This book is a collection of scientific papers concerning multilevel inverters examined from different points of view. Many applications are considered, such as renewable energy interface, power ...conditioning systems, electric drives, and chargers for electric vehicles. Different topologies have been examined in both new configurations and well-established structures, introducing novel and particular modulation strategies, and examining the effect of modulation techniques on voltage and current harmonics and the total harmonic distortion.
Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is ...considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate. In this study, we utilized SyncroPatch 768PE, one of the latest generation APC platforms which conducts parallel recording from two-384 modules with giga-seal data quality, to push these 2 boundaries. By optimizing various cell patching parameters and a two-step voltage protocol, we developed a high throughput APC assay for the voltage-gated sodium channel Nav1.7. By testing a group of Nav1.7 reference compounds' IC50, this assay was proved to be highly consistent with manual patch clamp (R > 0.9). In a pilot screening of 10,000 compounds, the success rate, defined by > 500 MΩ seal resistance and >500 pA peak current, was 79%. The assay was robust with daily throughput ~ 6,000 data points and Z' factor 0.72. Using the same platform, we also successfully recorded endogenous voltage-gated potassium channel Kv1.3 in primary T cells. Together, our data suggest that SyncroPatch 768PE provides a powerful platform for ion channel research and drug discovery.
Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. ...Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1–1.7 currents, with an IC50 of 1.9–3.8 μm, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures. We conclude that CBD's mode of action likely involves 1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and 2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.
Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. ...Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.
•Explain the operation of the proposed high gain Boost and buck-boost converters based on extendable Switch Capacitor cells.•Highlight the modes of operation for the proposed converters to justify ...converter utility for stand-alone PV systems.•Comparatively analyse the voltage gain and efficiency of the proposed converters against the conventional converters.•Guide for future work on B-BBC with extendable SC cells.
This paper presents transformerless high gain boost and buck-boost DC-DC converters (B-BBCs) with extendable switched capacitor cells (SCs), suitable for applications operating at high voltage, above 300 V. Boosting low voltage to a high-enough level, with low duty ratio, is beyond the practical capability of the conventional boost converter. In addition, high duty ratio needed for operation of the boost converter, results in higher component stress that suppresses the overall efficiency of the converter. Therefore, by a convenient integration of SCs with conventional B-BBCs, increased voltage gain is attained with fewer losses. Such converters can be employed for Photovoltaic (PV) systems. The operational principles and modes of operation are analyzed to justify the utility of converters for stand-alone PV systems. Moreover, the proposed modular structure allows to increase SC cells in order to obtain reduced voltage stress on switching components with a higher voltage gain. Simulation and experimental results based on 100 W laboratory prototype extol the theoretical analysis.
Grid faults are one of the most severe perturbations in power systems. During these extreme disturbances, the reliability of the grid is compromised and the risk of a power outage is increased. To ...prevent this issue, distributed generation inverters can help the grid by supporting the grid voltages. Voltage support mainly depends on two constraints: the amount of injected current and the grid impedance. This paper proposes a voltage support control scheme that joins these two features. Hence, the control strategy injects the maximum rated current of the inverter. Thus, the inverter takes advantage of the distributed capacities and operates safely during voltage sags. Also, the controller selects the appropriate power references depending on the resistive-inductive grid impedance. Therefore, the grid can be better supported since the voltage at the point of common coupling is improved. Several voltage objectives, which cannot be achieved together, are developed and discussed in detail. These objectives are threefold: to maximize the positive sequence voltage; to minimize the negative sequence voltage; and to maximize the difference between positive and negative sequence voltages. A mathematical optimal solution is obtained for each objective function. This solution is characterized by a safe peak current injection, and by the optimization of the voltage profile in any type of grid connection. Therefore, the proposed control scheme includes advanced features for voltage support during voltage sags, which are applicable to different power facilities in different types of networks. Due to system limitations, a suboptimal solution is also considered, analyzed, and discussed for each of the optimization problems. Experimental results are presented to validate the theoretical solutions.
In modern power distribution networks, voltage fluctuations and violations are becoming two major voltage quality issues due to high-level penetration of stochastic renewable energies (e.g. wind and ...solar power). In this study, a hybrid control strategy based on power inverters for voltage regulation in distribution networks is proposed. Firstly, a decentralised voltage control is designed to regulate voltage ramp-rate for mitigating voltage fluctuations. As a beneficial by-product, the var capacity from the inverters become smoothed. Then, a distributed voltage control is developed to fairly utilise the var capacity of each inverter to regulate the network voltage deviations. Furthermore, once there is a shortage of var capacity from inverters, on-load tap changers control will supplement to provide additional voltage regulation support. The simulation results on IEEE 33-bus distribution network with real-world data have validated the effectiveness of the proposed voltage regulation method.
Ancillary services for distributed generation (DG) systems become a challenging issue to smartly integrate renewable-energy sources into the grid. Voltage control is one of these ancillary services ...which can ride through and support the voltage under grid faults. Grid codes from the transmission system operators describe the behavior of the energy source, regulating voltage limits and reactive power injection to remain connected and support the grid under fault. On the basis that different kinds of voltage sags require different voltage support strategies, a flexible control scheme for three-phase grid-connected inverters is proposed. In three-phase balanced voltage sags, the inverter should inject reactive power in order to raise the voltage in all phases. In one- or two-phase faults, the main concern of the DG inverter is to equalize voltages by reducing the negative symmetric sequence and clear the phase jump. Due to system limitations, a balance between these two extreme policies is mandatory. Thus, over- and undervoltage can be avoided, and the proposed control scheme prevents disconnection while achieving the desired voltage support service. The main contribution of this work is the introduction of a control algorithm for reference current generation that provides flexible voltage support under grid faults. Two different voltage sags have been experimentally tested to illustrate the behavior of the proposed voltage support control scheme.
A semiactive variable-structure rectifier (SA-VSR) is proposed for the LLC resonant converter to achieve wide output voltage range power conversion. The SA-VSR is composed of two active switches and ...two diodes. The SA-VSR is operated as a voltage-doubler rectifier when the duty cycle of the active switches is 0.25, whereas it is a voltage-quadrupler rectifier when the duty cycle of the active switches is 0.5. Hence, the output voltage range is extended by adaptively changing the operation mode of the rectifier, which results in reduced switching frequency range, circulating current, and conduction losses of the LLC resonant converter. The switches' switching frequency of the SA-VSR is halved in comparison with the switches on the primary side of the LLC resonant converter, and zero voltage switching and zero current switching are achieved for all the active switches and diodes, respectively, to reduce the switching losses. The operation principles are analyzed and a 1.5-kW prototype with 400-V input voltage and 100-500-V output voltage is built and tested to verify the feasibility of the proposed method.
Objective
Voltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been ...associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN‐related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone.
Methods
We analyzed genotype‐phenotype correlations in large SCN‐patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders.
Results
Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation CNV cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy‐associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain‐of‐function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed.
Significance
Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.
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