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The present work addresses the topic of die clamping at the forging hammer in the context of the definition of a current requirement profile as well as the evaluation of individual influencing variables on the clamping process. In addition to the presentation of survey results for the requirements profile, the first part focus on the sensible minimization of influencing variables to be investigated and on the verification of a possible evaluation method. Based on this, in the second part exemplary influencing variables on the clamping condition are investigated by means of FEM. Thereby it can be shown by way of example, that the heat flow of the forging process and the friction conditions between the clamping elements have a noteworthy influence on the clamping condition of the dies and that deviations in the clamping force can lead to significant damage. [ABSTRACT FROM AUTHOR]

Domain microstructures in single crystal lamellae of 88%Pb(Zn1/3Nb2/3)O3-12%PbTiO3 (cut from bulk using focused ion beam milling) have been mapped using both piezoresponse force microscopy and transmission electron microscopy. Dramatic changes from mottled microstructures typical of relaxors to larger scale domains typical of ferroelectrics have been noted. Stresses associated with substrate clamping are suspected as the cause for the transition from short- to long-range polar order, akin to effects induced by cation ordering achieved by thermal quenching. [ABSTRACT FROM AUTHOR]

Domain microstructures in single crystal lamellae of 88%Pb(Zn1/3Nb2/3)O3-12%PbTiO3 (cut from bulk using focused ion beam milling) have been mapped using both piezoresponse force microscopy and transmission electron microscopy. Dramatic changes from mottled microstructures typical of relaxors to larger scale domains typical of ferroelectrics have been noted. Stresses associated with substrate clamping are suspected as the cause for the transition from short- to long-range polar order, akin to effects induced by cation ordering achieved by thermal quenching. [ABSTRACT FROM AUTHOR]

Although postoperative cholangioscopy (POC) guided electrohydraulic lithotripsy (EHL) is considered to be a conventional technique for residual biliary calculi, its efficacy still needs to be improved to fit in the managemet of refractory calculi. This study evaluated the efficacy and safety of combined lithotripsy of mechanical clamping and electrohydraulics in fragmentation and removal of refractory calculi. Totally, 281 patients, who suffered from residual biliary calculi after hepatectomy and underwnet POC from August 2016 to June 2018 were involved. The first 128 patients were subjected to conventional EHL, and later consective 153 to combined lithotripsyof mechanical clamping and EHL. Perioperative data, technical information, treatment outcomes and follow-up results were collected. Clinical characteristics were statistically comparable (P > 0.05). The overall POC interventional sessions (2.0 ± 0.65 vs. 2.9 ± 1.21 sessions), average operating time (99.1 ± 34.88 vs. 128.6 ± 72.87 minutes), incidence of intraoperative hemobilia (4.58% vs. 10.93%), cholangitis (6.54% vs. 14.06%), postoperative complications (10.45% vs. 21.87%), T-tube retaining time after first POC (20.7 ± 5.35 vs. 28.1 ± 8.28 days), and treatment costs ($2375 ± 661.72 vs. $3456.7 ± 638.07) were significantly lower in the combined lithotripsy group than those in the EHL group (P < 0.05). There were no differences between the two groups in calculi recurrence at half-a year, or one year follow-up. In conclusion, combined lithotripsy of mechanical clamping and electrohydraulics can safely and effectively benefit postoperative patients along with refractory residual biliary calculi. [ABSTRACT FROM AUTHOR]

A mechanics-based model is developed to examine the effects of clamping during wafer bonding processes. The model provides closed-form expressions that relate the initial geometry and elastic properties of the wafers to the final shape of the bonded pair and the strain energy release rate at the interface for two different clamping configurations. The results demonstrate that the curvature of bonded pairs may be controlled through the use of specific clamping arrangements during the bonding process. Furthermore, it is demonstrated that the strain energy release rate depends on the clamping configuration and that using applied loads usually leads to an undesirable increase in the strain energy release rate. The results are discussed in detail and implications for process development and bonding tool design are highlighted. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Catheters are widely used for therapeutic and diagnostic purposes in various medical applications. Along with frictional properties as well as the catheter profile the catheter stiffness mainly affects the deliverability and thus, the handling properties of the catheter. Within this study the bending stiffness of proximal and distal catheter samples was investigated with a custom made test setup. In particular, the influence of the catheter clamping length on the test results is discussed. Bending stiffness was calculated directly from the measured force, deflection and clamping length considering the test setup compliance. Measurements were performed three times at five positions in circumferential direction. Measured bending stiffness ranged from 629 ± 31 Nmm² to 733 ± 58 Nmm² for the proximal samples and from 30 ± 5 Nmm² to 98 ± 30 Nmm² for the distal samples, respectively. Bending stiffness varied depending on the free catheter length and the reaction force measured. The maximum reaction force decreased with increasing free catheter length leading to a higher measurement uncertainty. However, when considering the same free catheter length quantitative results were similar within the group of proximal and distal samples, respectively. [ABSTRACT FROM AUTHOR]

Cardiac two-pore-domain potassium (K 2P) channels have been proposed as novel antiarrhythmic targets. K 2P 13.1 (THIK-1) channels are expressed in the human heart, and atrial K 2P 13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K 2P 13.1 currents. Second, we assessed atrial K 2P 13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K 2P 13.1-based antiarrhythmic concepts. K 2P 13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K 2P 13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K 2P 13.1 channel pharmacology in Xenopus oocytes. Propafenone (−26%; 100 μM), mexiletine (−75%; 1.5 mM), propranolol (−38%; 200 μM), and lidocaine (−59%; 100 μM) significantly inhibited K 2P 13.1 currents. By contrast, K 2P 13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K 2P 13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K 2P 13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K 2P 13.1 channels in a porcine model resemble human findings and support a general role for K 2P 13.1 in AF pathophysiology. K 2P 13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm. [ABSTRACT FROM AUTHOR]

DC collection network offers an attractive alternative to AC network for photovoltaic, as it avoids the charging current issues and reduces the size and weight. Variable voltage gain DC/DC converters play an important role in DC collection network. Two topologies suitable for photovoltaic DC collection are studied. Boost and LLC converter and active clamp isolated full-bridge boost converter are two converters with high and variable voltage conversion ratio suitable for the photovoltaic system. This work investigates the two converters comprehensively. The topologies are analysed so as to summarise and compare the characteristic of the converters. Soft switching condition is compared to help extend the zero voltage switching range. Voltage and current stress of the two converters are calculated. Loss comparison is made with the theoretical analysis. Advantages and disadvantages are summarised to get a deep insight into their application field. [ABSTRACT FROM AUTHOR]

The interplay between excitatory and inhibitory neurons imparts rich functions of the brain. To understand the synaptic mechanisms underlying neuronal computations, a fundamental approach is to study the dynamics of excitatory and inhibitory synaptic inputs of each neuron. The traditional method of determining input conductance, which has been applied for decades, employs the synaptic current-voltage (I-V) relation obtained via voltage clamp. Due to the space clamp effect, the measured conductance is different from the local conductance on the dendrites. Therefore, the interpretation of the measured conductance remains to be clarified. Using theoretical analysis, electrophysiological experiments, and realistic neuron simulations, here we demonstrate that there does not exist a transform between the local conductance and the conductance measured by the traditional method, due to the neglect of a nonlinear interaction between the clamp current and the synaptic current in the traditional method. Consequently, the conductance determined by the traditional method may not correlate with the local conductance on the dendrites, and its value could be unphysically negative as observed in experiment. To circumvent the challenge of the space clamp effect and elucidate synaptic impact on neuronal information processing, we propose the concept of effective conductance which is proportional to the local conductance on the dendrite and reflects directly the functional influence of synaptic inputs on somatic membrane potential dynamics, and we further develop a framework to determine the effective conductance accurately. Our work suggests re-examination of previous studies involving conductance measurement and provides a reliable approach to assess synaptic influence on neuronal computation. [ABSTRACT FROM AUTHOR]

Effect of amino acid L-asparagine on electrical signalling of single Nitellopsis obtusa (Characeaen) cell was investigated using glass-microelectrode technique in current-clamp and voltage-clamp modes. Cell exposure for 30 min to 0.1 mM and 1 mM of asparagine resulted in changes of electrically stimulated action potential (AP) parameters in comparison to standard conditions. Results indicate that asparagine acts in dose-dependent manner: increases AP amplitude by hyperpolarizing AP threshold potential (Eth), prolongs action potential repolarization, increases maximum Cl− efflux amplitude along with the increase of activation and inactivation durations. Presented findings provide new aspects of exogenous amino acids' effect on plants' electrical signalling with emphasis on separate single plant cell excitability and AP characteristics. [ABSTRACT FROM AUTHOR]

Abstract Dynamic avalanche is one key factor limiting the safe operating area (SOA) of the gate commutated thyristors (GCTs). The current filament caused by dynamic avalanche and its failure mechanism still need to be studied in depth. In this paper, the relevant theoretical analysis and device simulations are firstly carried out. And a 2-D model describing quantitatively the plasma front velocity is derived to examine the behaviour of the filament. The results show that the avalanche effect at the pn- junction and the hole injection of p-anode region in the GCT can interact with each other during the turn-off, but it does not necessarily lead to the device destruction. However, when the GCT is turned off at high dc-link voltage, the interaction transforms into a positive feedback effect, and the anode-cathode voltage is clamped to a certain value, resulting in the formation of destructive filament. Additionally, the borderline limited by the voltage clamping is given. Highlights • The current filament in GCTs and its destruction mechanism are studied. • The hole injection of p anode can enhance the dynamic avalanche at the pn- junction. • The 2-D model describing quantitatively the plasma front velocity is derived. • A voltage clamping phenomenon during the turn-off of GCTs is found. • The borderline limited by voltage clamping is given. [ABSTRACT FROM AUTHOR]

Background: The prognostic impact of cross-clamp time (XCT) in patients undergoing isolated coronary artery bypass grafting (CABG) has not been thoroughly investigated.Material and Methods: 2957 patients who underwent on-pump isolated CABG from the prospective multicentre E-CABG study were the subjects of this analysis.Results: The mean XCT in this series was 58±25minutes Cross-clamp time was >60 minutes in 1134 patients (38.3%), >75minutes in 619 patients (20.9%) and >90minutes in 296 patients (10.0%). Multivariate analysis showed that XCT was an independent predictor of 30-day mortality (p<0.0001, OR 1.027, 95%CI 1.015-1.039) along with age (p<0.0001), female gender (p=0.001), pulmonary disease (p=0.001), poor mobility (p=0.002), urgency status (p=0.007), critical preoperative status (p=0.002) and participating centres (p=0.015). Adjusted risk of 30-day mortality was highest for XCT >75minutes (2.9% vs. 1.7%, p=0.002, OR 3.479, 95%CI 1.609-7.520). Analysis of 428 propensity score matched pairs showed that XCT >75minutes was associated with significantly increased risk of early mortality, prolonged use of inotropes, postoperative use of intra-aortic balloon pump, use of extracorporeal membrane oxygenation, atrial fibrillation, prolonged stay in the intensive care unit and of composite major adverse events.Conclusions: Isolated CABG is currently performed with prolonged XCT in a significant number of patients and this seems to be a determinant of poor early outcome. [ABSTRACT FROM AUTHOR]

The rhythmic pattern of breathing depends on the pre-Bötzinger complex (preBötC) in the brainstem, a vital circuit that contains a population of neurons with intrinsic oscillatory bursting behavior. Here, we investigate the specific kinetic properties that enable voltage-gated sodium channels to establish oscillatory bursting in preBötC inspiratory neurons, which exhibit an unusually large persistent Na+ current (INaP). We first characterize the kinetics of INaP in neonatal rat brainstem slices in vitro, using whole-cell patch-clamp and computational modeling, and then test the contribution of INaP to rhythmic bursting in live neurons, using the dynamic clamp technique. We provide evidence that subthreshold activation, persistence at suprathreshold potentials, slow inactivation, and slow recovery from inactivation are kinetic features of INaP that regulate all aspects of intrinsic rhythmic bursting in preBötC neurons. The slow and cumulative inactivation of INaP during the burst active phase controls burst duration and termination, while the slow recovery from inactivation controls the duration of the interburst interval. To demonstrate this mechanism, we develop a Markov state model of INaP that explains a comprehensive set of voltage clamp data. By adding or subtracting a computer-generated INaP from a live neuron via dynamic clamp, we are able to convert nonbursters into intrinsic bursters, and vice versa. As a control, we test a model with inactivation features removed. Adding noninactivating INaP into nonbursters results in a pattern of random transitions between sustained firing and quiescence. The relative amplitude of INaP is the key factor that separates intrinsic bursters from nonbursters and can change the fraction of intrinsic bursters in the preBötC. INaP could thus be an important target for regulating network rhythmogenic properties. [ABSTRACT FROM AUTHOR]

Provides information on an experimental study investigating current-voltage and brigthness-voltage characteristics showing that different dyes together with space-charge limited currents (SCLC) of holes have significant influence on electron injection already in single-layer devices. Methodology and materials used to conduct the study; Information on single-layer devices; Results of the study; Discussion on the results.

Abstract Neonicotinoid insecticides interact with the orthosteric sites of nicotinic acetylcholine receptors (nAChRs) formed at the interfaces of (a) two adjacent α subunits and (b) α and non-α subunits. However, little is known of the detailed contributions of these two orthosteric sites to neonicotinoid actions. We therefore applied voltage-clamp electrophysiology to the Dα1/chicken β2 hybrid nAChR expressed in Xenopus laevis oocytes to explore the agonist actions of imidacloprid and thiacloprid on wild type receptors and following binding site mutations. First, we studied the S221E mutation in loop C of the ACh binding site of the Dα1 subunit. Secondly, we explored the impact of combining this mutation in loop C with others in the loop D-E-G triangle (R57S; E78K; K140T; S221E). The S221E loop C mutation alone reduced the affinity of the neonicotinoids tested, while hardly affecting the concentration-response curve for acetylcholine. Addition of the three R57S; E78K; K140T mutations in the loop D-E-G triangle led to a further reduction in neonicotinoid sensitivity, suggesting that all four binding site loops (C, D, E, G) in the Dα1 subunit, which are located upstream of loop B in the N-terminal, extracellular domain, contribute to the selective actions of neonicotinoid insecticides. Graphical abstract Unlabelled Image Highlights • Serine221 was mutated to glutamate in loop C of Drosophila Dα1 subunit. • The S221E mutation reduced neonicotinoid affinity for (Dα1) 3 (chicken β2) 2 nAChR. • R57S; E78K; K140T triple mutations were added to the S221E Dα1 mutant. • The four amino acid mutations further reduced the neonicotinoid actions. • Thus, all four residues play critical roles in the interactions with neonicotinoids. [ABSTRACT FROM AUTHOR]

Key points: Physiologically relevant combinations of recombinant GABAA receptor (GABAR) subunits were expressed in HEK293 cells. Using whole‐cell voltage clamp and rapid drug application, we measured the GABAR‐subtype‐specific properties to convey either synaptic or extrasynaptic signalling in a range of physiological contexts. α4βδ GABARs are optimally tuned to submicromolar tonic GABA and transient surges of micromolar GABA concentrations. α5β2γ2l GABARs are better suited to higher tonic GABA levels, but also convey robust responses to brief synaptic and perisynaptic GABA fluctuations. α1β2/3δ GABARs function well at prolonged, micromolar (>2 μm) GABA levels, but not to low tonic (<1 μm GABA) or synaptic/transient GABAergic signalling. These results help illuminate the context‐ and isoform‐specific modes of GABAergic signalling in the brain. Abstract: GABAA receptors (GABARs) mediate a remarkable diversity of signalling modalities in vivo. Yet most published work characterizing responses to GABA has focused on the properties needed to convey fast, phasic synaptic inhibition. We therefore aimed to characterize the most prevalent (α4βδ, α5β3γ2L) and least prevalent (α1β2δ) non‐synaptic GABAR currents, using whole‐cell voltage clamp recordings of recombinant GABAR expressed in HEK293 cells and drug application protocols to recapitulate the GABA concentration profiles occurring during both fast synaptic and slow extrasynaptic signalling. We found that α4βδ GABARs were very sensitive to submicromolar GABA, with a rank order potency of α4β2δ ≥ α4β1δ ≈ α4β3δ GABARs. In comparison, the GABA EC50 was up to 20 times higher for α1β2γ2L GABARs, with α1β2δ and α5β3γ2L GABARs having intermediate GABA potency. Both α4βδ and α5β3γ2L GABAR currents exhibited slow, but substantial, desensitization as well as prolonged rates of deactivation. These GABAR current properties defined distinct ‘dynamic ranges’ of responsiveness to changing GABA for α4β2δ (0.1–1 μ m), α5β3γ2L (0.5–7 μ m) and α1β2γ2L (0.6–9 μ m) GABARs. Finally, α1β2δ GABARs were notable for their relative lack of desensitization and extremely quick deactivation. In summary, our results help delineate the roles that specific GABARs may play in mediating non‐synaptic GABA signals. Since ambient GABA levels may be altered during development as well as by drugs and disease states, these findings may help future efforts to understand disrupted inhibition underlying a variety of neurological illnesses, such as epilepsy. [ABSTRACT FROM AUTHOR]

Glycine receptors (GlyRs) are Cys-loop receptors that mediate fast synaptic inhibition in the brain stem and spinal cord. They are involved in the generation of motor rhythm, reflex circuit coordination, and sensory signal processing and therefore represent targets for therapeutic interventions. The extracellular domains (ECDs) of Cys-loop receptors typically contain many aromatic amino acids, but only those in the receptor binding pocket have been extensively studied. Here, we show that many Phe residues in theECDthat are not located in the binding pocket are also involved in GlyR function. We examined these Phe residues by creating several GlyR variants, characterizing these variants with the two-electrode voltage clamp technique in Xenopus oocytes, and interpreting changes in receptor parameters by using currently available structural information on the open and closed states of the GlyR. Substitution of six of the eight Phe residues in the ECD with Ala resulted in loss of function or significantly increased the EC50 and also altered the maximal response to the partial GlyR agonist taurine compared with glycine in those receptor variants that were functional. Substitutions with other amino acids, combined with examination of nearby residues that could potentially interact with these Phe residues, suggested interactions that could be important for GlyR function, and possibly similar interactions could contribute to the function of other members of the Cys-loop receptor family. Overall, our results suggest that many ECD regions are important for GlyR function and that these regions could inform the design of therapeutic agents targeting GlyR activity. [ABSTRACT FROM AUTHOR]

Amitriptyline, a tricyclic antidepressant, is commonly used to treat depression and neuropathic pain, but its mechanism is still unclear. We tested the effect of amitriptyline on 5-hydroxytryptamine 3 (5-HT3) receptor currents and studied its blocking mechanism because the clinical applications of amitriptyline overlapped with 5-HT3 receptor therapeutic potentials. Using a whole-cell voltage clamp method, we recorded the currents of the 5-HT3 receptor when 5-HT was applied alone or co-applied with amitriptyline in cultured NCB-20 neuroblastoma cells known to express 5-HT3 receptors. To elucidate the mechanism of amitriptyline, we simulated the 5-HT3 receptor currents using Berkeley Madonna® software and calculated the rate constants of the agonist binding and receptor transition steps. The 5-HT3 receptor currents were inhibited by amitriptyline in a concentration-dependent, voltage-independent manner, and a competitive mode. Amitriptyline accelerated the desensitization of the 5-HT3 receptor. When amitriptyline was applied before 5-HT treatment, the currents rose slowly until the end of 5-HT treatment. When amitriptyline was coapplied with 5-HT, currents rose and decayed rapidly. Peak current amplitudes were decreased in both applications. All macroscopic currents recorded in whole cell voltage clamping experiments were reproduced by simulation and the changes of rate constants by amitriptyline were correlated with macroscopic current recording data. These results suggest that amitriptyline blocks the 5-HT3 receptor by close and open state blocking mechanisms, in a competitive manner. We could expand an understanding of pharmacological mechanisms of amitriptyline related to the modulation of a 5-HT3 receptor, a potential target of neurologic and psychiatric diseases through this study. [ABSTRACT FROM AUTHOR]

A change in the membrane potential in nerve cells is thought to be generated and propagated mainly by a function of K + and Na + channels. The concurrent monitoring of multipoints on the axon has been generally conducted on the basis of the voltage-clamp or current-clamp method. Given that the respective membrane potentials have been evaluated by considering the applied potential, local current, and conductance, the propagation of the change in the membrane potential was measured. By using a nerve model system composed of some liquid membrane cells, we directly measured the actual membrane potentials and the local currents of the respective cells. We demonstrated that the local membrane current caused by an external voltage induced a change in the membrane potential and that the change was propagated by connecting the liquid membrane cells and mimicking voltage-gated Na + channels. It has been proved that hyperpolarization hardly occurs on the occasion of existence of the flux of K + and Na + only in the present model system and that the change in the membrane potential corresponding to the action potential is directionally propagated. [ABSTRACT FROM AUTHOR]

A series of new 6-substituted 3H-quinazolin-4-ones (3a-3d) were designed, synthesized and evaluated as the type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine (100 μM). The structure-activity relationship (SAR) analysis suggested that thiazolo[4,5-d]pyrimidin-7(6H)-one was the key biological skeleton. [ABSTRACT FROM AUTHOR]

We used voltage-clamp recordings from somatic outside-out macropatches to determine the amplitude and biophysical properties of putative Kv1-mediated currents in layer 5 pyramidal neurons (PNs) from mice expressing EGFP under the control of promoters for etv1 or glt. We then used whole cell current-clamp recordings and Kv1-specific peptide blockers to test the hypothesis that Kv1 channels differentially regulate action potential (AP) voltage threshold, repolarization rate, and width as well as rheobase and repetitive firing in these two PN types. We found that Kv1-mediated currents make up a similar percentage of whole cell K+ current in both cell types, and only minor biophysical differences were observed between PN types or between currents sensitive to different Kv1 blockers. Putative Kv1 currents contributed to AP voltage threshold in both PN types, but AP width and rate of repolarization were only affected in etv1 PNs. Kv1 currents regulate rheobase, delay to the first AP, and firing rate similarly in both cell types, but the frequencycurrent slope was much more sensitive to Kv1 block in etv1 PNs. In both cell types, Kv1 block shifted the current required to elicit an onset doublet of action potentials to lower currents. Spike frequency adaptation was also affected differently by Kv1 block in the two PN types. Thus, despite similar expression levels and minimal differences in biophysical properties, Kv1 channels differentially regulate APs and repetitive firing in etv1 and glt PNs. This may reflect differences in subcellular localization of channel subtypes or differences in the other K+ channels expressed. [ABSTRACT FROM AUTHOR]

Sodium channels play pivotal roles in health and diseases due to their ability to control cellular excitability. The pore-forming α-subunits (sodium channel alpha subunits) of the voltage-sensitive channels (i.e., Nav1.1-1.9) and the nonvoltage-dependent channel (i.e., Nax) share a common structural motif and selectivity for sodium ions. We hypothesized that the actin-based nonmuscle myosin II motor proteins, nonmuscle myosin heavy chain-IIA/myh9, and nonmuscle myosin heavy chain-IIB/myh10 might interact with sodium channel alpha subunits to play an important role in their transport, trafficking, and/or function. Immunochemical and electrophysiological assays were conducted using rodent nervous (brain and dorsal root ganglia) tissues and ND7/23 cells coexpressing Nav subunits and recombinant myosins. Immunoprecipitation of myh9 and myh10 from rodent brain tissues led to the coimmunoprecipitation of Nax, Nav 1.2, and Nav1.3 subunits, but not Nav1.1 and Nav1.6 subunits, expressed there. Similarly, immunoprecipitation of myh9 and myh10 from rodent dorsal root ganglia tissues led to the coimmunoprecipitation of Nav1.7 and Nav1.8 subunits, but not Nav1.9 subunits, expressed there. The functional implication of one of these interactions was assessed by coexpressing myh10 along with Nav1.8 subunits in ND7/23 cells. Myh10 overexpression led to three-fold increase (P<0.01) in the current density of Nav1.8 channels expressed in ND7/23 cells. Myh10 coexpression also hyperpolarized voltage-dependent activation and steady-state fast inactivation of Nav1.8 channels. In addition, coexpression of myh10 reduced (P<0.01) the offset of fast inactivation and the amplitude of the ramp currents of Nav1.8 channels. These results indicate that nonmuscle myosin heavy chain-IIs interact with sodium channel alpha subunits subunits in an isoform-dependent manner and influence their functional properties. [ABSTRACT FROM AUTHOR]

The S4-S5 linker physically links voltage sensor and pore domain in voltage-gated ion channels and is essential for electromechanical coupling between both domains. Little dynamic information is available on the movement of the cytosolic S4-S5 linker due to lack of a direct electrical or optical readout. To understand the movements of the gating machinery during activation and inactivation, we incorporated fluorescent unnatural amino acids at four positions along the linker of the Shaker KV channel. Using twocolor voltage-clamp fluorometry, we compared S4-S5 linker movements with charge displacement, S4 movement, and pore opening. We found that the proximal S4-S5 linker moves with the S4 helix throughout the gating process, whereas the distal portion undergoes a separate motion related to late gating transitions. Both pore and S4-S5 linker undergo rearrangements during C-type inactivation. In presence of accelerated C-type inactivation, the energetic coupling between movement of the distal S4-S5 linker and pore opening disappears. [ABSTRACT FROM AUTHOR]

Recent data have implicated voltage-gated calcium channels in the regulation of the excitability of neurons within the mesolimbic reward system. While the attention of most research has centered on high voltage L-type calcium channel activity, the presence and role of the low voltage-gated T-type calcium channel (T-channels) has not been well explored. Hence, we investigated T-channel properties in the neurons of the ventral tegmental area (VTA) utilizing wild-type (WT) rats and mice, Ca V 3.1 knock-out (KO) mice, and TH-eGFP knock-in (KI) rats in acute horizontal brain slices of adolescent animals. In voltage-clamp experiments, we first assessed T-channel activity in WT rats with characteristic properties of voltage-dependent activation and inactivation, as well as characteristic crisscrossing patterns of macroscopic current kinetics. T-current kinetics were similar in WT mice and WT rats but T-currents were abolished in Ca V 3.1 KO mice. In ensuing current-clamp experiments, we observed the presence of hyperpolarization-induced rebound burst firing in a subset of neurons in WT rats, as well as dopaminergic and non-dopaminergic neurons in TH-eGFP KI rats. Following the application of a pan-selective T-channel blocker TTA-P2, rebound bursting was significantly inhibited in all tested cells. In a behavioral assessment, the acute locomotor increase induced by a MK-801 (Dizocilpine) injection in WT mice was abolished in Ca V 3.1 KO mice, suggesting a tangible role for 3.1 T-type channels in drug response. We conclude that pharmacological targeting of Ca V 3.1 isoform of T-channels may be a novel approach for the treatment of disorders of mesolimbic reward system. [ABSTRACT FROM AUTHOR]

Benzodiazepines are positive allosteric modulators of the GABAA receptor (GABAAR), acting at the subunit interface to enhance GABAAR function. GABA or benzodiazepine binding induces distinct conformational changes in the GABAAR. The molecular rearrangements in the GABAAR following benzodiazepine binding remain to be fully elucidated. Using two molecular models of the GABAAR, we identified electrostatic interactions between specific amino acids at the α-β subunit interface that were broken by, or formed after, benzodiazepine binding. Using two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes, we investigated these interactions by substituting one or both amino acids of each potential pair. We found that Lys104 in the α1 subunit forms an electrostatic bond with Asp75 of the γ2 subunit after benzodiazepine binding and that this bond stabilizes the positively modified state of the receptor. Substitution of these two residues to cysteine and subsequent covalent linkage between them increased the receptor's sensitivity to low GABA concentrations and decreased its response to benzodiazepines, producing a GABAAR that resembles a benzodiazepine-boundWTGABAAR. Breaking this bond restored sensitivity to GABA to WT levels and increased the receptor's response to benzodiazepines. The α1 Lys104 and γ2 Asp75 interaction did not play a role in ethanol or neurosteroid modulation of GABAAR, suggesting that different modulators induce different conformational changes in the receptor. These findings may help explain the additive or synergistic effects of modulators acting at the GABAAR. [ABSTRACT FROM AUTHOR]

The retigabine analog 2-amino-4-[(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504) is a positive allosteric modulator (PAM) of γ-aminobutyric acid A receptors (GABA A Rs), and the modulator has been used in ex vivo / in vivo studies to probe the physiological roles of native δ-containing GABA A Rs. In this study, the functional properties and mode of action of AA29504 were investigated at human GABA A Rs expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology. AA29504 was found to be an allosteric GABA A R agonist displaying low intrinsic activities at 3–30 μM. AA29504 was essentially equipotent as a PAM at the 13 GABA A R subtypes tested (EC 50 : 0.45–5.2 μM), however GABA EC 5 -evoked currents through αβδ subtypes were modulated to substantially higher levels than those through αβγ 2S subtypes (relative to GABA I max ). While the δ/γ 2S -difference clearly was key for this differential GABA efficacy modulation, studies of the AA29504-mediated modulation of different α 4,5,6 -containing αβ, αβγ 2S and αβδ GABA A Rs revealed the α-subunit identity to be another important determinant. Based on its functional properties at numerous mutant GABA A Rs and on in silico analysis of its low-energy conformations, AA29504 is proposed to act through an allosteric site in the transmembrane β (+) /α (−) interface in the GABA A R also targeted by etomidate and several other modulators. In contrast to these modulators, however, AA29504 did not display substantial β 2 /β 3 -over-β 1 GABA A R preference, which challenges the notion of ligands targeting this site always possessing this subtype-selectivity profile. Hence, the detailed pharmacological profiling of AA29504 both highlights the complexity of allosteric GABA A R modulation and provides valuable information about this modulator as a pharmacological tool. [ABSTRACT FROM AUTHOR]

This paper presents a hybrid electrochemical discharge drilling method in which a metal tube is used as cathode tool and workpiece is used as anode. Liquid with weak conductivity flows at high speed between the metal tube and workpiece. Electrical discharge takes place mainly at the frontal gap, and electrochemical process takes place at both the frontal gap and side gap. The recast layer generated by electrical discharge at the side gap can be removed electrochemically. The machining phenomenon at the gap was observed through a designed transparent clamping fixture, voltage and current waveforms during machining were recorded, and the machining products and removal effect of recast layer were analyzed. The cross section of the hole and machining surface were analyzed, and the tool wear and machining efficiency were compared with those of other processes. Finally, the 4-mm-deep hole of 0.5-mm diameter can be produced with low tool wear and almost no recast layer. [ABSTRACT FROM AUTHOR]

By synchronizing neuronal activity, electrical transmission influences the coordination, pattern, and/or frequency of firing. In the hemaphroditic marine-snail, Aplysia calfornica, the neuroendocrine bag cell neurons use electrical synapses to synchronize a 30 min afterdischarge of action potentials for the release of reproductive hormone. During the afterdischarge, protein kinase C (PKC) is activated, although its impact on bag cell neuron electrical transmission is unknown. This was investigated here by monitoring electrical synapses between paired cultured bag cell neurons using dual whole-cell recording. Voltage clamp revealed a largely voltage-independent junctional current, which was enhanced by treating with a PKC activator, PMA, before recording. We also examined the transfer of presynaptic action potential-like waveforms (generated in voltage clamp) to the postsynaptic cell (measured in current clamp). For control pairs, the presynaptic spike-like waveforms mainly evoked electrotonic potentials; however, when PKC was triggered, these stimuli consistently produced postsynaptic action potentials. To assess whether this involved changes to postsynaptic responsiveness, single bag cell neurons were injected with junctional-like current mimicking that evoked by a presynaptic action potential. Unlike control neurons, which were less likely to spike, cells in PMA always fired action potentials to the junctional-like current. Furthermore, PKC activation increased a postsynaptic voltage-gated Ca2+ current, which was recruited even by modest depolarization associated with an electrotonic potential. Whereas PKC inhibits gap junctions in most systems, bag cell neurons are rather unique, as the kinase potentiates the electrical synapse; in turn, this synergizes with augmented postsynaptic Ca2+ current to promote synchronous firing. [ABSTRACT FROM AUTHOR]

AM2 and BM2 proton channels are attractive antiviral drug targets due to their essential roles during influenza virus replication. Although both AM2 and BM2 are proton-selective ion channels, they share little sequence similarity except for the HXXXW sequence, which suggests that their proton conductance properties might differ. To test this hypothesis, we applied two-electrode voltage clamp electrophysiological assays to study the specific conductance, leakage current, channel activation, and inhibition of AM2 and BM2 proton channels. It was found that BM2 channel has a higher specific conductance than AM2 channel at pH 5.5. Unlike AM2 channel, whose proton conductance is asymmetric (from viral exterior to interior), BM2 channel is capable of conducting proton in both directions. Moreover, BM2 requires a more acidic pH for channel activation than AM2, as revealed by its lower p K a values. Finally, both AM2 and BM2 can be inhibited by Cu(II) and Cu(I). Overall, the results from this side-by-side comparison of AM2 and BM2 channels reveal the structure-function relationships of these two viroporins, and such information might be important for the designing of novel ion channels. [ABSTRACT FROM AUTHOR]

A novel inchworm type piezoelectric rotary actuator based on wedge block clamping is presented in this paper. With the help of only one piezo-stack and two clamping blocks, the proposed actuator can imitate the walking mode of inchworm to deliver stable long range rotary motion accompanying with high driving resolution. Owing to the advantages of the distinctive clamping principle, the output torque of the actuator can be up to 7168.7 Nmm. The mechanical structure and the working principle of the actuator are introduced in detail. As a key component of the actuator, the clamping block is well designed and the curve function of its working surface is deduced. We manufacture an actuator prototype and establish a set of experimental system and conduct a series of experiments to test the performance of the prototype. The experimental results indicate that the prototype can output stable angular displacements step by step under various driving voltages and frequencies and all steps have high reproducibility. The driving resolution of the actuator is 0.567 μrad and the designed motion range is 5°. We can obtain a satisfactory driving velocity by choosing a proper driving voltage and frequency for the actuator. Under driving frequency of 1 Hz, the maximum velocity is 511.7 μrad s −1 when the driving voltage is 150 V and under driving voltage of 90 V, the velocity can reach to 42959.5 μrad s −1 when the driving frequency is 128 Hz. [ABSTRACT FROM AUTHOR]

PEM fuel cell stack assembly process, including clamping pressure, material properties of each component, design (component thickness and cell active area), and number of cells in the stack are important factors influencing the performance and durability of the PEM fuel cell stack. Furthermore, when temperature and relative humidity increase during operation, the membrane absorbs water and swells. Since the relative position between the top and bottom end plates is fixed, the polymer membrane is spatially confined. Thus the GDL will be further compressed under the land and the intrusion into channel becomes more significant. Assembly pressure, contact resistance, membrane swelling and operating conditions, etc., combine to yield an optimum assembly pressure. The clamping pressure is therefore a critical parameter for optimal fuel cell performance and durability. Too high, too low, or inhomogeneous compressions have negative effects on the performance and durability of the stack. In this study, full three-dimensional, non-isothermal computational fluid dynamics (CFD) detailed model of a PEM fuel cell stack has been developed and coupled with a solid mechanics model to simulate the stress distribution inside the stack, which are occurring during fuel cell assembly (bolt assembling), and membrane swelling and cell materials expansion during fuel cell running due to the changes of temperature and relative humidity. The PEM fuel cell stack model simulated includes the following all components in full details; two end-plates, two current plates, two bi-polar plates with straight flow channels for reactants and cooling serpentine water flow channel on the upper face of cathode bi-polar plate, two GDLs, two gaskets, and, an MEA (membrane plus two CLs). The model is shown to be able to understand the many interacting, complex electrochemical, transport phenomena, with stress distribution inside the stack during operation on the performance and durability of the stack that have limited experimental data. Furthermore, the model is shown to be able to provide a computer-aided tool for design and optimize future fuel cell stack with much higher power density, long stack life, and lower cost. [ABSTRACT FROM AUTHOR]

The series connection of IGBTs is essential for high-voltage applications where fast switching performances need to be maintained. However, unbalanced voltage sharing is a major resistance to the converter application of this structure. There are a number of causes leading to voltage unbalance, such as different signal delays, parasitic parameters, tail currents, and so on. A temporary clamp scheme performed by active voltage control (AVC) has been proven to be effective in solving the unbalanced voltage-sharing issue. However, the basic physics has not been investigated. In this paper, the physical principle of voltage unbalance within IGBTs series operation is discussed. The carrier storage region differences are concluded to be the intrinsic cause of unbalanced voltage sharing. By using an accurate Fourier-series-based IGBT simulation model with appropriate assumptions, a physical explanation for temporary clamp is provided in detail. At the end of the tail current period when the excess carrier concentration becomes close to the intrinsic doping density, the temporary clamp is able to achieve satisfactory equal voltage sharing. [ABSTRACT FROM PUBLISHER]

Classically, GABAB receptors are thought to regulate neuronal excitability via G-protein-coupled inwardly rectifying potassium ( GIRK) channels. Recent data, however, indicate that GABAB receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABAB receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 μ m) abolished outward currents evoked by GABAB receptors in CA1 pyramidal, but only partially blocked GABAB responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin-Q, a specific GIRK channel blocker. Tertiapin-Q partially blocked GABAB responses in CA1 pyramidal neurons, but was ineffective in blocking GABAB responses in neocortical layer 5 neurons. Consistent with the idea that GABAB receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABAB responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABAB responses mediated by two-pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABAB receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABAB inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity. [ABSTRACT FROM AUTHOR]

Evidence indicates that high salt (HS) intake activates presympathetic paraventricular nucleus (PVN) neurons, which contributes to sympathoexcitation of salt-sensitive hypertension. The present study determined whether 5 weeks of HS (2% NaCl) intake alters the small conductance Ca2+-activated potassium channel (SK) current in presympathetic PVN neurons and whether this change affects the neuronal excitability. In whole-cell voltage-clamp recordings, HS-treated rats had significantly decreased SK currents compared to rats with normal salt (NS, 0.4% NaCl) intake in PVN neurons. The sensitivity of PVN neuronal excitability in response to current injections was greater in HS group compared to NS controls. The SK channel blocker apamin augmented the neuronal excitability in both groups but had less effect on the sensitivity of the neuronal excitability in HS group compared to NS controls. In the HS group, the interspike interval (ISI) was significantly shorter than that in NS controls. Apamin significantly shortened the ISI in NS controls but had less effect in the HS group. This data suggests that HS intake reduces SK currents, which contributes to increased PVN neuronal excitability at least in part through a decrease in spike frequency adaptation and may be a precursor to the development of salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Single-phase Transformerless (TRL) inverters (1–10 kW) are gaining more attention for grid-connected photovoltaic (PV) system because of their significant benefits such as less complexity, higher efficiency, smaller volume, weight, and lower cost compared to transformer (TR) galvanic isolations. One of the most interesting topologies for TRL grid-connected PV application is Three-Level Neutral-Point-Clamped Voltage Source Inverter (3L-NPC VSI) due to inherent feature of eliminating leakage current and other several dramatic benefits compared to classical two-level topologies. Therefore, in this paper, firstly, a leakage current model is represented for 3L-NPC topology. Then, more than 45 new / integrated single-stage single-phase 3L topologies, with the special focus on 3L-NPC VSI family are reviewed. Several aspects, such as leakage current problem, Shoot-Through (S-T) issue, complexity of modulation methods, component count, etc., are investigated for all topologies and more than 10 comparison tables are provided. Other advantages and disadvantages of topologies are represented as well. Then, discussion and future trends are highlighted. And finally, conclusion is represented. [ABSTRACT FROM AUTHOR]

Retigabine (RTG) is a first-in-class antiepileptic drug that suppresses neuronal excitability through the activation of voltage-gated KCNQ2-5 potassium channels. Retigabine binds to the pore-forming domain, causing a hyperpolarizing shift in the voltage dependence of channel activation. To elucidate how the retigabine binding site is coupled to changes in voltage sensing, we used voltage-clamp fluorometry to track conformational changes of the KCNQ3 voltage-sensing domains (VSDs) in response to voltage, retigabine, and PIP2. Steady-state ionic conductance and voltage sensor fluorescence closely overlap under basal PIP2 conditions. Retigabine stabilizes the conducting conformation of the pore and the activated voltage sensor conformation, leading to dramatic deceleration of current and fluorescence deactivation, but these effects are attenuated upon disruption of channel:PIP2 interactions. These findings reveal an important role for PIP2 in coupling retigabine binding to altered VSD function. We identify a polybasic motif in the proximal C terminus of retigabine-sensitive KCNQ channels that contributes to VSD-pore coupling via PIP2, and thereby influences the unique gating effects of retigabine. [ABSTRACT FROM AUTHOR]

This paper presents the design and implementation of the 60-Hz ferroresonant transformer (FRT) for the light emitting diode (LED) street lamp to achieve high-frequency (HF) noise attenuation and ac-line voltage clamping. The HF transformer (HFT) used in the LED driver system for the outdoor LED street lamps cannot effectively suppress the surge current to avoid damage to the LED street lamp. However, instead of the HFT, the low-frequency transformer (LFT) can be applied to protect the LED street lamps from the surge current. The LFT has a higher turns number, which provides larger leakage inductances and parasitic capacitances that effectively suppress and shunt the surge current. With the magnetic shunt, a 60-Hz FRT is proposed to effectively regulate the ac-line voltage to not overstress the LED street lamp systems as compared with the conventional LFT. When the ac-line voltage is higher than the rated voltage, the additional magnetic flux generated from the primary-side winding flows through the magnetic shunt but not the secondary-side winding. The rated output voltage of the secondary side can be sustained to achieve ac-line voltage clamping. A prototype of the LED street lamp with a 60-Hz FRT has been designed and implemented to verify the feasibility of the HF noise attenuation and ac-line voltage clamping. [ABSTRACT FROM PUBLISHER]

This paper presents two hybrid six-phase machine drive systems. The topologies are considered to be hybrid because two three-phase groups of the machine are fed by different types of converters. The purpose of these topologies is to be alternative configurations, being midway between the conventional six-leg two-level (2L) inverter, composed of 12 switches, and more complex structures, such as the six-leg three-level neutral point clamped (3L-NPC) inverter, composed of 24 switches and 12 clamping diodes, or the conventional 12-leg dual inverter, composed of 24 switches. One of the hybrid topologies is composed of 18 switches and the other is composed of 18 switches and 6 clamping diodes. A comparative study of harmonic distortion, semiconductor losses, and machine torque ripple is performed. Compared with the conventional 2L inverter, the proposed systems provide better performance in terms of harmonic distortion, overall semiconductor losses, and machine torque ripple and are less complex than dual and NPC inverters. Pulse width modulation (PWM) strategy is discussed and simulated. A modification in PWM strategy of the hybrid configurations is performed in order to obtain similar torque ripple to the cases when dual and 3L-NPC converters are used, even with lower number of semiconductor devices. Experimental results are also presented in order to validate the PWM strategy. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to study a high-performance control scheme for neutral-point-clamping three-level (NPC-3L) inverter fed dual three-phase permanent magnet synchronous motor (PMSM) drives by considering some asymmetric factors such as the non-identical parameters in phase windings. To implement this, the system model is analyzed for dual three-phase PMSM drives with asymmetric factors based on the vector space decomposition (VSD) principle. Based on the equivalent circuits, PI controllers with feedforward compensation are used in the d-q subspace for regulating torque, where the cut-off frequency of the PI controllers are set at the twice the fundamental frequency for compensating both the additional DC component and the second order component caused by asymmetry. Meanwhile, proportional resonant (PR) controllers are proposed in the x-y subspace for suppressing the possible unbalanced currents in the phase windings. A dual three-phase space vector modulation (DT-SVM) is designed for the drive, and the balancing factor is designed based on the numerical fitting surface for balancing the DC link capacitor voltages. Experimental results are given to demonstrate the validity of the theoretical analysis and the proposed control scheme. [ABSTRACT FROM AUTHOR]

The molecular receptive range (MRR) of a mammalian odorant receptor (OR) is the set of odorant structures that activate the OR, while the distribution of these odorant structures across odor space is the tuning breadth of the OR. Variation in tuning breadth is thought to be an important property of ORs, with the MRRs of these receptors varying from narrowly to broadly tuned. However, defining the tuning breadth of an OR is a technical challenge. For practical reasons, a screening panel that broadly covers odor space must be limited to sparse coverage of the many potential structures in that space. When screened with such a panel, ORs with different odorant specificities, but equal tuning breadths, might appear to have different tuning breadths due to chance. We hypothesized that ORs would maintain their tuning breadths across distinct odorant panels. We constructed a new screening panel that was broadly distributed across an estimated odor space and contained compounds distinct from previous panels. We used this new screening panel to test several murine ORs that were previously characterized as having different tuning breadths. ORs were expressed in Xenopus laevis oocytes and assayed by two-electrode voltage clamp electrophysiology. MOR256-17, an OR previously characterized as broadly tuned, responded to nine novel compounds from our new screening panel that were structurally diverse and broadly dispersed across an estimated odor space. MOR256-22, an OR previously characterized as narrowly tuned, responded to a single novel compound that was structurally similar to a previously known ligand for this receptor. MOR174-9, a well-characterized receptor with a narrowly tuned MRR, did not respond to any novel compounds in our new panel. These results support the idea that variation in tuning breadth among these three ORs is not an artifact of the screening protocol, but is an intrinsic property of the receptors. [ABSTRACT FROM AUTHOR]

KCNE β-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the heart, KCNE1 associates with the α-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-to-gate coupling. [ABSTRACT FROM AUTHOR]

The present study investigated the effects of equol on cardiovascular K+ channel currents. The cardiovascular K+ channel currents were determined in HEK 293 cells stably expressing cloned differential cardiovascular K+ channels with conventional whole-cell patch voltage-clamp technique. We found that equol inhibited hKv1.5 (IC50: 15.3 μM), hKv4.3 (IC50: 29.2 μM and 11.9 μM for hKv4.3 peak current and charge area, respectively), IKs (IC50: 24.7 μM) and IhERG (IC50: 31.6 and 56.5 μM for IhERG.tail and IhERG.step, respectively), but not hKir2.1 current, in a concentration-dependent manner. Interestingly, equol increased BKCa current with an EC50 of 0.1 μM. It had no significant effect on guinea pig ventricular action potentials at concentrations of ≤3 μM. These results demonstrate that equol inhibits several cardiac K+ currents at relatively high concentrations, whereas it increases BKCa current at very low concentrations, suggesting that equol is a safe drug candidate for treating patients with cerebral vascular disorders. [ABSTRACT FROM AUTHOR]

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Durability and start-up ability in sub-zero environment are two technical bottlenecks of vehicular polymer electrolyte membrane (PEM) fuel cell systems. With exhaust gas recirculation on the anode and cathode side, the cell voltage at low current density can be reduced, and the membrane can be humidified without external humidifier. They may be helpful to prolong the working lifetime and to promote the start-up ability. This paper presents an experimental study on a PEM fuel cell system with anodic and cathodic recirculation. The system is built up based on a 10 kW fuel cell stack, which consists of 50 cells and has an active area of 261 cm 2 . A cathodic recirculation pump and a hydrogen recirculation pump are utilized on the cathode and anode side, respectively. Key parameters, e.g., stack current, stack voltage, cell voltage, air flow, relative humidity on the cathode side, oxygen concentration at the inlet and outlet of the cathode side, are measured. Results show that: 1) with a cathodic recirculation the system gets good self-humidification effect, which is similar to that with an external humidifier; 2) with a cathodic recirculation and a reduction of fresh air flux, the cell voltage can be obviously reduced; 3) with an anodic recirculation the cell voltage can also be reduced due to a reduction in the hydrogen partial pressure, the relative humidity on the cathode side is a little smaller than the case with only cathode recirculation. It indicates that, for our stack the cathodic recirculation is effective to clamp cell voltage at low current density, and a self-humidification system is possible with cathodic recirculation. Further study will focus on the dynamic model and control of the dual recirculation fuel cell system. [ABSTRACT FROM AUTHOR]

Clamping mechanisms have significant effect on the performance of polymer electrolyte membrane (PEM) fuel cells. In this paper, PEM fuel cell with new clamping mechanism is designed to study the contact pressure distribution over the active area of PEM fuel cell's membrane electrode assembly (MEA). The clamping pressure is pneumatically exerted on the PEM fuel cell assembly. A comparison between the conventional and new clamping mechanism is carried out with simulation, and the numerical results are validated against experimental investigation performed in the fuel cell technology research laboratory. The experimental results are gathered using embedded pressure measurement films in the designed single cell. The results achieved via finite element method are in good agreement with experimental results. It is concluded that the contact pressure distribution of MEA for the new clamping mechanism is more uniform than the conventional one. [ABSTRACT FROM AUTHOR]

Anxiolytics and anticonvulsants generally positively modulate the action of GABA, whereas many convulsants (including the chloride channel blocker picrotoxinin) negatively modulate the action of GABA on GABA A receptors. Like picrotoxinin, bilobalide and ginkgolide B, active constituents of Ginkgo biloba , have been shown to negatively modulate the action of GABA at α 1 β 2 γ 2L GABA A receptors. However, unlike picrotoxinin, bilobalide and ginkgolide B are not known to cause convulsions. We have assessed the action of bilobalide, ginkgolide B and picrotoxinin on a range of GABA A modulators (etomidate, loreclezole, propofol, thiopentone sodium, diazepam, and allopregnanolone), using two-electrode voltage clamp electrophysiology at recombinant α 1 β 2 γ 2L GABA A receptors expressed in Xenopus oocytes. The results indicate that bilobalide and ginkgolide B differ from picrotoxinin in their ability to inhibit the actions of a range of these structurally diverse GABA A positive modulators consistent with these modulators acting on a multiplicity of active sites associated with GABA A receptors. In the presence GABA, ginkgolide B was more potent than bilobalide in inhibiting the GABA-potentiating effect of propofol, equipotent against loreclezole and allopregnanolone, and less potent against etomidate, diazepam, and thiopentone sodium. This indicates that in comparison to picrotoxinin, bilobalide and ginkgolide B differ in their effects on the different modulators. [ABSTRACT FROM AUTHOR]