Persistent Current Research Articles

Induced Pluripotent Stem Cell-Derived Cardiomyocytes with SCN5A R1623Q Mutation Associated with Severe Long QT Syndrome in Fetuses and Neonates Recapitulates Pathophysiological Phenotypes.

Simple SummaryIn this study, the induced pluripotent stem cell-derived cardiomyocyte model from a patient with long QT syndrome harboring a heterozygous Nav1.5 R1623Q mutation exhibited prolonged field potential duration corrected by Fridericia’s formula (FPDcF, analogous to QTcF). FPDcF was shortened with mexiletine treatment and increased the frequency of arrhythmia-like EAD events following E4031, an Ikr blocker, administration. These characteristics partly reflect the patient phenotypes. As the R1623Q mutation is related to severe congenital LQT syndrome in fetuses and neonates, the effect of the neonatal variants on the electrophysiological properties of the R1623Q mutant was examined using an automated patch-clamp system. Our results demonstrated that both R1623Q and neonatal R1623Q delayed inactivation of INa and increased late Na current. We speculated that neonatal Nav1.5 ameliorates QTc prolongation. Developmental switching of neonatal/adult Nav1.5 isoforms might play a role in the mechanisms underlying severe long QT syndrome in fetuses and neonates.The SCN5A R1623Q mutation is one of the most common genetic variants associated with severe congenital long QT syndrome 3 (LQT3) in fetal and neonatal patients. To investigate the properties of the R1623Q mutation, we established an induced pluripotent stem cell (iPSC) cardiomyocyte (CM) model from a patient with LQTS harboring a heterozygous R1623Q mutation. The properties and pharmacological responses of iPSC-CMs were characterized using a multi-electrode array system. The biophysical characteristic analysis revealed that R1623Q increased open probability and persistent currents of sodium channel, indicating a gain-of-function mutation. In the pharmacological study, mexiletine shortened FPDcF in R1623Q-iPSC-CMs, which exhibited prolonged field potential duration corrected by Fridericia’s formula (FPDcF, analogous to QTcF). Meanwhile, E4031, a specific inhibitor of human ether-a-go-go-related gene (hERG) channel, significantly increased the frequency of arrhythmia-like early after depolarization (EAD) events. These characteristics partly reflect the patient phenotypes. To further analyze the effect of neonatal isoform, which is predominantly expressed in the fetal period, on the R1623Q mutant properties, we transfected adult form and neonatal isoform SCN5A of control and R1623Q mutant SCN5A genes to 293T cells. Whole-cell automated patch-clamp recordings revealed that R1623Q increased persistent Na+ currents, indicating a gain-of-function mutation. Our findings demonstrate the utility of LQT3-associated R1623Q mutation-harboring iPSC-CMs for assessing pharmacological responses to therapeutic drugs and improving treatment efficacy. Furthermore, developmental switching of neonatal/adult Nav1.5 isoforms may be involved in the pathological mechanisms underlying severe long QT syndrome in fetuses and neonates.

Stochastic Hopf bifurcations in vacuum optical tweezers

The forces acting on an isotropic microsphere in optical tweezers are effectively conservative. However, reductions in the symmetry of the particle or trapping field can break this condition. Here we theoretically analyze the motion of a particle in a linearly nonconservative optical vacuum trap, concentrating on the case where symmetry is broken by optical birefringence, causing nonconservative coupling between rotational and translational degrees of freedom. Neglecting thermal fluctuations, we first show that the underlying deterministic motion can exhibit a Hopf bifurcation in which the trapping point destabilizes and limit cycles emerge whose amplitude grows with decreasing viscosity. When fluctuations are included, the bifurcation of the underlying deterministic system is expressed as a transition in the statistical description of the motion. For high viscosities, the probability distribution is normal, with a kurtosis of three, and persistent probability currents swirl around the stable trapping point. As the bifurcation is approached, the distribution and currents spread out in phase space. Following the bifurcation, the probability distribution function hollows out, reflecting the underlying limit cycle, and the kurtosis halves abruptly. The system is seen to be a noisy self-sustained oscillator featuring a highly uneven limit cycle. A variety of applications, from autonomous stochastic resonance to synchronization, is discussed.

Persistent sodium currents in SCN1A developmental and degenerative epileptic dyskinetic encephalopathy.

Pathogenic variants in the voltage-gated sodium channel gene (SCN1A) are amongst the most common genetic causes of childhood epilepsies. There is considerable heterogeneity in both the types of causative variants and associated phenotypes; a recent expansion of the phenotypic spectrum of SCN1A associated epilepsies now includes an early onset severe developmental and epileptic encephalopathy with regression and a hyperkinetic movement disorder. Herein, we report a female with a developmental and degenerative epileptic-dyskinetic encephalopathy, distinct and more severe than classic Dravet syndrome. Clinical diagnostics indicated a paternally inherited c.5053G>T; p. A1685S variant of uncertain significance in SCN1A. Whole-exome sequencing detected a second de novo mosaic (18%) c.2345G>A; p. T782I likely pathogenic variant in SCN1A (maternal allele). Biophysical characterization of both mutant channels in a heterologous expression system identified gain-of-function effects in both, with a milder shift in fast inactivation of the p. A1685S channels; and a more severe persistent sodium current in the p. T782I. Using computational models, we show that large persistent sodium currents induce hyper-excitability in individual cortical neurons, thus relating the severe phenotype to the empirically quantified sodium channel dysfunction. These findings further broaden the phenotypic spectrum of SCN1A associated epilepsies and highlight the importance of testing for mosaicism in epileptic encephalopathies. Detailed biophysical evaluation and computational modelling further highlight the role of gain-of-function variants in the pathophysiology of the most severe phenotypes associated with SCN1A.

Estimates of persistent inward currents are reduced in upper limb motor units of older adults.

Ageing is a natural process causing alterations in the neuromuscular system, which contributes to reduced quality of life. Motor unit (MU) contributes to weakness, but the mechanisms underlying reduced firing rates are unclear. Persistent inward currents (PICs) are crucial for initiation, gain control and maintenance of motoneuron firing, and are directly proportional to the level of monoaminergic input. Since concentrations of monoamines (i.e. serotonin and noradrenaline) are reduced with age, we sought to determine if estimates of PICs are reduced in older (>60years old) compared to younger adults (<35years old). We decomposed MU spike trains from high-density surface electromyography over the biceps and triceps brachii during isometric ramp contractions to 20% of maximum. Estimates of PICs (ΔFrequency; or simply ΔF) were computed using the paired MU analysis technique. Regardless of the muscle, peak firing rates of older adults were reduced by ∼1.6 pulses per second (pps) (P=0.0292), and ΔF was reduced by ∼1.9pps (P<0.0001), compared to younger adults. We further found that age predicted ΔF in older adults (P=0.0261), resulting in a reduction of ∼1pps per decade, but there was no relationship in younger adults (P=0.9637). These findings suggest that PICs are reduced in the upper limbs of older adults during submaximal isometric contractions. Reduced PIC magnitude represents one plausible mechanism for reduced firing rates and function in older individuals, but further work is required to understand the implications in other muscles and during a variety of motor tasks. KEY POINTS: Persistent inward currents play an important role in the neural control of human movement and are influenced by neuromodulation via monoamines originating in the brainstem. During ageing, motor unit firing rates are reduced, and there is deterioration of brainstem nuclei, which may reduce persistent inward currents in alpha motoneurons. Here we show that estimates of persistent inward currents (ΔF) of both elbow flexor and extensor motor units are reduced in older adults. Estimates of persistent inward currents have a negative relationship with age in the older adults, but not in the young. This novel mechanism may play a role in the alteration of motor firing rates that occurs with ageing, which may have consequences for motor control.

A Novel Treatment of the Josephson Effect

A new picture of the Josephson effect is devised. The radio-frequency (RF) signal, observed in a Josephson junction, is shown to stem from bound electrons, tunneling periodically through the insulating film. This holds also for the microwave mediated tunneling. The Josephson effect is found to be conditioned by the same prerequisite worked out previously for persistent currents, thermal equilibrium and occurence of superconductivity. The observed negative resistance behaviour is shown to originate from the interplay between normal and superconducting currents.

The effect of lamotrigine and other antiepileptic drugs on respiratory rhythm generation in the pre-Bötzinger complex.

Lamotrigine and other sodium-channel blocking agents are among the most commonly used antiepileptic drugs (AEDs). Because other sodium channel blockers, such as riluzole, can severely alter respiratory rhythm generation during hypoxia, we wanted to investigate if AEDs can have similar effects. This is especially important in the context of sudden unexpected death in epilepsy (SUDEP), the major cause of death in patients suffering from therapy-resistant epilepsy. Although the mechanism of action is not entirely understood, respiratory dysfunction after generalized tonic-clonic seizures seems to play a major role. We used transverse brainstem slice preparations from neonatal and juvenile mice containing the pre-Bötzinger complex (PreBötC) and measured population as well as intracellular activity of the rhythm-generating network under normoxia and hypoxia in the presence or absence of AEDs. We found a substantial inhibition of the gasping response induced by the application of sodium channel blockers (lamotrigine and carbamazepine). In contrast, levetiracetam, an AED-modulating synaptic function, had a much smaller effect. The inhibition of gasping by lamotrigine was accompanied by a significant reduction of the persistent sodium current (INap) in PreBötC neurons. Surprisingly, the suppression of persistent sodium currents by lamotrigine did not affect the voltage-dependent bursting activity in PreBötC pacemaker neurons, but led to a hypoxia-dependent shift of the action potential rheobase in all measured PreBötC neurons. Our results contribute to the understanding of the effects of AEDs on the vital respiratory functions of the central nervous system. Moreover, our study adds further insight into sodium-dependent changes occurring during hypoxia and the contribution of cellular properties to the respiratory rhythm generation in the pre-Bötzinger complex. It raises the question of whether sodium channel blocking AEDs could, in conditions of extreme hypoxia, contribute to SUDEP, an important issue that warrants further studies.

Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy.

SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A, which encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general.SIGNIFICANCE STATEMENTSCN8A epileptic encephalopathy is a devastating neurological disorder that results from de novo mutations in the sodium channel isoform Nav1.6. Inhibitory neurons express NaV1.6, yet their contribution to seizure generation in SCN8A epileptic encephalopathy has not been determined. We show that mice expressing a human-derived SCN8A variant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that SCN8A mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure because of depolarization block. Furthermore, chemogenetic activation of WT SST interneurons leads to audiogenic seizure activity. These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in SCN8A epileptic encephalopathy, but for epilepsy broadly.

Probing the BCS-BEC crossover with persistent currents

We study the persistent currents of an attractive Fermi gas confined in a tightly-confining ring trap and subjected to an artificial gauge field all through the BCS-BEC crossover. At weak attractions, on the BCS side, fermions display a parity effect in the persistent currents, ie their response to the gauge field is paramagnetic or diamagnetic depending on the number of pairs on the ring. At resonance and on the BEC side of the crossover we find a doubling of the periodicity of the ground-state energy as a function of the artificial gauge field and disappearance of the parity effect, indicating that persistent currents can be used to infer the formation of tightly-bound bosonic pairs. Our predictions can be accessed in ultracold atoms experiments through noise interferograms.

Decoherence effects break reciprocity in matter transport

The decoherence of quantum states defines the transition between the quantum world and classical physics. Decoherence or, analogously, quantum mechanical collapse events pose fundamental questions regarding the interpretation of quantum mechanics and are technologically relevant because they limit the coherent information processing performed by quantum computers. We have discovered that the transition regime enables a novel type of matter transport. Applying this discovery, we present nanoscale devices in which decoherence, modeled by random quantum jumps, produces fundamentally novel phenomena by interrupting the unitary dynamics of electron wave packets. Noncentrosymmetric conductors with mesoscopic length scales act as two-terminal rectifiers with unique properties. In these devices, the inelastic interaction of itinerant electrons with impurities acting as electron trapping centers leads to a novel steady state characterized by partial charge separation between the two leads, or, in closed circuits to the generation of persistent currents. The interface between the quantum and the classical worlds therefore provides a novel transport regime of value for the realization of a new category of mesoscopic electronic devices.

Cavity Optomechanical Sensing and Manipulation of an Atomic Persistent Current.

This theoretical work initiates contact between two frontier disciplines of physics, namely, atomic superfluid rotation and cavity optomechanics. It considers an annular Bose-Einstein condensate, which exhibits dissipationless flow and is a paradigm of rotational quantum physics, inside a cavity excited by optical fields carrying orbital angular momentum. It provides the first platform that can sense ring Bose-Einstein condensate rotation with minimal destruction, insitu and in real time, unlike demonstrated techniques, all of which involve fully destructive measurement. It also shows how light can actively manipulate rotating matter waves by optomechanically entangling persistent currents. Our work opens up a novel and useful direction in the sensing and manipulation of atomic superflow.

Electronic States and Persistent Currents in Rings with Inhomogeneous Rashba Spin–Orbit Coupling

Electronic States and Persistent Currents in Rings with Inhomogeneous Rashba Spin–Orbit Coupling

On the effects of rotation and spiral dislocation topology on the persistent currents and quantum revivals in a cylindrical wire

On the effects of rotation and spiral dislocation topology on the persistent currents and quantum revivals in a cylindrical wire

Preliminary demonstration of a persistent Josephson phase-slip memory cell with topological protection

Superconducting computing promises enhanced computational power in both classical and quantum approaches. Yet, scalable and fast superconducting memories are not implemented. Here, we propose a fully superconducting memory cell based on the hysteretic phase-slip transition existing in long aluminum nanowire Josephson junctions. Embraced by a superconducting ring, the memory cell codifies the logic state in the direction of the circulating persistent current, as commonly defined in flux-based superconducting memories. But, unlike the latter, the hysteresis here is a consequence of the phase-slip occurring in the long weak link and associated to the topological transition of its superconducting gap. This disentangles our memory scheme from the large-inductance constraint, thus enabling its miniaturization. Moreover, the strong activation energy for phase-slip nucleation provides a robust topological protection against stochastic phase-slips and magnetic-flux noise. These properties make the Josephson phase-slip memory a promising solution for advanced superconducting classical logic architectures or flux qubits.

Roadmap on Atomtronics: State of the art and perspective

Atomtronics deals with matter-wave circuits of ultracold atoms manipulated through magnetic or laser-generated guides with different shapes and intensities. In this way, new types of quantum networks can be constructed in which coherent fluids are controlled with the know-how developed in the atomic and molecular physics community. In particular, quantum devices with enhanced precision, control, and flexibility of their operating conditions can be accessed. Concomitantly, new quantum simulators and emulators harnessing on the coherent current flows can also be developed. Here, the authors survey the landscape of atomtronics-enabled quantum technology and draw a roadmap for the field in the near future. The authors review some of the latest progress achieved in matter-wave circuits' design and atom-chips. Atomtronic networks are deployed as promising platforms for probing many-body physics with a new angle and a new twist. The latter can be done at the level of both equilibrium and nonequilibrium situations. Numerous relevant problems in mesoscopic physics, such as persistent currents and quantum transport in circuits of fermionic or bosonic atoms, are studied through a new lens. The authors summarize some of the atomtronics quantum devices and sensors. Finally, the authors discuss alkali-earth and Rydberg atoms as potential platforms for the realization of atomtronic circuits with special features.

High-temperature superconducting screens for magnetic field-error cancellation in accelerator magnets

Accelerators magnets must have minimal magnetic field imperfections to reduce particle-beam instabilities. In the case of coils made of high-temperature superconducting (HTS) tapes, the magnetization due to persistent currents adds an undesired field contribution, potentially degrading the magnetic field quality. In this paper we study the use of superconducting screens based on HTS tapes for reducing the magnetic field imperfections in accelerator magnets. The screens exploit the magnetization by persistent currents to cancel out the magnetic field error. The screens are aligned with the main field component, such that only the undesired field components are compensated. The screens are self-regulating, and do not require any externally applied source of energy. Measurements in liquid nitrogen at show for dipole-field configurations a significant reduction of the magnetic field error up to a factor of four. The residual error is explained via numerical simulations accounting for the geometric defects in the HTS screens, achieving satisfactory agreement with experimental results. Simulations show that if screens are increased in width and thickness, and operated at , field errors may be eliminated almost entirely for the typical excitation cycles of accelerator magnets.

How Aromatic Are Molecular Nanorings? The Case of a Six-Porphyrin Nanoring*.

Large conjugated rings with persistent currents are novel promising structures in molecular‐scale electronics. A six‐porphyrin nanoring structure that allegedly sustained an aromatic ring current involving 78π electrons was recently synthesized. We provide here compelling evidence that this molecule is not aromatic, contrary to what was inferred from the analysis of 1H‐NMR data and computational calculations that suffer from large delocalization errors. The main reason behind the absence of an aromatic ring current in these nanorings is the low delocalization in the transition from the porphyrins to the bridging butadiyne linkers, which disrupts the overall conjugated circuit. These results highlight the importance of choosing a suitable computational method to study large conjugated molecules and the appropriate aromaticity descriptors to identify the part of the molecule responsible for the loss of aromaticity.

How Aromatic Are Molecular Nanorings? The Case of a Six‐Porphyrin Nanoring**

AbstractLarge conjugated rings with persistent currents are novel promising structures in molecular‐scale electronics. A six‐porphyrin nanoring structure that allegedly sustained an aromatic ring current involving 78π electrons was recently synthesized. We provide here compelling evidence that this molecule is not aromatic, contrary to what was inferred from the analysis of 1H‐NMR data and computational calculations that suffer from large delocalization errors. The main reason behind the absence of an aromatic ring current in these nanorings is the low delocalization in the transition from the porphyrins to the bridging butadiyne linkers, which disrupts the overall conjugated circuit. These results highlight the importance of choosing a suitable computational method to study large conjugated molecules and the appropriate aromaticity descriptors to identify the part of the molecule responsible for the loss of aromaticity.

The insecticide deltamethrin enhances sodium channel slow inactivation of human Nav1.9, Nav1.8 and Nav1.7

The insecticide deltamethrin of the pyrethroid class mainly targets voltage-gated sodium channels (Navs). Deltamethrin prolongs the opening of Navs by slowing down fast inactivation and deactivation. Pyrethroids are supposedly safe for humans, however, they have also been linked to the gulf-war syndrome, a neuropathic pain condition that can develop following exposure to certain chemicals. Inherited neuropathic pain conditions have been linked to mutations in the Nav subtypes Nav1.7, Nav1.8, and Nav1.9. Here, we examined the effect of deltamethrin on the human isoforms Nav1.7, Nav1.8, and Nav1.9_C4 (chimera containing the C-terminus of rat Nav1.4) heterologously expressed in HEK293T and ND7/23 cells using whole-cell patch-clamp electrophysiology. For all three Nav subtypes, we observed increased persistent and tail currents that are typical for Nav channels modified by deltamethrin. The most surprising finding was an enhanced slow inactivation induced by deltamethrin in all three Nav subtypes. An enhanced slow inactivation is contrary to the prolonged opening caused by pyrethroids and has not been described for deltamethrin or any other pyrethroid before. Furthermore, we found that the fraction of deltamethrin-modified channels increased use-dependently. However, for Nav1.8, the use-dependent potentiation occurred only when the holding potential was increased to −90 mV, a potential at which the tail currents decay more slowly. This indicates that use-dependent modification is due to an accumulation of tail currents. In summary, our findings support a novel mechanism whereby deltamethrin enhances slow inactivation of voltage-gated sodium channels, which may, depending on the cellular resting membrane potential, reduce neuronal excitability and counteract the well-described pyrethroid effects of prolonging channel opening.

Genesis and fading away of persistent currents in a Corbino disk geometry

The detailed analytical and numerical analysis of the electron spectrum, persistent currents, and their densities for an annulus placed in a constant magnetic field (Corbino disk geometry) is presented. We calculate the current density profiles and study their dependence on the inner and outer radii of the annular. We study evolution of the persistent currents and track their emergence and decay for different limiting cases of such a geometry, starting from a nanodot and ending by a macroscopic circle. Our analytical results for the currents are confirmed by the agreement between the integration of the corresponding current densities and the application of the Byers-Yang formula, when it is applicable. Among other results we find the general expression for the persistent current in a narrow annulus, which in the one channel approximation reproduces the well-known result for quasi-one dimensional mesoscopic metallic ring. Moreover it allows to analyze the multi-channel case of a relatively wide annulus. Our study can be used for more accurate treatment and interpretation of the experimental data with measurements of the persistent currents in different doubly-connected systems.

From Macrocycles to Quantum Rings: Does Aromaticity Have a Size Limit?

ConspectusThe ring currents of aromatic and antiaromatic molecules are remarkable emergent phenomena. A ring current is a quantum-mechanical feature of the whole system, and its existence cannot be inferred from the properties of the individual components of the ring. Hückel's rule states that when an aromatic molecule with a circuit of [4n + 2] π electrons is placed in a magnetic field, the field induces a ring current that creates a magnetic field opposing the external field inside the ring. In contrast, antiaromatic rings with 4n π electrons exhibit ring currents in the opposite direction. This rule bears the name of Erich Hückel, and it grew from his molecular orbital theory, but modern formulations of Hückel's rule incorporate contributions from others, particularly William Doering and Ronald Breslow. It is often assumed that aromaticity is restricted to small molecular rings with up to about 22 π electrons. This Account outlines the discovery of global ring currents in large macrocycles with circuits of up to 162 π electrons. The largest aromatic rings yet investigated are cyclic porphyrin oligomers, which exhibit global ring currents after oxidation, reduction or optical excitation but not in the neutral ground state. The global aromaticity in these porphyrin nanorings leads to experimentally measurable aromatic stabilization energies in addition to magnetic effects that can be studied by NMR spectroscopy. Wheel-like templates can be bound inside these nanorings, providing excellent control over the molecular geometry and allowing the magnetic shielding to be probed inside the nanoring. The ring currents in these systems are well-reproduced by density functional theory (DFT), although the choice of DFT functional often turns out to be critical. Here we review recent contributions to this field and present a simple method for determining the ring current susceptibility (in nA/T) in any aromatic or antiaromatic ring from experimental NMR data by classical Biot-Savart calculations. We use this method to quantify the ring currents in a variety of aromatic rings. This survey confirms that Hückel's rule reliably predicts the direction of the ring current, and it reveals that the ring current susceptibility is surprisingly insensitive to the size of the ring. The investigation of aromaticity in even larger molecular rings is interesting because ring currents are also observed when mesoscopic metal rings are placed in a magnetic field at low temperatures. The striking similarity between the ring currents in molecules and mesoscopic metal rings arises because the effects have a common origin: a field-dependent phase shift in the electronic wave function. The main difference is that the magnetic flux through mesoscopic rings is much greater because of their larger areas, so their persistent currents are nonlinear and oscillatory with the applied field, whereas the flux through aromatic molecules is so small that their response is approximately linear in the applied field. We discuss how nonlinearity is expected to emerge in large molecular nanorings at high magnetic fields. The insights from this work are fundamentally important for understanding aromaticity and for bridging the gap between chemistry and mesoscopic physics, potentially leading to new functions in molecular electronics.