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This paper describes a process for forming a buried field shield in GaN by an etch-and-regrowth process, which is intended to protect the gate dielectric from high fields in the blocking state. GaN trench MOSFETs made at Sandia serve as the baseline to show the limitations in making a trench gated device without a method to protect the gate dielectric. Device data coupled with simulations show device failure at 30% of theoretical breakdown for devices made without a field shield. Implementation of a field shield reduces the simulated electric field in the dielectric to below 4 MV/cm at breakdown, which eliminates the requirement to derate the device in order to protect the dielectric. For realistic lithography tolerances, however, a shield-to-channel distance of 0.4 μm limits the field in the gate dielectric to 5 MV/cm and requires a small margin of device derating to safeguard a long-term reliability and lifetime of the dielectric.

Abstract Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan‐Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV1.5 block and to support the observed clinical safety of lamotrigine. We used HEK‐293 cells stably expressing the hNaV1.5 channel and voltage clamp electrophysiology to quantify the potency (half‐maximal inhibitory concentration) against peak and late channel current, on‐/off‐rate binding kinetics, voltage‐dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.

Summary: The mechanical properties of the actin cortex regulate shape changes during cell division, cell migration, and tissue morphogenesis. We show that modulation of myosin II (MII) filament composition allows tuning of surface tension at the cortex to maintain cell shape during cytokinesis. Our results reveal that MIIA generates cortex tension, while MIIB acts as a stabilizing motor and its inclusion in MII hetero-filaments reduces cortex tension. Tension generation by MIIA drives faster cleavage furrow ingression and bleb formation. We also show distinct roles for the motor and tail domains of MIIB in maintaining cytokinetic fidelity. Maintenance of cortical stability by the motor domain of MIIB safeguards against shape instability-induced chromosome missegregation, while its tail domain mediates cortical localization at the terminal stages of cytokinesis to mediate cell abscission. Because most non-muscle contractile systems are cortical, this tuning mechanism will likely be applicable to numerous processes driven by myosin-II contractility. : Taneja et al. describe distinct roles for the two myosin-II paralogs in regulating actin cortex mechanics during cell division. Myosin-IIA generates cortex tension, while myosin-IIB maintains cortical stability. Optimal levels of the two paralogs within hetero-filaments at the cortex are required for shape stability and cytokinetic fidelity during cell division. Keywords: myosin IIA, myosin IIB, actin cortex, binucleation, cortex tension, hydrostatic pressure, cytokinesis, cell division, bleb, spindle

The potential of advanced tree-based models and optimized deep learning algorithms to predict fluvial bedload transport was explored, identifying the most flexible and accurate algorithm, and the optimum set of readily available and reliable inputs. Using 926 datasets for 20 rivers, the performance of three groups of models was tested: (1) standalone tree-based models Alternating Model Tree (AMT) and Dual Perturb and Combine Tree (DPCT); (2) ensemble tree-based models Iterative Absolute Error Regression (IAER), ensembled with AMT and DPCT; and (3) optimized deep learning models Long Short-Term Memory (LSTM) and Recurrent Neural Network (RNN) ensembled with Grey Wolf Optimizer. Comparison of the predictive performance of the models with that of commonly used empirical equations and sensitivity analysis of the driving variables revealed that: (i) the coarse grain-size percentile D90 was the most effective variable in bedload transport prediction (where Dx is the xth percentile of the bed surface grain size distribution), followed by D84, D50, flow discharge, D16, and channel slope and width; (ii) all tree-based models and optimized deep learning algorithms displayed ‘very good’ or ‘good’ performance, outperforming empirical equations; and (iii) all algorithms performed best when all input parameters were used. Thus, a range of different input variable combinations must be considered in the optimization of these models. Overall, ensemble algorithms provided more accurate predictions of bedload transport than their standalone counterpart. In particular, the ensemble tree-based model IAER-AMT performed most strongly, displaying great potential to produce robust predictions of bedload transport in coarse-grained rivers based on a few readily available flow and channel variables.

Reconfigurable and tunable terahertz electronic devices are promising for various technological applications, for which metamaterials are receiving interest. Here, a graphene/gold bilayer metasurface enables the creation of a frequency-selective absorber with electrical tuning in the 0.1–1 THz range.

Summary: Defects in primary cilia, cellular antennas that control multiple intracellular signaling pathways, underlie several neurodevelopmental disorders, but it remains unknown how cilia control essential steps in human brain formation. Here, we show that cilia are present on the apical surface of radial glial cells in human fetal forebrain. Interfering with cilia signaling in human organoids by mutating the INPP5E gene leads to the formation of ventral telencephalic cell types instead of cortical progenitors and neurons. INPP5E mutant organoids also show increased Sonic hedgehog (SHH) signaling, and cyclopamine treatment partially rescues this ventralization. In addition, ciliary expression of SMO, GLI2, GPR161, and several intraflagellar transport (IFT) proteins is increased. Overall, these findings establish the importance of primary cilia for dorsal and ventral patterning in human corticogenesis, indicate a tissue-specific role of INPP5E as a negative regulator of SHH signaling, and have implications for the emerging roles of cilia in the pathogenesis of neurodevelopmental disorders.

A common variant in the Histone Deacetylase 9 (HDAC9) gene is the strongest genetic risk for large-vessel stroke, and HDAC9 offers a novel target for therapeutic modulation. However, the mechanisms linking the HDAC9 variant with increased stroke risk is still unclear due to the lack of relevant models to study the underlying molecular mechanisms. We generated vascular smooth muscle cells using human induced pluripotent stem cells with the HDAC9 stroke risk variant to assess HDAC9-mediated phenotypic changes in a relevant cells model and test the efficacy of HDAC inhibitors for potential therapeutic strategies. Our human induced pluripotent stem cells derived vascular smooth muscle cells show enhanced HDAC9 expression and allow us to assess HDAC9-mediated effects on promoting smooth muscle cell dysfunction, including proliferation, migration, apoptosis and response to inflammation. These phenotypes could be reverted by treatment with HDAC inhibitors, including sodium valproate and small molecules inhibitors. By demonstrating the relevance of the model and the efficacy of HDAC inhibitors, our model provides a robust phenotypic screening platform, which could be applied to other stroke-associated genetic variants.

Flooding and erosion will pose increasing challenges to urban settlements and critical infrastructure, such as roads and power grids in the future. Improved projections on the impact of climate change to critical infrastructure are essential to assist future planning. This paper uses hydro-sedimentary modelling to predict river erosion threats to electricity transmission infrastructure in an urbanised river valley under multiple increasing flow magnitude scenarios. We use a coupled hydrodynamic and landscape evolution model, CAESAR-Lisflood, to simulate river channel changes along a reach of the River Mersey, UK from the present day to 2050. A range of synthetic flow scenarios, based on recent hydrological records, was used in the model ranging from ‘no change’ up to a flow with 50% higher magnitude. The results revealed: (1) riverbank erosion will pose significant threats to several transmission towers located along the river, requiring intervention to avoid destabilisation by the moving channel; (2) the total area of floodplain erosion and deposition ≥ 0.5 m deep was positively related to increasing projected flow magnitudes. However, through running a ‘low’ and ‘high’ erosion version of the model, the simulations revealed these threats were most sensitive to the calibration of the erosion component of the model, illustrating the challenges and uncertainty in forecasting long-term river channel change; and (3) how long-term simulations can assist in adaptation planning for electricity transmission towers. Further reach- and catchment-scale modelling will be necessary to determine the timings of large floods more accurately, which produce the most significant erosion and deposition events, and to evaluate the efficacy of protections to transmission towers.

Climate change is projected to cause considerable pressure on our environment and communities. In particular, an increase in flooding and extreme erosion events is foreseeable as a result of an anticipated increase in the frequency and severity of storms. In the absence of timely and strategic intervention, climate change is taking us closer to more uncertain (non-linear, stochastic) and potentially more catastrophic climatic impacts. This paper develops a state-of-the-art modelling framework to assess the economic impact of erosion hazards on critical infrastructure and evaluate their vulnerability and resilience to differing storm regimes. This framework is trialled on a UK town (Cockermouth, NW England) that has experienced significant storm-related erosion and flood damage in recent years, highlighting its ability to determine current and future erosion hazard to critical infrastructure. A hydro-sedimentary model is used to simulate fluvial and hillslope sediment erosion and deposition caused by extreme storms within river catchments (sheet, rill, gully and channel bank and bed erosion). The model is applied for current climate conditions and for two future epochs (2021–2040 & 2061–2080) to assess changing erosion hazard to critical infrastructure. Climate conditions for the two epochs are obtained using the UKCP18 high resolution realisation projections under emission scenario RCP8.5. The economic loss caused by these hazards is projected based on new, non-linear depth-cost curves derived from previous assessments. The results show that: 1) due to a warming climate, total rainfall in the Cockermouth area (and likely across the UK) may be higher for all storm durations and annual exceedance probabilities, until epoch 2061–2080 when the rainfall regime may shift towards shorter duration events with higher rainfall and longer duration events with less rainfall; 2) the total area that undergoes flooding, erosion and sediment deposition, and the magnitude of the hazard, may increase as the climate shifts; 3) the economic damage caused by erosion and deposition is positively related to rainfall total, and the highest costs are likely to be associated with damage caused to bridges (£102-130 million), followed by sediment deposition in the urban fabric (£9-82 million), and erosion damage to agricultural land (£16-26 million), buildings (£0.4-18 million) and roads (£0.4-4 million); and 4) the Estimated Annual Damage costs suggest that investment in bridges (£4-6 million) in the Cockermouth area is required now to ensure their resilience to extreme storm events, and interventions are likely to be needed within the next 20 years to prevent high economic costs associated with significant sediment deposition in the urban fabric (£0.3-4 million) and damage to roads (£0.08-0.1 million) and agricultural land (£0.6-2 million). This new framework can help support operational (immediate) and strategic (medium to long term i.e. 10+ years) erosion control decision making through the provision of an assessment of the scale and consequences of erosion.

Cognitive decline is among the most feared aspects of ageing. We have generated induced pluripotent stem cells (iPSCs) from 24 people from the Lothian Birth Cohort 1936, whose cognitive ability was tested in childhood and in older age. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using non-integrating oriP/EBNA1 backbone plasmids expressing six iPSC reprogramming factors (OCT3/4 (POU5F1), SOX2, KLF4, L-Myc, shp53, Lin28, SV40LT). All lines demonstrated STR matched karyotype and pluripotency was validated by multiple methods. These iPSC lines are a valuable resource to study molecular mechanisms underlying individual differences in cognitive ageing and resilience to age-related neurodegenerative diseases.