 vaccine doses administered and SARS-CoV-2 test positive cases were estimated. A modified self-controlled case series (SCCS) analysis using the data from the Hong Kong territory-wide electronic health and vaccination records. Seasonal effect was adjusted by month. Findings: A total of 5,526,547 doses of BNT162b2 and 3,146,741 doses of CoronaVac were administered. A total of 334 and 402 thromboembolic events, and 57 and 49 hemorrhagic stroke cases occurred within 28 days after BNT162b2 and CoronaVac vaccination, respectively. The crude incidence of thromboembolic events and hemorrhagic stroke per 100,000 doses administered for both covid-19 vaccines were smaller than that per 100,000 SARS-CoV-2 test positive cases. The modified SCCS detected an increased risk of hemorrhagic stroke in BNT162b2 14-27 days after first dose with adjusted IRR of 2.53 (95% CI 1.48-4.34), and 0-13 days after second dose with adjusted IRR 2.69 (95% CI 1.54-4.69). No statistically significant risk was observed for thromboembolic events for both vaccines. Interpretation: We detected a possible safety signal for hemorrhagic stroke following BNT162b2 vaccination. The incidence of thromboembolic event or hemorrhagic stroke following vaccination is lower than that among SARS-CoV-2 test positive cases; therefore, vaccination against covid-19 remains an important public health intervention. Funding: This study was funded by a research grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (reference COVID19F01).

Abstract The sensitivity of pneumothorax diagnosis via handheld ultrasound is low, and there is no equipment suitable for use with life-threatening tension pneumothorax in a prehospital setting. This study proposes a novel technology involving optical fibers and near-infrared spectroscopy to assist in needle thoracostomy decompression. The proposed system via the optical fibers emitted dual wavelengths of 690 and 850 nm, allowing distinction among different layers of tissue in vivo. The fundamental principle is the modified Beer–Lambert law (MBLL) which is the basis of near-infrared tissue spectroscopy. Changes in optical density corresponding to different wavelengths (690 and 850 nm) and hemoglobin parameters (levels of Hb and HbO2) were examined. The Kruskal–Wallis H test was used to compare the differences in parameter estimates among tissue layers; all p-values were

The presence of hydrogen in structural alloys reduces their ductility, a phenomenon called hydrogen embrittlement. Bake-out heat treatments are employed during processing to allow hydrogen trapped in microstructural features to effuse from the samples, but the optimal times and temperatures depend on the kinetics of hydrogen diffusion in the material. In this work, Gaussian process surrogate models are employed to emulate the outputs of microstructure-sensitive diffusion differential equations in steel. Training the models by sequentially increasing the number of dimensions results in better performances and shorter training times. Two main approaches are developed: single output models with experimental design for the prediction of optimal bake-out times, and multi-output principal component analysis models for the prediction of hydrogen concentration evolution. A novel approach is implemented to shorten the training times of multi-trap models by exploiting the symmetry of the equations with respect to different kinds of traps. The resulting models pave the way for the implementation of Gaussian processes on more computationally expensive diffusion simulations for the optimisation of heat treatments and other applications.

Abstract We successfully prepared water-soluble fullerenol [C60(OH)46] that exhibited a high singlet oxygen quantum yield and efficiently generated reactive oxygen species. Additionally, the water-soluble C60(OH)46 with a higher composition of exposed hydroxyl groups had superior two-photon stability and characteristics compared with that with a lower composition of such groups. Therefore, the prepared fullerenol can be an effective two-photon photosensitizer. The water-soluble C60(OH)46 had favorable two-photon properties. During two-photon photodynamic therapy, the water-soluble C60(OH)46 had substantial antimicrobial activity against Escherichia coli at an ultralow-energy level of 211.2 nJ pixel−1 with 800 scans and a photoexcited wavelength of 760 nm.

In thoracic surgery, the double lumen endotracheal tube (DLT) is used for differential ventilation of the lung. DLT allows lung collapse on the surgical side that requires access to the thoracic and mediastinal areas. DLT placement for a given patient depends on two settings: a tube of the correct size (or ‘size’) and to the correct insertion depth (or ‘depth’). Incorrect DLT placements cause oxygen desaturation or carbon dioxide retention in the patient, with possible surgical failure. No guideline on these settings is currently available for anesthesiologists, except for the aid by bronchoscopy. In this study, we aimed to predict DLT ‘depths’ and ‘sizes’ applied earlier on a group of patients (n = 231) using a computer modeling approach. First, for these patients we retrospectively determined the correlation coefficient (r) of each of the 17 body parameters against ‘depth’ and ‘size’. Those parameters having r > 0.5 and that could be easily obtained or measured were selected. They were, for both DLT settings: (a) sex, (b) height, (c) tracheal diameter (measured from X-ray), and (d) weight. For ‘size’, a fifth parameter, (e) chest circumference was added. Based on these four or five parameters, we modeled the clinical DLT settings using a Support Vector Machine (SVM). After excluding statistical outliers (±2 SD), 83.5% of the subjects were left for ‘depth’ in the modeling, and similarly 85.3% for ‘size’. SVM predicted ‘depths’ matched with their clinical values at a r of 0.91, and for ‘sizes’, at an r of 0.82. The less satisfactory result on ‘size’ prediction was likely due to the small target choices (n = 4) and the uneven data distribution. Furthermore, SVM outperformed other common models, such as linear regression. In conclusion, this first model for predicting the two DLT key settings gave satisfactory results. Findings would help anesthesiologists in applying DLT procedures more confidently in an evidence-based way.

Lung segmentation of chest X-ray (CXR) images is a fundamental step in many diagnostic applications. Most lung field segmentation methods reduce the image size to speed up the subsequent processing time. Then, the low-resolution result is upsampled to the original high-resolution image. Nevertheless, the image boundaries become blurred after the downsampling and upsampling steps. It is necessary to alleviate blurred boundaries during downsampling and upsampling. In this paper, we incorporate the lung field segmentation with the superpixel resizing framework to achieve the goal. The superpixel resizing framework upsamples the segmentation results based on the superpixel boundary information obtained from the downsampling process. Using this method, not only can the computation time of high-resolution medical image segmentation be reduced, but also the quality of the segmentation results can be preserved. We evaluate the proposed method on JSRT, LIDC-IDRI, and ANH datasets. The experimental results show that the proposed superpixel resizing framework outperforms other traditional image resizing methods. Furthermore, combining the segmentation network and the superpixel resizing framework, the proposed method achieves better results with an average time score of 4.6 s on CPU and 0.02 s on GPU.

Introduction. Disaster medical assistance team (DMAT) and urban search and rescue team (USAR) need to cooperate seamlessly to save lives in disasters, but related research is limited. Objectives. To estimate the disaster preparedness of the DMAT and the barriers affecting interagency cooperation between the DMAT and the USAR team. Methods. This was an observational study of a full-scale exercise conducted in Taiwan from November 16 to 18, 2018. The exercise scenario simulated a magnitude 7 earthquake in Tainan City. DMATs from other counties were deployed and cooperated with local USAR teams to carry out disaster relief. Our study invited 7 experts to evaluate DMATs on disaster preparedness capabilities and the interagency collaboration between DMATs and USAR. Results. A total of eight DMATs, consisting of 30 physicians, 65 nurses, 74 logisticians, 5 health bureau personnel, and 85 USAR teams, participated in this exercise. During the mission, 176 patients were treated. The capabilities of each team were generally consistent with the basic technical standards for type I emergency medical teams, but the compliance rates for basic local anesthesia, cold chain equipment for medication, rapid blood test tools, and sterilization devices were only 50%, 12.5%, 12.5%, and 9%, respectively. In addition, 53% of participants reported abnormal vital signs, indicating that it was a high-stress situation. Moreover, the main barriers to interagency collaboration were differing perspectives and poor mutual understanding. Conclusion. A full-scale exercise carried out jointly with DMATs and USAR teams was valuable for disaster preparedness, particularly in terms of understanding the weaknesses of those teams and the barriers to interagency collaboration.

Background: Artemisinin (ART) is an anti-malarial agent reported to influence endocrine function. Methods: Effects of ART on ionic currents and action potentials (APs) in pituitary tumor (GH3) cells were evaluated by patch clamp techniques. Results: ART inhibited the amplitude of delayed-rectifier K+ current (IK(DR)) in response to membrane depolarization and accelerated the process of current inactivation. It exerted an inhibitory effect on IK(DR) with an IC50 value of 11.2 µM and enhanced IK(DR) inactivation with a KD value of 14.7 µM. The steady-state inactivation curve of IK(DR) was shifted to hyperpolarization by 10 mV. Pretreatment of chlorotoxin (1 µM) or iloprost (100 nM) did not alter the magnitude of ART-induced inhibition of IK(DR) in GH3 cells. ART also decreased the peak amplitude of voltage-gated Na+ current (INa) with a concentration-dependent slowing in inactivation rate. Application of KMUP-1, an inhibitor of late INa, was effective at reversing ART-induced prolongation in inactivation time constant of INa. Under current-clamp recordings, ART alone reduced the amplitude of APs and prolonged the duration of APs. Conclusion: Under ART exposure, the inhibitory actions on both IK(DR) and INa could be a potential mechanisms through which this drug influences membrane excitability of endocrine or neuroendocrine cells appearing in vivo.

Carfilzomib (CFZ, Kyprolis®) is widely recognized as an irreversible inhibitor of proteasome activity; however, its actions on ion currents in electrically excitable cells are largely unresolved. The possible actions of CFZ on ionic currents and membrane potential in pituitary GH3, A7r5 vascular smooth muscle, and heart-derived H9c2 cells were extensively investigated in this study. The presence of CFZ suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in a time-, state-, and concentration-dependent manner in pituitary GH3 cells. Based on minimal reaction scheme, the value of dissociation constant for CFZ-induced open-channel block of IK(DR) in these cells was 0.33 µM, which is similar to the IC50 value (0.32 µM) used for its efficacy on inhibition of IK(DR) amplitude. Recovery from IK(DR) block by CFZ (0.3 µM and 1 µM) could be well fitted by single exponential with 447 and 645 ms, respectively. The M-type K+ current, another type of K+ current elicited by low-threshold potential, was slightly suppressed by CFZ (1 µM). Under current-clamp condition, addition of CFZ depolarized GH3 cells, broadened the duration of action potentials as well as raised the firing frequency. In A7r5 vascular smooth muscle cells or H9c2 cardiac cells, the CFZ-induced inhibition of IK(DR) remained efficacious. Therefore, our study led us to reflect that CFZ or other structurally similar compounds should somehow act on the activity of membrane KV channels through which they influence the functional activities in different types of electrically excitable cells such as endocrine, neuroendocrine cells, smooth muscle cells, or heart cells, if similar in vivo findings occur.

One of the contributors to the published paper [1] did not provide permission for the datapresented to be published and we have therefore taken the decision to retract the paper [...]

Pterostilbene (PTER), a natural dimethylated analog of resveratrol, has been demonstrated to produce anti-neoplastic or neuroprotective actions. However, how and whether this compound can entail any perturbations on ionic currents in electrically excitable cells remains unknown. In whole-cell current recordings, addition of PTER decreased the amplitude of macroscopic Ih during long-lasting hyperpolarization in GH3 cells in a concentration-dependent manner, with an effective IC50 value of 0.84 μM. Its presence also shifted the activation curve of Ih along the voltage axis to a more hyperpolarized potential, by 11 mV. PTER at a concentration greater than 10 μM could also suppress l-type Ca2+ and transient outward K+ currents in GH3 cells. With the addition of PTER, IK(Ca) amplitude was increased, with an EC50 value of 2.23 μM. This increase in IK(Ca) amplitude was attenuated by further addition of verruculogen, but not by tolbutamide or TRAM-39. Neither atropine nor nicotine, in the continued presence of PTER, modified the PTER-stimulated IK(Ca). PTER (10 μM) slightly suppressed the amplitude of l-type Ca2+ current and transient outward K+ current. The presence of PTER (3 μM) was also effective at increasing the open-state probability of large-conductance Ca2+-activated K+ (BKCa) channels identified in hippocampal mHippoE-14 neurons; however, its inability to alter single-channel conductance was detected. Our study highlights evidence to show that PTER has the propensity to perturb ionic currents (e.g., Ih and IK(Ca)), thereby influencing the functional activities of neurons, and neuroendocrine or endocrine cells.

Accumulated evidence suggests a pathogenic role of reactive oxygen species (ROS) in perpetually rheumatoid joints. Therefore, the application of radical scavengers for reducing the accumulation of ROS is beneficial for patients with rheumatoid arthritis (RA). We synthesized water-soluble fullerenols that could inhibit the production of ROS and applied intra-articular (i.a.) injection in an experimental arthritis model to examine the anti-arthritic effect of the synthesized compound. RAW 264.7 cells were used to examine the activity of the synthesized fullerenol. Collagen-induced arthritis (CIA) was induced in Sprague−Dawley rats by injecting their joints with fullerenol. The therapeutic effects were evaluated using the articular index as well as radiological and histological scores. Dose-dependent suppression of nitric oxide (NO) production caused by the fullerenol was demonstrated in the RAW 264.7 cell culture, thus confirming the ability of fullerenol to reduce ROS production. In the fullerenol-injected joints, articular indexes, synovial expression of ROS, histological and radiological scores, pannus formation, and erosion of cartilage and bone were all reduced. Moreover, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) levels were reduced, and fewer von Willebrand factor (vWF)-stained areas were identified in the fullerenol-treated joints than in control joints. The i.a. injection of fullerenol for reducing ROS production can ameliorate arthritis in joints by suppressing pro-inflammatory cytokine production and the angiogenesis process. Thus, the i.a. injection of fullerenol for reducing the production of ROS can be used as a pharmacological approach for RA patients.

Bisoprolol (BIS) is a selective antagonist of β1 adrenergic receptors. We examined the effects of BIS on M-type K+ currents (IK(M)) or erg-mediated K+ currents (IK(erg)) in pituitary GH3, R1220 cells, and hippocampal mHippoE-14 cells. As GH3 cells were exposed to BIS, amplitude of IK(M) was suppressed with an IC50 value of 1.21 μM. The BIS-induced suppression of IK(M) amplitude was not affected by addition of isoproterenol or ractopamine, but attenuated by flupirtine or ivabradine. In cell-attached current, BIS decreased the open probability of M-type K+ (KM) channels, along with decreased mean opening time of the channel. BIS decreased IK(erg) amplitude with an IC50 value of 6.42 μM. Further addition of PD-118057 attenuated BIS-mediated inhibition of IK(erg). Under current-clamp conditions, BIS depolarization increased the firing of spontaneous action potentials in GH3 cells; addition of flupirtine, but not ractopamine, reversed BIS-induced firing rate. In R1220 cells, BIS suppressed IK(M); subsequent application of ML-213(Kv7.2 channel activator) reversed BIS-induced suppression of the current. In hippocampal mHippoE-14 neurons, BIS inhibited IK(M) to a greater extent compared to its depressant effect on IK(erg). This demonstrated that in pituitary cells and hippocampal neurons the presence of BIS is capable of directly and differentially suppressing IK(M) and IK(erg), despite its antagonism of β1-adrenergic receptors.

Background/Aims: The objective of this study is to examine the current signals in response to large hyperpolarizations with the aid of principal component analysis (PCA) to search for or even predict current fluctuations related to membrane electroporation-induced current (IMEP). Methods: The characteristics of principal eigenvalues generated for IMEP and the current signals at 10 sec prior to the start of initial IMEP (IPre) were examined. As membrane hyperpolarizations were applied at 0.1 Hz, the appearance of IMEP coincided with the higher principal eigenvalues extracted in PCA. Results: Subsequent addition of LaCl3 (100 µM) greatly reduced IMEP and associated principal eigenvalues. In real-time analysis for a single frame (i.e, 300 msec), in response to large hyperpolarization, multiple runs of heralded minuscule inward currents (Imin) occurring before large rise in current amplitudes were detected. With PCA, such heralded Imin was noted to coincide with the extreme principal eigenvalues. The duration of Imin together with large principal eigenvalues was influenced by different levels of membrane hyperpolarization. In GH3 cells, palmitoyl-L-carnitine (PALCAR), a long-chain acylcarnitine, effectively increased the IMEP amplitude with an EC50 value of 2.4 µM. However, in PALCAR-treated cells, the Imin together with higher principal eigenvalues disappeared, while in isoflurane-treated cells, Imin occurring before large rise of current amplitude remained intact. Similarly, the PCA analysis from IPre in RAW 264.6 macrophages showed the presence of herald Imin accompanied by the extreme principal eigenvalues. Conclusion: It is clear from this study that these large principal eigenvalues are representative of MEP-associated formation of electropores. Therefore, different compositions around the surface membrane of cells may alter the appearance of Imin followed by IMEP emergence.

As the need for effective antiviral treatment intensifies, such as with the coronavirus disease 19 (COVID-19) infection, it is crucial to understand that while the mechanisms of action of these drugs or compounds seem apparent, they might also interact with unexplored targets, such as cell membrane ion channels in diverse cell types. In this review paper, we demonstrate that many different drugs or compounds, in addition to their known interference with viral infections, may also directly influence various types of ionic currents on the surface membrane of the host cell. These agents include artemisinin, cannabidiol, memantine, mitoxantrone, molnupiravir, remdesivir, SM-102, and sorafenib. If achievable at low concentrations, these regulatory effects on ion channels are highly likely to synergize with the identified initial mechanisms of viral replication interference. Additionally, the immediate regulatory impact of these agents on the ion-channel function may potentially result in unintended adverse effects, including changes in cardiac electrical activity and the prolongation of the QTc interval. Therefore, it is essential for patients receiving these related agents to exercise additional caution to prevent unnecessary complications. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is one of the leading causes of death globally. Currently, clinical diagnosis of CVD primarily relies on electrocardiograms (ECG), which are relatively easier to identify compared to other diagnostic methods. However, ensuring the accuracy of ECG readings requires specialized training for healthcare professionals. Therefore, developing a CVD diagnostic system based on ECGs can provide preliminary diagnostic results, effectively reducing the workload of healthcare staff and enhancing the accuracy of CVD diagnosis. In this study, a deep neural network with a cross-stage partial network and a cross-attention-based transformer is used to develop an ECG-based CVD decision system. To accurately represent the characteristics of ECG, the cross-stage partial network is employed to extract embedding features. This network can effectively capture and leverage partial information from different stages, enhancing the feature extraction process. To effectively distill the embedding features, a cross-attention-based transformer model, known for its robust scalability that enables it to process data sequences with different lengths and complexities, is employed to extract meaningful embedding features, resulting in more accurate outcomes. The experimental results showed that the challenge scoring metric of the proposed approach is 0.6112, which outperforms others. Therefore, the proposed ECG-based CVD decision system is useful for clinical diagnosis. [ABSTRACT FROM AUTHOR]

This review paper delves into the current body of evidence, offering a thorough analysis of the impact of large-conductance Ca2+-activated K+ (BKCa or BK) channels on the electrical dynamics of the heart. Alterations in the activity of BKCa channels, responsible for the generation of the overall magnitude of Ca2+-activated K+ current at the whole-cell level, occur through allosteric mechanisms. The collaborative interplay between membrane depolarization and heightened intracellular Ca2+ ion concentrations collectively contribute to the activation of BKCa channels. Although fully developed mammalian cardiac cells do not exhibit functional expression of these ion channels, evidence suggests their presence in cardiac fibroblasts that surround and potentially establish close connections with neighboring cardiac cells. When cardiac cells form close associations with fibroblasts, the high single-ion conductance of these channels, approximately ranging from 150 to 250 pS, can result in the random depolarization of the adjacent cardiac cell membranes. While cardiac fibroblasts are typically electrically non-excitable, their prevalence within heart tissue increases, particularly in the context of aging myocardial infarction or atrial fibrillation. This augmented presence of BKCa channels' conductance holds the potential to amplify the excitability of cardiac cell membranes through effective electrical coupling between fibroblasts and cardiomyocytes. In this scenario, this heightened excitability may contribute to the onset of cardiac arrhythmias. Moreover, it is worth noting that the substances influencing the activity of these BKCa channels might influence cardiac electrical activity as well. Taken together, the BKCa channel activity residing in cardiac fibroblasts may contribute to cardiac electrical function occurring in vivo. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve's steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The IK(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K+ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na+ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (Ih) with an IC50 of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of Ih was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on Ih elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD's modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo. [ABSTRACT FROM AUTHOR]

Arsenic compounds have been applied treating acute promyelocytic 1eukemia and solid tumors with brief mechanism investigations. In fact, we have demonstrated that sodium arsenite plus dimethylarsenic acid could activate apoptosis in MA‐10 mouse Leydig tumor cells by inducing caspase pathways. However, detail underlying mechanisms how caspase cascade is regulated remains elusive. Therefore, the apoptotic mechanism of sodium arsenite plus dimethylarsenic acid were examined in MA‐10 cells in this study. Our results reveal that Fas/FasL protein expressions were stimulated by sodium arsenite plus dimethylarsenic acid in MA‐10 cells. In addition, reactive oxygen species (ROS) generation, cytochrome C release, Bid truncation, and Bax translocation were induced in MA‐10 cells by arsenic compounds. Moreover, activation of p38, JNK and ERK1/2, MAPK pathways was stimulated while Akt phosphorylated levels and Akt expression were decreased by sodium arsenite plus dimethylarsenic in MA‐10 cells. In conclusion, sodium arsenite and dimethylarsenic acid did activate MAPK pathway plus ROS generation, but suppress Akt pathway, to modulate caspase pathway and then induce MA‐10 cell apoptosis. [ABSTRACT FROM AUTHOR]