Tail Currents Research Articles

Improvement of Switching Characteristics in 6.5-kV SiC IGBT with Novel Drift Layer Structure

6.5-kV SiC IGBT with novel drift layer structure is developed to eliminate collector voltage steepening during turn-off and thus to suppress a ringing noise. The proposed IGBT has a depletion-controlled structure (DCS) of a two-step drift layer to suppress the increase of a depletion layer during the turn-off. We fabricated n-channel SiC IGBTs with DCS designed for a blocking voltage of 6.5 kV. Also, we applied our original backside-grinding-last (BG-last) process that enables low switching loss. The DCS device successfully reduced a riging of the gate voltage and had a turn-off loss of 17.6 mJ with 3.6-kV and 32-A switching operation. Although this value is larger than that of the conventional devices (8.8 mJ) due to a tail current, it is still quite low compared with the reported switching loss of SiC IGBTs with the proper switching curves, which is estimated to be 46.1 mJ with the same rated voltage and current.

Empirical Modeling of the Geomagnetosphere for SIR and CME‐Driven Magnetic Storms

AbstractDuring geomagnetic disturbances, the solar wind arrives in the form of characteristic sequences lasting from tens of hours to days. The most important magnetic storm drivers are the coronal mass ejections (CMEs) and the slow‐fast stream interaction regions (SIRs). Previous data‐based magnetic field models did not distinguish between these types of the solar wind driving. In the present work we retained the basic structure of the Tsyganenko and Andreeva (2015) model but fitted it to data samples corresponding to (1) SIR‐driven storms, (2) CME‐driven storms preceded with a shock ahead of the CME, and (3) CME‐driven storms without such shocks. The storm time dynamics of the model current systems has been represented using the parametrization method developed by Tsyganenko and Sitnov (2005), based on dynamical variables Wi, calculated from concurrent solar wind characteristics and their previous history. The database included observations of THEMIS, Polar, Cluster, Geotail, and Van Allen Probes missions during 155 storms in 1997–2016. The model current systems drastically differ from each other with respect to decay rate and total current magnitudes. During SIR‐induced storms, all current systems saturate, while during CME‐induced disturbances, the saturation occurs only for the symmetric ring current and the tail current. The partial ring current parameters are drastically different between SIR‐ and CME‐induced storm sets. In the case of SIR‐driven storms, the total partial ring current is comparable with symmetric ring current, whereas for all CME‐induced events it is nearly twice higher. The results are compared with GOES 15 magnetometer observations.

Temperature Dependence of the Biophysical Mechanisms Underlying the Inhibition and Enhancement Effect of Amiodarone on hERG Channels.

hERG K+ channel is important for controlling the duration of cardiac action potentials. Amiodarone (AMD), a widely prescribed class III antiarrhythmic, could inhibit hERG currents with relatively few tachyarrhythmic adverse events. We use injected Xenopus oocyte with two-electrode voltage clamp techniques to characterize the action of AMD on hERG channels. We found that AMD binds to the resting hERG channel with an apparent dissociation constant of ∼1.4 μM, and inhibits hERG currents at mild and strong depolarization pulses by slowing activation and enhancing inactivation, respectively, at 22°C. The activation kinetics of hERG channel activation are much faster, but inactivation kinetics are slower at 37°C. AMD accordingly has a 15% to 20% weaker and stronger inhibitory effect at mild and strong depolarization (e.g., -60 and +30 mV, 0.3-second pulse), respectively. In the meanwhile, the resurgent hERG tail currents are dose-dependently inhibited by AMD without altering the kinetics of current decay at both 22°C and 37°C, indicating facilitation of recovery from inactivation via the silent route. Most importantly, AMD no longer inhibits but enhances hERG currents at a mild pulse shortly after a prepulse at 37°C, but not so much at 22°C. We conclude that AMD is an effective hERG channel-gating modifier capable of lengthening the plateau phase of cardiac action potential (without increasing the chance of afterdepolarization). AMD, however, should be used with caution in hypothermia or the other scenarios that slow hERG channel activation. SIGNIFICANCE STATEMENT: It is known that amiodarone (AMD) acts on hERG K+ channels to treat cardiac arrhythmias with relatively little arrhythmogenicity. We found that AMD enhances hERG channel inactivation but slows activation as well as recovery from inactivation, and thus has a differential inhibition and enhancement effect on hERG currents at different phases of membrane voltage changes, especially at 37°C, but not so much at 22°C. AMD is therefore a relatively ideal agent against tachyarrhythmia at 37°C, but should be more cautiously used at lower temperatures or relevant pathophysiological/pharmacological scenarios associated with slower hERG channel activation because of the increased chances of adverse events.

A Low Phase Noise, High Phase Accuracy Quadrature LC-VCO With Dual-Tail Current Biasing to Insert Reconfigurable Phase Delay

This brief presents a novel low phase noise and low phase error quadrature LC-tank voltage controlled oscillator (LC-VCO), which utilizes the dual-tail current biasing technique to insert a phase shift in the coupling path. The dual-tail current bias each oscillation branch, and are gated by quadrature signals. One tail current, named coupling-tail current, is gated by the quadrature phase signal to force the voltage controlled oscillator to keep quadrature state. The other tail current, named self-tail current, is gated by the anti-phase signal to introduce a phase shift in total bias current. The phase shift is reconfigurable by adjusting the DC biasing voltage of tail current transistors to resist the performance deterioration caused by process variations. Compared with the conventional quadrature LC-VCO, the proposed quadrature LC-VCO enhances the phase accuracy and optimize the phase noise simultaneously. Additionally, it has the distinct advantage of reconfigurability. The core was fabricated in 180 nm 1P6M CMOS process, and occupied a die area of 0.96 mm2 totally. The measurement results show it achieves a phase noise of −129.3 dBc/Hz @1 MHz offset and a phase error of 0.09° while $k=0.4$ , $V_{\mathrm {b0}}= 0.8$ V, and $V_{\mathrm {b1}}= 0.6$ V @2.5 GHz. The total power consumption is 20.6 mW with a supply voltage of 1.8 V.

A Modulation Technique for Sensorless Control of Switched Reluctance Motor

The switched reluctance motor (SRM) uniquely bears several merits with respect to other motor configurations. Especially, the construction of the rotor is simple in the sense that it neither contains copper not contains permanent magnets. Because of this construction, likelihood of rotor’s failure is less than the other motor configurations. This makes this motor more suitable for harsh environments. On the flip side, this motor cannot directly operate with AC or DC power source and needs electronic commutation. For commutation, the information on instantaneous orientation of the rotor is essential. Since inclusion of appropriate sensor adds to the cost and complexity of the system, sensor-less commutation of SRM gained interest among the researchers and has been studied extensively in literature. The techniques for sensorless control of SRM can be broadly classified into Active phase and Idle phase techniques. Idle phase techniques are generally believed to be not suitable for high speed operation beause of tail current in a phase, i.e., because of inductive nature of the phase, it takes time for flow of current to stop. This paper proposes a novel idle phase technique that is conducive for high speed operation of switched reluctance motor.

Altered Activity of SK Channel Underpins Morphine Withdrawal Relevant Psychiatric Deficiency in Infralimbic to Accumbens Shell Pathway.

Drug addiction can be viewed as a chronic psychiatric disorder that is related to dysfunction of neural circuits, including reward deficits, stress surfeits, craving changes, and compromised executive function. The nucleus accumbens (NAc) plays a crucial role in regulating craving and relapse, while the medial prefrontal cortex (mPFC) represents a higher cortex projecting into the NAc that is active in the management of executive function. In this study, we investigated the role of the small conductance calcium-activated potassium channels (SK channels) in NAc and mPFC after morphine withdrawal. Action potential (AP) firing of neurons in the NAc shell was enhanced via the downregulations of the SK channels after morphine withdrawal. Furthermore, the expression of SK2 and SK3 subunits in the NAc was significantly reduced after 3 weeks of morphine withdrawal, but was not altered in the dorsal striatum. In mPFC, the SK channel subunits were differentially expressed. To be specific, the expression of SK3 was upregulated, while the expression of SK2 was unchanged. Furthermore, the AP firing in layer 5 pyramidal neurons of the infralimbic (IL) cortex was decreased via the upregulations of the SK channel-related tail current after 3 weeks of morphine withdrawal. These results suggest that the SK channel plays a specific role in reward circuits following morphine exposure and a period of drug withdrawal, making it a potential target for the prevention of relapse.

Effects of cariprazine on hERG 1A and hERG 1A/3.1 potassium channels

Cariprazine is a novel atypical antipsychotic drug that is widely used for the treatment of schizophrenia and bipolar mania/mixed disorder. We used the whole-cell patch-clamp technique to investigate the effects of cariprazine on hERG channels that are stably expressed in HEK cells. Cariprazine inhibited the hERG 1A and hERG 1A/3.1 tail currents at −50 mV in a concentration-dependent manner with IC50 values of 4.1 and 12.2 μM, respectively. The block of hERG 1A currents by cariprazine was voltage-dependent, and increased over a range of voltage for channel activation. Cariprazine shifted the steady-state inactivation curve of the hERG 1A currents in a hyperpolarizing direction and produced a use-dependent block. A fast application of cariprazine inhibited the hERG 1A currents elicited by a 5 s depolarizing pulse to +60 mV to fully inactivate the hERG 1A currents. During a repolarizing pulse wherein the hERG 1A current was deactivated slowly, cariprazine rapidly and reversibly blocked the open state of the hERG 1A current. However, cariprazine did not affect hERG 1A and hERG 1A/3.1 channel trafficking to the cell membrane. Our results indicated that cariprazine concentration-dependently inhibited hERG 1A and hERG 1A/3.1 currents by preferentially interacting with the open states of the hERG 1A channel, but not by the disruption of hERG 1A and hERG 1A/3.1 channel protein trafficking. Our study examined cariprazine's mechanism of action provides a biophysical profile that is necessary to assess the potential therapeutic effects of this drug.

CRISPR/Cas9 Engineered Q3925E-RyR2 Mutation in Human Induced Pluripotent Stem Cells Impairs Caffeine Triggered Ca2+ Release

CRISPR/Cas9 mediated gene editing of human induced pluripotent stem cells (hiPSCs) provides a novel approach in human disease studies. Here we report on a ryanodine receptor (RyR2) mutation, Q3925E, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT1), located in the Ca2+ binding site of the near atomic level model of RyR structure. Simultaneous Ca2+ imaging in patch clamped hiPSC derived cardiomyocytes (hiPSC-CMs) allowed quantifications of Ca2+ signaling and electrophysiological parameters associated with the mutant hiPSC-CMs. We found that ICa density by depolarizations to zero mV and its accompanying Ca-transients in Q3925E hiPSC-CMs were comparable to the WT hiPSC-CMs, but ICa induced Ca2+ release (CICR) was smaller, when measured by rapid and brief ICa tail currents activated by repolarizations from +100mV to −50mVs, as compared to WT cardiomyocytes. Unexpectedly SR Ca2+ release, triggered by 5mM caffeine, was fully suppressed in mutant cardiomyocytes. Higher, 20 mM caffeine concentrations, also failed to trigger significant Ca2+ release or the accompanying Na+/Ca2+ exchange current in most mutant patch-clamped cells, but showed significant Fluo4 quenching signals, indicative of rapid rise of cytosolic caffeine. In intact mutant cardiomyocytes, however, the higher 20mM caffeine concentrations triggered either irregular Ca2+ “puffs” or smaller and slower rises of cytosolic Ca2+ in less than 50% of cells. Such signals were mostly suppressed by 10μm of IP3R blocker, 2-APB, suggestive of expression of IP3 stores in developing hiPSC-CMs. Spontaneous Ca2+ sparks were also absent in most Q3925E hiPSC-CMs. Our data suggests that Q3925E-RyR2 mutation may decrease the sensitivity of CICR and suppress caffeine-triggered release either by depletion of SR Ca2+ stores or by impairing caffeine binding to RyR2, consistent with the proximity and possible interaction of the Ca2+ and caffeine binding sites. (NIH, RO1 HL16152, P20GM103499).

Pyrethroid neurotoxicity studies with bifenthrin indicate a mixed Type I/II mode of action.

BACKGROUNDBifenthrin is usually considered a Type I pyrethroid, because it lacks an α‐CN group present in Type II pyrethroids, but some previous studies suggest a mixed Type I/II mode‐of‐action. Results are presented for bifenthrin in a rat developmental neurotoxicity (DNT) study along with effects on Na currents in human VGSC subtypes. Molecular modeling comparisons were also made for bifenthrin and other pyrethroids.RESULTSIn a rat DNT study, bifenthrin produced tremors and clonic convulsions in dams and pups and slightly reduced acoustic startle response amplitude, and increased Tmax, at PND20 in females. Similar blood levels of bifenthrin were measured in dams and pups at each dose level i.e. no concentration in pups. In human VGSC experiments, using the Nav1.8 subtype, bifenthrin's effects on inactivation were slight, as for Type II pyrethroids, but without large prolongation of the tail current (deactivation) seen with Type II. Molecular modeling of bifenthrin indicates that the o‐Me group may occupy a similar space to the α‐CN group of cypermethrin and fenpropathrin.CONCLUSIONIn a DNT study and on human Nav1.8 tail currents bifenthrin showed Type I and II effects, similar to some published studies. Overall, bifenthrin acts as a mixed Type I/II pyrethroid. © 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Blockade of the Human Ether A-Go-Go-Related Gene (hERG) Potassium Channel by Fentanyl.

The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). Drug-mediated or medical condition-mediated disruption of hERG function is the primary cause of acquired long-QT syndrome, which predisposes affected individuals to ventricular arrhythmias and sudden death. Fentanyl abuse poses a serious health concern, with abuse and death rates rising over recent years. As fentanyl has a propensity to cause sudden death, we investigated its effects on the hERG channel. The effects of norfentanyl, the main metabolite, and naloxone, an antidote used in fentanyl overdose, were also examined. Currents of hERG channels stably expressed in HEK293 cells were recorded using the whole-cell voltage-clamp method. When hERG tail currents were analyzed upon -50 mV repolarization after a 50 mV depolarization, fentanyl and naloxone blocked hERG current (IhERG) with IC50 values of 0.9 and 74.3 μM, respectively, whereas norfentanyl did not block. However, fentanyl-mediated block of IhERG was voltage dependent. When a voltage protocol that mimics a human ventricular action potential (AP) was used, fentanyl blocked IhERG with an IC50 of 0.3 μM. Furthermore, fentanyl (0.5 μM) prolonged AP duration and blocked IKr in ventricular myocytes isolated from neonatal rats. The concentrations of fentanyl used in this study were higher than seen with clinical use but overlap with postmortem overdose concentrations. Although mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to the death of individuals with high-concentration overdose or compromised cardiac repolarization.

A Snapback-Free and Low Turn-Off Loss Reverse-Conducting SOI-LIGBT With Embedded Diode and MOSFET

A novel snapback-free and low turn-off loss reverse-conducting (RC) SOI-LIGBT is proposed and investigated by numerical simulations. An n-MOSFET (MN2) is embedded in the anode side of the LIGBT to short the P-anode/N-buffer junction during the turn-off transient, thus allowing the LIGBT to be turned off rapidly without excessive tail current. In addition, MN2 enable the LIGBT to conduct the reverse conducting current like the freewheeling diode. In the forward-conducting state, MN2 is turned off, then the proposed LIGBT operates like a conventional one and the snap-back is avoided. The gate electrode of MN2 can be controlled synchronously by the gate signal of the LIGBT which is level-shifted by a p-i-n diode (D1) and processed by an anode-controlling circuit, and therefore, the proposed RC-LIGBT still maintains a three-terminal configuration. D1 and MN2 are embedded in the drift region and anode-side of the LIGBT, respectively, and they can be isolated by deep-oxide trenches. The numerical simulation results reveal that the turn-off loss ( ${E} _{\mathrm{ off}}$ ) and reverse recovery charge of the proposed LIGBT is reduced by 58.3% and 38.9%, respectively, compared with the conventional LIGBT combining with antiparallel freewheeling diode.

Cholesterol Protects Against Acute Stress-Induced T-Tubule Remodeling in Mouse Ventricular Myocytes.

Efficient excitation-contraction coupling in ventricular myocytes depends critically on the presence of the t-tubular network. It has been recently demonstrated that cholesterol, a major component of the lipid bilayer, plays an important role in long-term maintenance of the integrity of t-tubular system although mechanistic understanding of underlying processes is essentially lacking. Accordingly, in this study we investigated the contribution of membrane cholesterol to t-tubule remodeling in response to acute hyposmotic stress. Experiments were performed using isolated left ventricular cardiomyocytes from adult mice. Depletion and restoration of membrane cholesterol was achieved by applying methyl-β-cyclodextrin (MβCD) and water soluble cholesterol (WSC), respectively, and t-tubule remodeling in response to acute hyposmotic stress was assessed using fluorescent dextran trapping assay and by measuring t-tubule dependent IK1 tail current (IK1,tail). The amount of dextran trapped in t-tubules sealed in response to stress was significantly increased when compared to control cells, and reintroduction of cholesterol to cells treated with MβCD restored the amount of trapped dextran to control values. Alternatively, application of WSC to normal cells significantly reduced the amount of trapped dextran further suggesting the protective effect of cholesterol. Importantly, modulation of membrane cholesterol (without osmotic stress) led to significant changes in various parameters of IK1, tail strongly suggesting significant but essentially hidden remodeling of t-tubules prior to osmotic stress. Results of this study demonstrate that modulation of the level of membrane cholesterol has significant effects on the susceptibility of cardiac t-tubules to acute hyposmotic stress.

Electrophysiological evaluation of pentamidine and 17-AAG in human stem cell-derived cardiomyocytes for safety assessment

Human ether-a-go-go-related gene (hERG) trafficking inhibition is known to be one of the mechanisms of indirect hERG inhibition, resulting in QT prolongation and lethal arrhythmia. Pentamidine, an antiprotozoal drug, causes QT prolongation/Torsades de Pointes (TdP) via hERG trafficking inhibition, but 17-AAG, a geldanamycin derivative heat shock protein 90 (Hsp90) inhibitor, has not shown torsadogenic potential clinically, despite Hsp90 inhibitors generally being hypothesized to cause TdP by hERG trafficking inhibition. In the present study, we investigated the underlying mechanisms of both drugs’ actions on hERG channels using hERG-overexpressing CHO cells (hERG-CHOs) and human embryonic stem cell-derived cardiomyocytes (hES-CMs). The effects on hERG tail current and protein levels were evaluated using population patch clamp and Western blotting in hERG-CHOs. The effects on field potential duration (FPD) were recorded by a multi-electrode array (MEA) in hES-CMs. Neither drug affected hERG tail current acutely. Chronic treatment with each drug inhibited hERG tail current and decreased the mature form of hERG protein in hERG-CHOs, whereas the immature form of hERG protein was increased by pentamidine but decreased by 17-AAG. In MEA assays using hES-CMs, pentamidine time-dependently prolonged FPD, but 17-AAG shortened it. The FPD prolongation in hES-CMs upon chronic pentamidine exposure is relevant to its clinically reported arrhythmic risk. Cav1.2 or Nav1.5 current were not reduced by chronic application of either drug at a relevant concentration to hERG trafficking inhibition in human embryonic kidney (HEK293) cells. Therefore, the reason why chronic 17-AAG shortened the FPD despite the hERG trafficking inhibition occur is still unknown.

A voltage tunable CMOS differential active resistor and its application

SummaryWe propose a novel CMOS differential voltage‐controlled equivalent active resistor based on a modified common‐source cross‐coupled pair. The equivalent resistance exhibited by the circuit can be tuned to be either positive or negative through the tail current, which is controlled by a bias voltage. The complete cell comprises four transistors, two resistors in addition to the bias voltage, and tail current source. Application to the design of oscillators is demonstrated by theoretical analysis, circuit simulations, and verified experimentally through measurements on prototypes implemented using discrete transistors.

The role and mechanism of chaperones Calnexin/Calreticulin in which ALLN selectively rescues the trafficking defective of HERG-A561V mutation.

Long QT (LQT) type 2 (LQT2) is caused by HERG mutation. L539fs/47 encodes a truncated protein, and its mechanisms in HERG mutation are unknown. HERG mutation plasmids were overexpressed in HEK293T cells, respectively, followed by analyzing lysates with Western blot. Transfected HEK293T cells were treated with or without N-acetyl-l-leucyl-l-leucyl-l-norleucinal (ALLN) and Propranolol (Prop) at 24 or 48 h. HERG-WT, HERG-A561V, WT/A561V, HERG-L539fs/47, WT/L539fs/47, and Calnexin (CNX)/Calreticulin (CRT) protein expression and their interactions were detected by Western blot and immunoprecipitation. Each group with HERG currents (Ikr) were detected by Patch-clamp technique. Treated with ALLN, the expression of mature HERG protein and the CNX/CRT protein increased. The interaction of HERG-A561V and WT/A561V protein with the chaperone CNX/CRT increased significantly. The maximum peak currents and tail currents density increased by 70% and 73%, respectively, while maximal peak currents density (24%) and tail currents density (19%) were slight increased in WT-HERG cells. Treated with Prop, the expression and interaction of mature HERG and chaperones CNX/CRT had no difference in each group. The maximal currents and tail currents density were slight increased. CNX/CRT might play a crucial role in the trafficking-deficient process and degradation of HERG-A561V mutant protein, however they had no effect on L539fs/47 HERG due to protein transport deletion. ALLN can restore HERG-A561V mutant protein trafficking process and rescue the dominant negative suppression of WT-HERG.

The Investigation of an IGBT With Hole-Carrier Movement Control

A novel hole-controlled lateral-insulated-gate bipolar transistor (HC-LIGBT) device that is free of tail current is proposed and investigated. The device utilizes a poly-p-i-n-diode as the field plate to guarantee high breakdown voltage (BV) at the blocking state. With the introduction of an extra electric field, the movement of the hole carrier is regulated. At the device ON-state, more hole carriers are injected into the drift region to amplify the ON-state current density; when the device is about to be turned OFF, the hole carrier rapidly neutralizes the extra electrons residing in the drift region to eliminate the tail current. A material with high permittivity is required as the dielectric to generate the electric field that is strong enough to impact the movement of the hole carrier. HC-LIGBTs with a dielectric permittivity of 29 (HfO2) and 200 (PZT) under both BV conditions of 250 and 600 V are investigated. The numerical simulation results indicate that under different conditions, the ON-state current density of the HC-LIGBT is up to $7\times $ that of the conventional LIGBT, whereas the switching periods remain at 5 ns for all conditions. The total energy losses for the HC-LIGBT, including the losses in both transition period and switching period, are 10% of the energy loss at the turn- OFF operation of the conventional LIGBT. Moreover, the tradeoff between the ON-state current density and the switching period of the conventional LIGBT is transferred to the tradeoff between the ON-state current density and the transition period of the HC-LIGBT.

Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia.

Peroxisome proliferator‐activated receptor‐γ coactivator‐1 deficient (Pgc‐1β −/−) murine hearts model the increased, age‐dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch‐clamp techniques in intact young and aged, wild‐type (WT) and Pgc‐1β −/−, ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage‐dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two‐way analysis of variance associated Pgc‐1β −/− genotype with independent reductions in maximum peak ventricular Na+ currents from −36.63 ± 2.14 (n = 20) and −35.43 ± 1.96 (n = 18; young and aged WT, respectively), to −29.06 ± 1.65 (n = 23) and −27.93 ± 1.63 (n = 20; young and aged Pgc‐1β −/−, respectively) pA/μm2 (p < 0.0001), without independent effects of, or interactions with age. Voltages at half‐maximal current V*, and steepness factors k in plots of voltage dependences of both Na+ current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K+) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current–voltage properties directly implicate decreases specifically in maximum available Na+ current with unchanged voltage dependences and unaltered K+ current properties, in proarrhythmic reductions in AP conduction velocity in Pgc‐1β−/− ventricles.

Laboratory Studies on Nearshore Density-Driven Exchange Flow over a Partly Vegetated Slope

Density-driven exchange flows, which are important to the transport of nutrients, pollutants and chemical substances without external forcing, were studied through laboratory lock-exchange experiments. Rigid and emergent cylinders were placed in one of two reservoirs in a partitioned wedge-shaped tank to simulate a partly vegetated slope. The experimental results found that cylinders placed on only one side of the tank lead to different current speeds in the current head and tail that subsequently create various flow patterns and significantly affect the downslope current motions. By fitting with the experimental data, some unknown coefficients can be obtained in the theoretical formulae that are able to predict the intrusion length and exchange flowrate in real field systems. Compared to the flat bed cases, the total exchange discharge over a steep slope decreases by up to 4% for vegetation distributed in shallow water and increases by 14% for vegetation distributed in deeper regions. These results suggest that bed slope and vegetation distribution are crucial to the density-driven exchange flows in the flushing of nearshore regions.

Characterization and molecular basis for the block of Kv1.3 channels induced by carvedilol in HEK293 cells

Carvedilol is a non-selective β-adrenoreceptor antagonist and exhibits a wide range of biological activities. The voltage-gated K+ (Kv) channel is one of the target ion channels of this compound. The rapidly activating Kv1.3 channel is expressed in several different tissues and plays an important role in the regulation of physiological functions, including cell proliferation and apoptosis. However, little is known about the possible action of carvedilol on Kv1.3 currents. Using the whole-cell configuration of the patch-clamp technique, we have revealed that exposure to carvedilol produced a concentration-dependent blocking of Kv1.3 channels heterologously expressed in HEK293 cells, with an IC50 value of 9.7 μM. This chemical decelerated the deactivation tail current of Kv1.3 currents, resulting in a tail crossover phenomenon. In addition, carvedilol generated a markedly hyperpolarizing shift (20 mV) of the inactivation curve, but failed to affect the activation curve. Mutagenesis experiments of Kv1.3 channels identified G427 and H451, two related sites of TEA block, as important residues for carvedilol-mediated blocking. The present results suggest that carvedilol acts directly on Kv1.3 currents by inducing closed- and open-channel block and helps to elucidate the mechanisms of action of this compound on Kv channels.

Veratridine modifies the gating of human voltage-gated sodium channel Nav1.7

Veratridine is a lipid-soluble neurotoxin derived from plants in the family Liliaceae. It has been broadly investigated for its action as a sodium channel agonist. However, the effects of veratridine on subtypes of sodium channels, especially Nav1.7, remain to be studied. Here, we investigated the effects of veratridine on human Nav1.7 ectopically expressed in HEK293A cells and recorded Nav1.7 currents from the cells using whole-cell patch clamp technique. We found that veratridine exerted a dose-dependent inhibitory effect on the peak current of Nav1.7, with the half-maximal inhibition concentration (IC50) of 18.39 µM. Meanwhile, veratridine also elicited tail current (linearly) and sustained current [half-maximal concentration (EC50): 9.53 µM], also in a dose-dependent manner. Veratridine (75 µM) shifted the half-maximal activation voltage of the Nav1.7 activation curve in the hyperpolarized direction, from -21.64 ± 0.75 mV to -28.14 ± 0.66 mV, and shifted the half-inactivation voltage of the steady-state inactivation curve from -59.39 ± 0.39 mV to -73.78 ± 0.5 mV. An increased frequency of stimulation decreased the peak and tail currents of Nav1.7 for each pulse along with pulse number, and increased the accumulated tail current at the end of train stimulation. These findings reveal the different modulatory effects of veratridine on the Nav1.7 peak current and tail current.