Caveolin-3 and Caveolae regulate ventricular repolarization.

RATIONALE: Flask-shaped invaginations of the cardiomyocyte sarcolemma called caveolae require the structural protein caveolin-3 (Cav-3) and host a variety of ion channels, transporters, and signaling molecules. Reduced Cav-3 expression has been reported in models of heart failure, and variants in CAV3 have been associated with the inherited long-QT arrhythmia syndrome. Yet, it remains unclear whether alterations in Cav-3 levels alone are sufficient to drive aberrant repolarization and increased arrhythmia risk. OBJECTIVE: To determine the impact of cardiac-specific Cav-3 ablation on the electrophysiological properties of the adult mouse heart. METHODS AND RESULTS: Cardiac-specific, inducible Cav3 homozygous knockout (Cav-3KO) mice demonstrated a marked reduction in Cav-3 expression by Western blot and loss of caveolae by electron microscopy. However, there was no change in macroscopic cardiac structure or contractile function. The QTc interval was increased in Cav-3KO mice, and there was an increased propensity for ventricular arrhythmias. Ventricular myocytes isolated from Cav-3KO mice exhibited a prolonged action potential duration (APD) that was due to reductions in outward potassium currents (Ito, Iss) and changes in inward currents including slowed inactivation of ICa,L and increased INa,L. Mathematical modeling demonstrated that the changes in the studied ionic currents were adequate to explain the prolongation of the mouse ventricular action potential. Results from human iPSC-derived cardiomyocytes showed that shRNA knockdown of Cav-3 similarly prolonged APD. CONCLUSION: We demonstrate that Cav-3 and caveolae regulate cardiac repolarization and arrhythmia risk via the integrated modulation of multiple ionic currents.

Acceptability of Social Robots and Adaptation of Hybrid-Face Robot for Dementia Care in India: A Qualitative Study.

OBJECTIVES: This study aims to understand the acceptability of social robots and the adaptation of the Hybrid-Face Robot for dementia care in India. METHODS: We conducted a focus group discussion and in-depth interviews with persons with dementia (PwD), their caregivers, professionals in the field of dementia, and technical experts in robotics to collect qualitative data. RESULTS: This study explored the following themes: Acceptability of Robots in Dementia Care in India, Adaptation of Hybrid-Face Robot and Future of Robots in Dementia Care. Caregivers and PwD were open to the idea of social robot use in dementia care; caregivers perceived it to help with the challenges of caregiving and positively viewed a future with robots. DISCUSSION: This study is the first of its kind to explore the use of social robots in dementia care in India by highlighting user needs and requirements that determine acceptability and guiding adaptation.

Fusion Models for Generalized Classification of Multi-Axial Human Movement: Validation in Sport Performance.

We introduce a set of input models for fusing information from ensembles of wearable sensors supporting human performance and telemedicine. Veracity is demonstrated in action classification related to sport, specifically strikes in boxing and taekwondo. Four input models, formulated to be compatible with a broad range of classifiers, are introduced and two diverse classifiers, dynamic time warping (DTW) and convolutional neural networks (CNNs) are implemented in conjunction with the input models. Seven classification models fusing information at the input-level, output-level, and a combination of both are formulated. Action classification for 18 boxing punches and 24 taekwondo kicks demonstrate our fusion classifiers outperform the best DTW and CNN uni-axial classifiers. Furthermore, although DTW is ostensibly an ideal choice for human movements experiencing non-linear variations, our results demonstrate deep learning fusion classifiers outperform DTW. This is a novel finding given that CNNs are normally designed for multi-dimensional data and do not specifically compensate for non-linear variations within signal classes. The generalized formulation enables subject-specific movement classification in a feature-blind fashion with trivial computational expense for trained CNNs. A commercial boxing system, 'Corner', has been produced for real-world mass-market use based on this investigation providing a basis for future telemedicine translation.

A Multimodal Intention Detection Sensor Suite for Shared Autonomy of Upper-Limb Robotic Prostheses.

Neurorobotic augmentation (e.g., robotic assist) is now in regular use to support individuals suffering from impaired motor functions. A major unresolved challenge, however, is the excessive cognitive load necessary for the human-machine interface (HMI). Grasp control remains one of the most challenging HMI tasks, demanding simultaneous, agile, and precise control of multiple degrees-of-freedom (DoFs) while following a specific timing pattern in the joint and human-robot task spaces. Most commercially available systems use either an indirect mode-switching configuration or a limited sequential control strategy, limiting activation to one DoF at a time. To address this challenge, we introduce a shared autonomy framework centred around a low-cost multi-modal sensor suite fusing: (a) mechanomyography (MMG) to estimate the intended muscle activation, (b) camera-based visual information for integrated autonomous object recognition, and (c) inertial measurement to enhance intention prediction based on the grasping trajectory. The complete system predicts user intent for grasp based on measured dynamical features during natural motions. A total of 84 motion features were extracted from the sensor suite, and tests were conducted on 10 able-bodied and 1 amputee participants for grasping common household objects with a robotic hand. Real-time grasp classification accuracy using visual and motion features obtained 100%, 82.5%, and 88.9% across all participants for detecting and executing grasping actions for a bottle, lid, and box, respectively. The proposed multimodal sensor suite is a novel approach for predicting different grasp strategies and automating task performance using a commercial upper-limb prosthetic device. The system also shows potential to improve the usability of modern neurorobotic systems due to the intuitive control design.

A Novel Fetal Movement Simulator for the Performance Evaluation of Vibration Sensors for Wearable Fetal Movement Monitors.

Fetal movements (FM) are an important factor in the assessment of fetal health. However, there is currently no reliable way to monitor FM outside clinical environs. While extensive research has been carried out using accelerometer-based systems to monitor FM, the desired accuracy of detection is yet to be achieved. A major challenge has been the difficulty of testing and calibrating sensors at the pre-clinical stage. Little is known about fetal movement features, and clinical trials involving pregnant women can be expensive and ethically stringent. To address these issues, we introduce a novel FM simulator, which can be used to test responses of sensor arrays in a laboratory environment. The design uses a silicon-based membrane with material properties similar to that of a gravid abdomen to mimic the vibrations due to fetal kicks. The simulator incorporates mechanisms to pre-stretch the membrane and to produce kicks similar to that of a fetus. As a case study, we present results from a comparative study of an acoustic sensor, an accelerometer, and a piezoelectric diaphragm as candidate vibration sensors for a wearable FM monitor. We find that the acoustic sensor and the piezoelectric diaphragm are better equipped than the accelerometer to determine durations, intensities, and locations of kicks, as they have a significantly greater response to changes in these conditions than the accelerometer. Additionally, we demonstrate that the acoustic sensor and the piezoelectric diaphragm can detect weaker fetal movements (threshold wall displacements are less than 0.5 mm) compared to the accelerometer (threshold wall displacement is 1.5 mm) with a trade-off of higher power signal artefacts. Finally, we find that the piezoelectric diaphragm produces better signal-to-noise ratios compared to the other two sensors in most of the cases, making it a promising new candidate sensor for wearable FM monitors. We believe that the FM simulator represents a key development towards enabling the eventual translation of wearable FM monitoring garments.

Fusion of Enhanced and Synthetic Vision System Images for Runway and Horizon Detection.

Networked operation of unmanned air vehicles (UAVs) demands fusion of information from disparate sources for accurate flight control. In this investigation, a novel sensor fusion architecture for detecting aircraft runway and horizons as well as enhancing the awareness of surrounding terrain is introduced based on fusion of enhanced vision system (EVS) and synthetic vision system (SVS) images. EVS and SVS image fusion has yet to be implemented in real-world situations due to signal misalignment. We address this through a registration step to align EVS and SVS images. Four fusion rules combining discrete wavelet transform (DWT) sub-bands are formulated, implemented, and evaluated. The resulting procedure is tested on real EVS-SVS image pairs and pairs containing simulated turbulence. Evaluations reveal that runways and horizons can be detected accurately even in poor visibility. Furthermore, it is demonstrated that different aspects of EVS and SVS images can be emphasized by using different DWT fusion rules. The procedure is autonomous throughout landing, irrespective of weather. The fusion architecture developed in this study holds promise for incorporation into manned heads-up displays (HUDs) and UAV remote displays to assist pilots landing aircraft in poor lighting and varying weather. The algorithm also provides a basis for rule selection in other signal fusion applications.

Telehealth, Wearable Sensors, and the Internet: Will They Improve Stroke Outcomes Through Increased Intensity of Therapy, Motivation, and Adherence to Rehabilitation Programs?

BACKGROUND AND PURPOSE: Stroke, predominantly a condition of older age, is a major cause of acquired disability in the global population and puts an increasing burden on health care resources. Clear evidence for the importance of intensity of therapy in optimizing functional outcomes is found in animal models, supported by neuroimaging and behavioral research, and strengthened by recent meta-analyses from multiple clinical trials. However, providing intensive therapy using conventional treatment paradigms is expensive and sometimes not feasible because of social and environmental factors. This article addresses the need for cost-effective increased intensity of practice and suggests potential benefits of telehealth (TH) as an innovative model of care in physical therapy. SUMMARY OF KEY POINTS: We provide an overview of TH and present evidence that a web-supported program, used in conjunction with constraint-induced therapy (CIT), can increase intensity and adherence to a rehabilitation regimen. The design and feasibility testing of this web-based program, "LifeCIT," is presented. We describe how wearable sensors can monitor activity and provide feedback to patients and therapists. The methodology for the development of a wearable device with embedded inertial and mechanomyographic sensors, algorithms to classify functional movement, and a graphical user interface to present meaningful data to patients to support a home exercise program is explained. RECOMMENDATIONS FOR CLINICAL PRACTICE: We propose that wearable sensor technologies and TH programs have the potential to provide most-effective, intensive, home-based stroke rehabilitation.

hERG 1b is critical for human cardiac repolarization.

The human ether-à-go-go-related gene (hERG; or KCNH2) encodes the voltage-gated potassium channel underlying IKr, a repolarizing current in the heart. Mutations in KCNH2 or pharmacological agents that reduce IKr slow action potential (AP) repolarization and can trigger cardiac arrhythmias associated with long QT syndrome. Two channel-forming subunits encoded by KCNH2 (hERG 1a and 1b) are expressed in cardiac tissue. In heterologous expression systems, these subunits avidly coassemble and exhibit biophysical and pharmacological properties distinct from those of homomeric hERG 1a channels. Despite these findings, adoption of hERG 1a/1b heteromeric channels as a model for cardiac IKr has been hampered by the lack of evidence for a direct functional role for the 1b subunit in native tissue. In this study, we measured IKr and APs at physiological temperature in cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs). We found that specific knockdown of the 1b subunit using shRNA caused reductions in 1b mRNA, 1b protein levels, and IKr magnitude by roughly one-half. AP duration was increased and AP variability was enhanced relative to controls. Early afterdepolarizations, considered cellular substrates for arrhythmia, were also observed in cells with reduced 1b expression. Similar behavior was elicited when channels were effectively converted from heteromers to 1a homomers by expressing a fragment corresponding to the 1a-specific N-terminal Per-Arnt-Sim domain, which is omitted from hERG 1b by alternate transcription. These findings establish that hERG 1b is critical for normal repolarization and that loss of 1b is proarrhythmic in human cardiac cells.

IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes.

Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier (IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately -80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger (P < 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs (P < 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. IK1-enhanced iPS-CMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms.

Fetal movements as a predictor of health.

The key determinant to a fetus maintaining its health is through adequate perfusion and oxygen transfer mediated by the functioning placenta. When this equilibrium is distorted, a number of physiological changes, including reduced fetal growth, occur to favor survival. Technologies have been developed to monitor these changes with a view to prolong intrauterine maturity while reducing the risks of stillbirth. Many of these strategies involve complex interpretation, for example Doppler ultrasound for fetal blood flow and computerized analysis of fetal heart rate changes. However, even with these modalities of fetal assessment to determine the optimal timing of delivery, fetal movements remain integral to clinical decision-making. In high-risk cohorts with fetal growth restriction, the manifestation of a reduction in perceived movements may warrant an expedited delivery. Despite this, there has been little evolution in the development of technologies to objectively evaluate fetal movement behavior for clinical application. This review explores the available literature on the value of fetal movement analysis as a method of assessing fetal wellbeing, and demonstrates how interdisciplinary developments in this area may aid in the improvement of clinical outcomes.

Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia.

The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I(K1)), which is important for maintenance of the cell resting membrane potential, and the sodium current (I(Na)), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I(K1) modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation. Additionally, I(K1)-I(Na) interactions are key determinants of electrical rotor frequency responsible for abnormal, often lethal, cardiac reentrant activity. Here, we have used a multidisciplinary approach based on molecular and biochemical techniques, acute gene transfer or silencing, and electrophysiology to show that I(K1)-I(Na) interactions involve a reciprocal modulation of expression of their respective channel proteins (Kir2.1 and Na(V)1.5) within a macromolecular complex. Thus, an increase in functional expression of one channel reciprocally modulates the other to enhance cardiac excitability. The modulation is model-independent; it is demonstrable in myocytes isolated from mouse and rat hearts and with transgenic and adenoviral-mediated overexpression/silencing. We also show that the post synaptic density, discs large, and zonula occludens-1 (PDZ) domain protein SAP97 is a component of this macromolecular complex. We show that the interplay between Na(v)1.5 and Kir2.1 has electrophysiological consequences on the myocardium and that SAP97 may affect the integrity of this complex or the nature of Na(v)1.5-Kir2.1 interactions. The reciprocal modulation between Na(v)1.5 and Kir2.1 and the respective ionic currents should be important in the ability of the heart to undergo self-sustaining cardiac rhythm disturbances.

The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1: physiology and pathology related to long qt syndrome 9 (LQT9).

Mutations in CAV3 cause LQT syndrome 9 (LQT9). A previously reported LQT9 patient had prominent U waves on ECG, a feature that has been correlated with Kir2.1 loss of function. Our objective was to determine whether caveolin 3 (Cav3) associates with Kir2.1 and whether LQT9-associated CAV3 mutations affect the biophysical properties of Kir2.1. Kir2.1 current (IK1) density was measured using the whole-cell voltage clamp technique. WT-Cav3 did not affect IK1. However, F97C-Cav3 and T78M-Cav3 decreased IK1 density significantly by ∼60%, and P104L-Cav3 decreased IK1 density significantly by ∼30% at -60 mV. Immunostained rat heart cryosections and HEK293 cells cotransfected with Kir2.1 and WT-Cav3 both demonstrated colocalization of Kir2.1 and WT-Cav3 by confocal imaging. Cav3 coimmunoprecipitated with Kir2.1 in human ventricular myocytes and in heterologous expression systems. Additionally, FRET efficiency was highly specific, with a molecular distance of 5.6 ± 0.4 nm, indicating close protein location. Colocalization experiments found that Cav3 and Kir2.1 accumulated in the Golgi compartment. On-cell Western blot analysis showed decreased Kir2.1 cell surface expression by 60% when expressed with F97C-Cav3 and by 20% when expressed with P104L-Cav3 compared with WT-Cav3. This is the first report of an association between Cav3 and Kir2.1. The Cav3 mutations F97C-Cav3, P104L-Cav3, and T78M-Cav3 decreased IK1 density significantly. This effect was related to a reduced cell surface expression of Kir2.1. Kir2.1 loss of function is additive to the increase described previously in late INa, prolonging repolarization and leading to arrhythmia generation in Cav3-mediated LQT9.

A unique architecture based on 1 D semiconductor, reduced graphene oxide, and chalcogenide with multifunctional properties.

A unique heterostructured optoelectronic material (HOM), consisting of a reduced graphene oxide (RGO) layer with spatially distributed CdS, suspended by zinc oxide (ZnO) nanorods, is presented. The key features of this HOM are the assembly of the components in a manner so as to realize an effective integration between the constituents and the ability to modify the electronic properties of the RGO. For the first time, the location of RGO (as a suspended layer) along with the tuning of its charge-transport properties (n-/p-type) and its influence on the photo(electro)chemical processes has been examined systematically by using this ZnO/RGO/CdS HOM as a case study. The n-type RGO interlayer facilitates >100 % increase in the photocurrent density and 25 % increase in the photodegradation of a dye, compared to ZnO/CdS, thus demonstrating its multifunctionality. At 3.2 mA cm(-2) , this HOM architecture helps to achieve the highest photocurrent density utilizing ZnO, RGO, and CdS as building blocks in any form. The work is significant for the following reasons: i) other one dimensional (1D) oxides/chalcogenides or 1D oxides/dyes may be designed with similar architectures; ii) HOMs with tunable optical absorbance and charge-transport properties could be realized; iii) related application areas (e.g., sensing or solar fuel generation) should be greatly benefited.

Role of reduced graphene oxide in the critical components of a CdS-sensitized TiO2 -based photoelectrochemical cell.

Nitrogen (N)-doped reduced graphene oxide (nRGO) is systematically incorporated into a TiO(2) -CdS photoelectrochemical (PEC) cell and its role is examined in the three main components of the cell: 1) the CdS-sensitized TiO(2) photoanode, 2) the cathode, and 3) the S(2-)/S(.-) aqueous redox electrolyte. The nRGO layer is sandwiched between TiO(2) nanorods (deposited by using a solvothermal method) and CdS (deposited by using the successive ionic-layer-adsorption and -reaction method). Scanning electron microscopy with energy dispersive X-ray analysis (EDS) reveals the spatial distribution of CdS and nRGO, whereas nRGO formation is evident from Mott Schottky analysis. Chronoamperometry and PEC analysis indicate that upon incorporation of nRGO, a photocurrent density that is at least 27 times higher than that of pristine TiO(2) is achieved; this increase is attributable to the ability of the nRGO to efficiently separate and transport charges. Stability analysis performed by continuous photoillumination over ∼3 h indicates a 26% and 42 % reduction in the photocurrent in the presence and absence of the nRGO respectively. Formation of SO(4)(2-) is identified as the cause for this photocurrent reduction by using X-ray photoelectron spectroscopy. It is also shown that nRGO-coated glass is as effective as a Pt counter electrode in the PEC cell. Unlike the benefits offered by nRGO at the anode and cathode, introducing it in the redox electrolyte is detrimental. Systematic and complementary electrolyte and film-based studies on this aspect reveal evidence of the capacitive behavior of nRGO. Competition between the nRGO and the oxidized electrolyte is identified, based on linear-sweep voltammetry analysis, as the limiting step to efficient charge transport in the electrolyte.

Mn-modified Bi2Ti2O7 photocatalysts: bandgap engineered multifunctional photocatalysts for hydrogen generation.

In this study, a hydrogen generation photocatalyst based on bismuth titanate (Bi2Ti2O7 - BTO) modified with manganese (Mn) has been developed. Mn of varying weight percent was added to construct a modified BTO catalyst (Mn_BTO), in order to enhance the opto-electronic and photocatalytic hydrogen generation capabilities of the pristine BTO. The structural, morphological, and optical properties of the photocatalysts were evaluated by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and UV-visible spectrophotometry. The XRD, SEM, and TEM analyses indicate the formation of the pyrochlore BTO phase with particles of dimensions 30 ± 10 nm. The UV-visible study revealed a reduction in the bandgap of Mn_BTO and enhanced absorption in the visible range, compared to the pristine BTO. The catalyst was optimized for maximum hydrogen generation from a water-methanol (sacrificial electron donor) system in a slurry reactor. The photocatalytic hydrogen evolution studies indicate that the Mn_BTO with up to 1 wt% Mn facilitates an optimal 140% increase in the hydrogen yield. The role of formic acid and formaldehyde as additives in photocatalytic hydrogen evolution has also been examined. The effect of Mn content, mechanistic overview, and reusability of the catalyst are discussed.

Digital remote monitoring for screening and early detection of urinary tract infections.

Urinary Tract Infections (UTIs) are one of the most prevalent bacterial infections in older adults and a significant contributor to unplanned hospital admissions in People Living with Dementia (PLWD), with early detection being crucial due to the predicament of reporting symptoms and limited help-seeking behaviour. The most common diagnostic tool is urine sample analysis, which can be time-consuming and is only employed where UTI clinical suspicion exists. In this method development and proof-of-concept study, participants living with dementia were monitored via low-cost devices in the home that passively measure activity, sleep, and nocturnal physiology. Using 27828 person-days of remote monitoring data (from 117 participants), we engineered features representing symptoms used for diagnosing a UTI. We then evaluate explainable machine learning techniques in passively calculating UTI risk and perform stratification on scores to support clinical translation and allow control over the balance between alert rate and sensitivity and specificity. The proposed UTI algorithm achieves a sensitivity of 65.3% (95% Confidence Interval (CI) = 64.3-66.2) and specificity of 70.9% (68.6-73.1) when predicting UTIs on unseen participants and after risk stratification, a sensitivity of 74.7% (67.9-81.5) and specificity of 87.9% (85.0-90.9). In addition, feature importance methods reveal that the largest contributions to the predictions were bathroom visit statistics, night-time respiratory rate, and the number of previous UTI events, aligning with the literature. Our machine learning method alerts clinicians of UTI risk in subjects, enabling earlier detection and enhanced screening when considering treatment.

Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes.

Advances in hiPSC isolation and reprogramming and hPSC-CM differentiation have prompted their therapeutic application and utilization for evaluating potential cardiovascular safety liabilities. In this perspective, we showcase key efforts toward the large-scale production of hiPSC-CMs, implementation of hiPSC-CMs in industry settings, and recent clinical applications of this technology. The key observations are a need for traceable gender and ethnically diverse hiPSC lines, approaches to reduce cost of scale-up, accessible clinical trial datasets, and transparent guidelines surrounding the safety and efficacy of hiPSC-based therapies.

Channelopathies from mutations in the cardiac sodium channel protein complex.

The cardiac sodium current underlies excitability in heart, and inherited abnormalities of the proteins regulating and conducting this current cause inherited arrhythmia syndromes. This review focuses on inherited mutations in non-pore forming proteins of sodium channel complexes that cause cardiac arrhythmia, and the deduced mechanisms by which they affect function and dysfunction of the cardiac sodium current. Defining the structure and function of these complexes and how they are regulated will contribute to understanding the possible roles for this complex in normal and abnormal physiology and homeostasis. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Caveolin-3 suppresses late sodium current by inhibiting nNOS-dependent S-nitrosylation of SCN5A.

AIMS: Mutations in CAV3-encoding caveolin-3 (Cav3) have been implicated in type 9 long QT syndrome (LQT9) and sudden infant death syndrome (SIDS). When co-expressed with SCN5A-encoded cardiac sodium channels these mutations increased late sodium current (INa) but the mechanism was unclear. The present study was designed to address the mechanism by which the LQT9-causing mutant Cav3-F97C affects the function of caveolar SCN5A. METHODS AND RESULTS: HEK-293 cells expressing SCN5A and LQT9 mutation Cav3-F97C resulted in a 2-fold increase in late INa compared to Cav3-WT. This increase was reversed by the neural nitric oxide synthase (nNOS) inhibitor L-NMMA. Based on these findings, we hypothesized that an nNOS complex mediated the effect of Cav3 on SCN5A. A SCN5A macromolecular complex was established in HEK-293 cells by transiently expressing SCN5A, α1-syntrophin (SNTA1), nNOS, and Cav3. Compared with Cav3-WT, Cav3-F97C produced significantly larger peak INa amplitudes, and showed 3.3-fold increase in the late INa associated with increased S-nitrosylation of SCN5A. L-NMMA reversed both the Cav3-F97C induced increase in late and peak INa and decreased S-nitrosylation of SCN5A. Overexpression of Cav3-F97C in adult rat cardiomyocytes caused a significant increase in late INa compared to Cav3-WT, and prolonged the action potential duration (APD90) in a nNOS-dependent manner. CONCLUSIONS: Cav3 is identified as an important negative regulator for cardiac late INa via nNOS dependent direct S-nitrosylation of SCN5A. This provides a molecular mechanism for how Cav3 mutations increase late INa to cause LQT9. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Transferring Gait Predictors Across EMG Acquisition Systems with Domain Adaptation.

Lower limb assistive technology (e.g. exoskeletons) can benefit significantly from higher resolution information related to physiological state. High-density electromyography (HD-EMG) grids offer valuable spatial information on muscle activity; however their hardware is impractical, and bipolar electrodes remain the standard in practice. Exploiting information rich HD-EMG datasets to train machine learning models could help overcome the spatial limitations of bipolar electrodes. Unfortunately, differences in signal characteristics across acquisition systems prevent the direct transfer of models without a drop in performance. This study investigated Domain Adaptation (DA) to render EMG-based models invariant to different acquisition systems. This approach was evaluated using a Temporal Convolutional Network (TCN) that mapped EMG signals to the subject's knee angle, using HD-EMG as source data and Delsys bipolar EMG as target data. Furthermore, the feature extraction learnt by the TCN was also applied across muscle groups, evaluating the transferability of the sensor agnostic features. The DA implementation shows promise in both scenarios, with an average increase in accuracy (angular error normalised by the range of motion) of 7.36% for the Rectus Femoris, Biceps Femoris and Tibialis Anterior, as well as a cross-muscle performance increase of up to 10.80%. However, when the domain discrepancy is severe, the model is currently unable to generate a reliable walking trajectory due to inherent limitations related to the applied regression scheme and the chosen Mean Squared Error loss function. Therefore, future research should focus on exploring advanced loss functions and classification-based DA models that prioritise restoring key features of the gait.