A Massively Parallel Trafficking Assay Accurately Predicts Loss of Channel Function in KCNH2 Variants

High throughput genomics has greatly facilitated identification of genetic variants. However, determining which variants contribute to disease causation is challenging with more than half of all missense variants now classified as variants of uncertain significance (VUS). A VUS leaves patients and their clinicians unable to utilize the variant information in clinical decision-making. In long QT syndrome type 2, KCNH2 channel function is directly associated with disease presentation. Therefore, functional phenotyping of KCNH2 variants can provide direct evidence to aid variant classification. Here, we investigated the expression of all codon variants in exon 2 of KCNH2 using a massively parallel trafficking assay and for a subset of 458 single nucleotide variants compared the results with peak tail current density and gating using automated patch clamp electrophysiology. Trafficking could correctly classify loss of peak tail current density variants with an AUC reaching 0.94 compared to AUCs of 0.75 to 0.8 for in silico variant classifiers. We suggest massively parallel trafficking assays can provide prospective and accurate functional assessment for all missense variants in KCNH2 and most likely many other ion channels and membrane proteins.

Fluctuation of Lower Ionosphere Associated with Energetic Electron Precipitations during a Substorm

In this paper, using the combined observations of the NOAA 16, LANL-01A, IMAGE satellites, VLF radio wave, and ground-based riometers, we study the fluctuation of lower ionosphere-associated precipitating energetic electrons during a geomagnetic storm on 8 November 2004. Associated with the substorm dispersion injection observed by the LANL-01A satellite, the riometers observed obvious enhancements of ionospheric absorption within the electron isotropic zone, which they attributed to the tail current sheet scattering (TCS) mechanism. Through observations of the NOAA 16 satellite, we found a sharp enhancement of the precipitating electron flux within the anisotropic zone, which entailed an obvious separation of energetic electron precipitation at high latitudes. This energetic electron precipitation within the anisotropic zone leads to the significant enhancement of electron density in the D region, thus resulting in the variations of VLF radio wave amplitudes, which propagate in the middle latitudes. Since the projection of the electron precipitation region within the anisotropic zone is at the inner edge of the plasmapause observed by the IMAGE EUV, the precipitation of energetic electrons should be attributed to the ELF hiss-ring current electron interaction. As a result, the energetic electron precipitations due to the tail current sheet scattering mechanism and wave-particle interaction in the inner magnetosphere were both observed and analyzed as they were associated with a substorm during a geomagnetic storm.

Asymmetry in the Earth’s magnetotail neutral sheet rotation due to IMF $$B_y$$ sign?

Evidence suggests that a non-zero dawn–dusk interplanetary magnetic field (IMF $$B_y$$ B y ) can cause a rotation of the cross-tail current sheet/neutral sheet around its axis aligned with the Sun–Earth line in Earth’s magnetotail. We use Geotail, THEMIS and Cluster data to statistically investigate how the rotation of the neutral sheet depends on the sign and magnitude of IMF $$B_y$$ B y . In our dataset, we find that in the tail range of $$-30<$$ - 30 < XGSM $$<-15$$ < - 15 $$R_{\mathrm{E}}$$ R E , the degree of the neutral sheet rotation is clearly smaller, there appears no significant rotation or even, the rotation is clearly to an unexpected direction for negative IMF $$B_y$$ B y , compared to positive IMF $$B_y$$ B y . Comparison to a model by Tsyganenko et al. (2015, doi:10.5194/angeo-33-1-2015) suggests that this asymmetry in the neutral sheet rotation between positive and negative IMF $$B_y$$ B y conditions is too large to be explained only by the currently known factors. The possible cause of the asymmetry remains unclear.

Detecting near-tail current sheet formation using isotropic boundaries: lessons from global MHD.

A number of recent studies suggests an existence of magnetotail current sheet configurations with tailward Bz gradient during the growth phase of the substorm. Such configurations are especially interesting since they are potentially unstable for different types of instabilities and can lead to explosive reconfiguration of the magnetosphere. However, the observations are rare and ability to observe tailward gradients is very limited. Here we use the global MHD configuration with near-tail Bz minimum to investigate the regions with adiabatic and non-adiabatic behavior of energetic particles. Thus we estimate the locations of the isotropic boundaries for the modelled POES-type spacecraft flybys. We expect that the lessons learned from global MHD simulation may become helpful in exploration of non-monotonic tail current sheet configuration using observations on low-orbiting spacecraft.

High-Speed Rail-to-Rail Class-AB Buffer Amplifier with Compact, Adaptive Biasing for FPD Applications

A high-slew-rate, low-power, CMOS, rail-to-rail buffer amplifier for large flat-panel-display (FPD) applications is proposed. The major circuit of the output buffer is a rail-to-rail, folded-cascode, class-AB amplifier which can control the tail current source using a compact, novel, adaptive biasing scheme. The proposed output buffer amplifier enhances the slew rate throughout the entire rail-to-rail input signal range. To obtain a high slew rate and low power consumption without increasing the static current, the tail current source of the adaptive biasing generates extra current during the transition time of the output buffer amplifier. A column driver IC incorporating the proposed buffer amplifier was fabricated in a 1.6-μm 18-V CMOS technology, whose evaluation results indicated that the static current was reduced by up to 39.2% when providing an identical settling time. The proposed amplifier also achieved up to 49.1% (90% falling) and 19.9 % (99.9% falling) improvements in terms of settling time for almost the same static current drawn and active area occupied.

Exchange protein directly activated by cAMP (Epac) mediates cardiac repolarization and arrhythmogenesis during chronic heart failure

Most sudden cardiac death in chronic heart failure (CHF) is caused by malignant ventricular arrhythmia (VA). However, the molecular mechanism remains unclear. This study aims to explore the effect of exchange proteins directly activated by cAMP (Epac) on VA in CHF and the potential molecular mechanism. Transaortic constriction was performed to prepare CHF guinea pigs. Epac activation model was obtained with 8-pCPT administration. Programmed electrical stimulation (PES) was performed to detect effective refractory period (ERP) or induce VA. Isolated adult cardiomyocytes were treated with 8-pCPT and/or the Epac inhibitor. Cellular electrophysiology was examined by whole-cell patch clamp. With Epac activation, corrected QT duration (QTc) was lengthened by 12.6%. 8-pCPT increased action potential duration (APD) (APD50: 236.9±18.07ms vs. 328.8±11.27ms, p<0.05; APD90: 264.6±18.22ms vs. 388.6±6.47ms, p<0.05) and decreased IKr current (tail current density: 1.1±0.08pA/pF vs. 0.7±0.03pA/pF, p<0.05). PES induced more malignant arrhythmias in the 8-pCPT group than in the control group (3/4 vs. 0/8, p<0.05). The selective Epac1 inhibitor CE3F4 rescued the drop in IKr after 8-pCPT stimulation (tail current density: 0.5 ± 0.02pA/pF vs. 0.6 ± 0.03pA/pF, p<0.05). In conclusion, Epac1 regulates IKr, APD and ERP in guinea pigs, which could contribute to the proarrhythmic effect of Epac1 in CHF.