Search Results (236)

Several mutations of the uppermost arginine, R219, in the voltage-sensing sliding helix S4_I of cardiac sodium channel Nav1.5 are reported in the ClinVar databases, but the clinical significance of the respective variants is unknown (VUSs). AlphaFold 3 models predicted a significant downshift of S4_I in the R219C VUS. Analogous downshift S4_I, upon its in silico deactivation, resulted in a salt bridge between R219 and the uppermost glutamate, E161, in helix S2_I. To understand how salt bridge elimination affects biophysical characteristics, we generated mutant channel R219E, expressed it in the HEK293-T cells, and employed the patch-clamp method in a whole-cell configuration. Mutation R219E did not change the peak current density but shortened time to the peak current at several potentials, significantly enhanced activation, enhanced steady-state inactivation and steady-state fast inactivation, and slowed recovery from inactivation. Taken together, these data suggest that mutation R219E destabilized the resting state of Nav1.5. Cardiac syndromes associated with mutations R219P/H/C/P or E161Q/K are consistent with the observed changes of biophysical characteristics of mutant channel R219E suggesting pathogenicity of the respective VUSs, as well as ClinVar-reported VUSs involving arginine or glutamate in homologous positions of several Nav1.5 paralogs. Full article

Hepatic fibrosis (HF) is an important pathological state in the progression of chronic liver disease to end-stage liver disease and is usually triggered by alcohol, nonalcoholic fatty liver, chronic hepatitis viruses, autoimmune hepatitis (AIH), or cholestatic liver disease. Research on novel therapies has become a hot topic due to the reversibility of HF. Research into the molecular mechanisms of the pathology of HF and potential drug screening relies on reliable and rational biological models, mainly including animals and cells. Hence, a number of modeling approaches have been attempted based on human dietary, pathological, and physiological factors in the development of HF. In this review, classical and novel methods of modeling HF in the last 10 years were collected from electronic databases, including Web of Science, PubMed, ScienceDirect, ResearchGate, Baidu Scholar, and CNKI. Animal models of HF are usually induced by chemical toxicants, special diets, pathogenic microorganisms, surgical operations, and gene editing. The advantages and limitations of hepatic stellate cells (HSCs), organoids, and 3D coculture-based HF modeling methods established in vitro were also proposed and summarized. This information provides a scientific basis for the discovery of the pathological mechanism and treatment of HF. Full article

Telomeres play a key role in maintaining chromosome stability and cellular aging. They consist of repetitive DNA sequences that protect chromosome ends and regulate cell division. Telomerase is a reverse transcriptase enzyme counteracts the natural shortening of telomeres during cell division by extending them. Its activity is pivotal in stem cells and cancer cells but absent in most normal somatic cells. Recent advances in biosensor technologies have facilitated the in situ detection of telomerase activity, which is essential for understanding its role in aging and cancer. Techniques such as fluorescence, electrochemistry, and DNA nanotechnology are now being employed to monitor telomerase activity in living cells, providing real-time insights into cellular processes. DNA-based biosensors, especially those incorporating molecular beacons, DNA walkers, and logic gates, have shown promise for enhancing sensitivity and specificity in telomerase imaging. These approaches also facilitate the simultaneous analysis of related cellular pathways, offering potential applications in early cancer detection and precision therapies. This review explores recent developments in intracellular telomerase imaging, highlighting innovative approaches such as DNA-functionalized nanoparticles and multi-channel logic systems, which offer non-invasive, real-time detection of telomerase activity in complex cellular environments. Full article

Laser reduction of graphene oxide (GO) is a promising approach for achieving flexible, robust, and electrically conductive graphene/polymer composites. Resulting composite materials show significant technological potential for energy storage, sensing, and bioelectronics. However, in the case of insulating polymers, the properties of electrodes show severely limited performance. To overcome these challenges, we report on a post-processing redox treatment that allows the tuning of the electrochemical properties of laser-induced rGO/polymer composite electrodes. We show that the polymer substrate plays a crucial role in the electrochemical modulation of the composites’ properties, such as the electrode impedance, charge transfer resistance, and areal capacitance. The mechanism behind the reversible control of electrochemical properties of the rGO/polymer composites is the cleavage of polymer chains in the vicinity of rGO flakes during redox cycling, which exposes rGO active sites to interact with the electrolyte. Sequential redox cycling improves composite performance, allowing the development of devices such as electrolyte-gated transistors, which are widely used in chemical sensing applications. Our strategy enables the engineering of the electrochemical properties of rGO/polymer composites by post-treatment with dynamic switching, opening up new possibilities for flexible electronics and electrochemical applications having tunable properties. Full article

Interference gating (iGate) has emerged as a groundbreaking technique for ultrafast time-resolved electron holography in transmission electron microscopy, delivering nanometer spatial and nanosecond temporal resolution with minimal technological overhead. This study employs iGate to dynamically observe the local projected electric potential within the space-charge region of a contacted transmission electron microscopy (TEM) lamella manufactured from a silicon diode during switching between unbiased and reverse-biased conditions, achieving a temporal resolution of 25 ns at a repetition rate of 3 MHz. By synchronizing the holographic acquisition with the applied voltage, this approach enables the direct visualization of time-dependent potential distributions with high precision. Complementary static and dynamic experiments reveal a remarkable correspondence between modeled and measured projected potentials, validating the method’s robustness. The observed dynamic phase progressions resolve and allow one to differentiate between localized switching dynamics and preparation-induced effects, such as charge recombination near the sample edges. These results establish iGate as a transformative tool for operando investigations of semiconductor devices, paving the way for advancing the nanoscale imaging of high-speed electronic processes. Full article

Split Gate SiC MOSFETs (SG-MOSFETs) have been demonstrated to exhibit excellent power dissipation at high operating frequencies due to their low specific reverse transfer capacitance (C_rss,sp); however, there are several reliability issues of SG-MOSFETs, including electric field crowding at the gate oxide and insufficient short-circuit (SC) robustness. In this paper, we propose a device structure to enhance the short-circuit withstand time (SCWT) of 1.2 kV SG-MOSFETs. The proposed P-shielded SG-MOSFETs (PSG-MOSFETs) feature a P-shielding region that expands the depletion region within the JFET region under both blocking mode and SC conditions. Compared to the conventional structure, this reduces the maximum electric field in the gate oxide, enabling a higher doping concentration in the JFET region, which can reduce the specific on-resistance (R_on,sp) to minimize power dissipation during device operation. The SC robustness of PSG-MOSFETs, with an R_on,sp identical to those of SG-MOSFETs, was investigated by adjusting the width of the P-shielding region (W_P). Furthermore, the C_rss,sp of PSG-MOSFETs was compared with that of SG-MOSFETs to analyze the relationship between the W_P and high-frequency figure of merit (HF-FOM), defined as R_on,sp × C_rss,sp. These results demonstrated that the PSG-MOSFET achieved an enhanced SC robustness and HF-FOM in comparison to the SG-MOSFET. Thus, the proposed PSG-MOSFET is a highly suitable candidate for high-frequency and reliable applications. Full article

This study proposes an AlGaN/GaN current aperture vertical electron transistor (CAVET) featuring a double superjunction (SJ) to enhance breakdown voltage (BV) and investigates its electrical characteristics via technology computer-aided design (TCAD) Silvaco Atlas simulation. An additional p-pillar was formed beneath the gate current blocking layer to create a lateral depletion region that provided a high off-state breakdown voltage. To address the tradeoff between the drain current and off-state breakdown voltage, the key design parameters were carefully optimized. The proposed device exhibited a higher off-state breakdown voltage (2933 V) than the device with a single SJ (2786 V), although the specific on-resistance of the proposed method (1.29 mΩ·cm⁻²) was slightly higher than that of the single SJ device (1.17 mΩ·cm⁻²). In addition, the reverse transfer capacitance was improved by 15.6% in the proposed device. Full article

A novel planar silicon carbide (SiC) MOSFET integrated with both MOS-channel diode (MCD) and junction barrier Schottky diode (JBS) on the same chip (MCD-JBSFET) is proposed and investigated through Technology Computer-Aided Design (TCAD) simulations in this paper. The proposed device features the lowest turn-on voltage and the best current conduction capability under the reverse-biased conditions, allowing it to achieve the same reverse conduction capability with fewer MCDs compared to conventional MOSFET with MCD structures (MCDFET). This reduction in the number of MCDs enables more channels to operate under forward-biased conditions, thereby improving power density. Compared to a conventional MOSFET integrated with JBS structure (JBSFET), the reverse current in the MCD-JBSFET flows through both the MCD and JBS, which suppresses the peak lattice temperature at Schottky contact and enhances the high-temperature robustness, especially under surge current conditions. In addition, the split-gate structure in the proposed structure optimizes the reverse capacitance and the figure of merit R_on,sp × Q_g by factors of 0.65 and 2.15, respectively. Finally, the switching losses are reduced by 40.2%, indicating the suitability of MCD-JBSFET for high-frequency and high-current applications. Full article

Sensitization of primary afferents is essential for the development of pain, but the molecular events involved in this process and its reversal are poorly defined. Recent studies revealed that acid-sensing ion channels (ASICs) control the excitability of nociceptors in the urinary bladder. Using genetic and pharmacological tools we show that ASICs are functionally coupled with voltage-gated Ca²⁺ channels to mediate Ca²⁺ transients evoked by acidification in sensory neurons. Genetic deletion of Asic3 of these sensory neurons does not alter the mechanical response of bladder afferents to distension in naïve mice. Both control and sensory neuron conditional Asic3 knockout (Asic3-KO) mice with chemical cystitis induced by cyclophosphamide (CYP) administration exhibit frequent low volume voiding events. However, these changes are transient and revert over time. Of major significance, in Asic3-KO mice, CYP treatment results in the sensitization of a subset of bladder afferents and pelvic allodynia that persist beyond the resolution of the inflammatory process. Thus, ASICs function is necessary to prevent long-term sensitization of visceral nociceptors. Full article

A review of recent advances in spacetime optics is given, with special emphasis on time refraction. This is a basic optical process, occurring at a temporal discontinuity or temporal boundary, which is able to produce various different effects, such as frequency shifts, energy amplification, time reflection, and photon emission. If, instead of a single discontinuity, we have two reverse temporal boundaries, we can form a temporal beam splitter, where temporal interferences can occur. It will also be shown that, in the presence of an axis of symmetry, such as a magnetic field, the temporal beam splitter can induce a rotation of the initial polarization state, similar to a Faraday rotation. Recent work on time crystals, superluminal fronts, and superfluid light will be reviewed. Time gates based on spacetime optical effects will be discussed. We also mention recent work on optical metamaterials. Finally, the quantum properties of time refraction, which imply the emission of photon from vacuum, are considered, while similar problems in high-energy QED associated with electron–positron pairs are briefly mentioned. Full article

Within the phylum Cnidaria, sea anemones (class Anthozoa) express a rich diversity of ion-channel peptide modulators with biomedical applications, but corollary discoveries from jellyfish (subphylum Medusozoa) are lacking. To bridge this gap, bioactivities of previously unexplored proteinaceous and small molecular weight (~15 kDa to 5 kDa) venom components were assessed in a mouse dorsal root ganglia (DRG) high-content calcium-imaging assay, known as constellation pharmacology. While the addition of crude venom led to nonspecific cell death and Fura-2 signal leakage due to pore-forming activity, purified small molecular weight fractions of venom demonstrated three main, concentration-dependent and reversible effects on defined heterogeneous cell types found in the primary cultures of mouse DRG. These three phenotypic responses are herein referred to as phenotype A, B and C: excitatory amplification (A) or inhibition (B) of KCl-induced calcium signals, and test compound-induced disturbances to baseline calcium levels (C). Most notably, certain Alatina alata venom fractions showed phenotype A effects in all DRG neurons; Physalia physalis and Chironex fleckeri fractions predominantly showed phenotype B effects in small- and medium-diameter neurons. Finally, specific Physalia physalis and Alatina alata venom components induced direct excitatory responses (phenotype C) in glial cells. These findings demonstrate a diversity of neuroactive compounds in jellyfish venom potentially targeting a constellation of ion channels and ligand-gated receptors with broad physiological implications. Full article

This paper details the approach to the efficient design and optimization of a reversible adder and multiplier utilizing Peres gates, which is a three-input, three-output gate. Peres gates are recognized for their universality and energy-efficient properties and present an intriguing option for constructing reversible circuits. Reversible logic is characterized by its ability to uniquely determine input states from output states. The design methodology involves a cascading arrangement of Peres gates, each performing a reversible XOR operation on corresponding bits of the input numbers and the carry-out from the preceding stage. This paper presents a detailed schematic representation, simulation results, and analysis of the proposed designs of different adders and multipliers, showcasing their potential for reversible applications. The integration of Peres gates in the adder and multiplier design signifies a step forward in the exploration of reversible logic circuits and their applications in contemporary computing paradigms. The overall hardware reduction is the main achievement of this research in terms of quantum cost. Full article

Thyroid hormone binds to specific nuclear receptors, regulating the expression of target genes, with major effects on cardiac function. Triiodothyronine (T3) increases the expression of key proteins related to calcium homeostasis, such as the sarcoplasmic reticulum calcium ATPase pump, but the detailed mechanism of gene regulation by T3 in cardiac voltage-gated calcium (Cav1.2) channels remains incompletely explored. Furthermore, the effects of T3 on Cav1.2 auxiliary subunits have not been investigated. We conducted quantitative reverse transcriptase polymerase chain reaction, Western blot, and immunofluorescence experiments in H9c2 cells derived from rat ventricular tissue, examining the effects of T3 on the expression of α1c, the principal subunit of Cav1.2 channels, and Cavβ4, an auxiliary Cav1.2 subunit that regulates gene expression. The translocation of phosphorylated cyclic adenosine monophosphate response element-binding protein (pCREB) by T3 was also examined. We found that T3 has opposite effects on these channel proteins, upregulating α1c and downregulating Cavβ4, and that it increases the nuclear translocation of pCREB while decreasing the translocation of Cavβ4. Finally, we found that overexpression of Cavβ4 represses the mRNA expression of α1c, suggesting that T3 upregulates the expression of the α1c subunit in response to a decrease in Cavβ4 subunit expression. Full article

Phosphorylation, a reversible and widespread post-translational modification of proteins, is essential for numerous cellular processes. However, due to technical limitations, large-scale detection of phosphorylation sites, especially those infected by SARS-CoV-2, remains a challenging task. To address this gap, we propose a method called GBMPhos, a novel method that combines convolutional neural networks (CNNs) for extracting local features, gating mechanisms to selectively focus on relevant information, and a bi-directional gated recurrent unit (Bi-GRU) to capture long-range dependencies within protein sequences. GBMPhos leverages a comprehensive set of features, including sequence encoding, physicochemical properties, and structural information, to provide an in-depth analysis of phosphorylation sites. We conducted an extensive comparison of GBMPhos with traditional machine learning algorithms and state-of-the-art methods. Experimental results demonstrate the superiority of GBMPhos over existing methods. The visualization analysis further highlights its effectiveness and efficiency. Additionally, we have established a free web server platform to help researchers explore phosphorylation in SARS-CoV-2 infections. The source code of GBMPhos is publicly available on GitHub. Full article

The effects of quantum mechanics dominate nanoscale devices, where Moore’s law no longer holds true. Additionally, with the recent rapid development of quantum computers, the development of reversible gates to overcome the problems of energy and information loss and the nano-level quantum-dot cellular automata (QCA) technology to efficiently implement them are in the spotlight. In this study, a full adder-subtractor, a core operation of the arithmetic and logic unit (ALU), the most important hardware device in computer operations, is implemented as a circuit capable of reversible operation using QCA-based reversible gates. The proposed circuit consists of one reversible QCA gate and two Feynman gates and is designed as a multi-layer structure for efficient use of area and minimization of delay. The proposed circuit is tested on QCADesigner 2.0.3 and QCADesigner-E 2.2 and shows the best performance and lowest energy dissipation. In particular, it shows tremendous improvement rates of 180% and 562% in two representative standard design cost indicators compared to the best existing studies, and also shows the highest circuit average output polarization. Full article