Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways

Aims Cardiac myopathies are the second leading cause of death in patients with Duchenne and Becker muscular dystrophy, the two most common and severe forms of a disabling striated muscle disease. Although the genetic defect has been identified as mutations of the dystrophin gene, very little is known about the molecular and cellular events leading to progressive cardiac muscle damage. Dystrophin is a protein linking the cytoskeleton to a complex of transmembrane proteins that interact with the extracellular matrix. The fragility of the cell membrane resulting from the lack of dystrophin is thought to cause an excessive susceptibility to mechanical stress. Here, we examined cellular mechanisms linking the initial membrane damage to the dysfunction of dystrophic heart. Methods and results Cardiac ventricular myocytes were enzymatically isolated from 5- to 9-month-old dystrophic mdx and wild-type (WT) mice. Cells were exposed to mechanical stress, applied as osmotic shock. Stress-induced cytosolic and mitochondrial Ca2+ signals, production of reactive oxygen species (ROS), and mitochondrial membrane potential were monitored with confocal microscopy and fluorescent indicators. Pharmacological tools were used to scavenge ROS and to identify their possible sources. Osmotic shock triggered excessive cytosolic Ca2+ signals, often lasting for several minutes, in 82% of mdx cells. In contrast, only 47% of the WT cardiomyocytes responded with transient and moderate intracellular Ca2+ signals. On average, the reaction was 6-fold larger in mdx cells. Removal of extracellular Ca2+ abolished these responses, implicating Ca2+ influx as a trigger for abnormal Ca2+ signalling. Our further experiments revealed that osmotic stress in mdx cells produced an increase in ROS production and mitochondrial Ca2+ overload. The latter was followed by collapse of the mitochondrial membrane potential, an early sign of cell death. Conclusion Overall, our findings reveal that excessive intracellular Ca2+ signals and ROS generation link the initial sarcolemmal injury to mitochondrial dysfunctions. The latter possibly contribute to the loss of functional cardiac myocytes and heart failure in dystrophy. Understanding the sequence of events of dystrophic cell damage and the deleterious amplification systems involved, including several positive feed-back loops, may allow for a rational development of novel therapeutic strategie

A personal computer based controller for an active power filter

This paper presents the development of controllers used in active power filters, applied to improve power quality in electrical systems. These active filters can be able to compensate for the following current or voltage related problems: short blackouts, current or voltage distortion due to harmonics, current or voltage unbalance in three-phase systems, flicker (subharmonics) and momentary over or under voltages. There are several causes for current and voltage distortion, namely, non linear loads, some types of voltage sources and thunderstorms. These problems cause instant and long term effects on the electrical equipment. The short term effects are imperfections, malfunctioning, interferences and degradation of the performance of devices or equipments. Effects in the long run are, basically, overheating and premature aging of the electric devices. The main goal of the work described in this paper is to develop an active power filter controller based on a personal computer and a standard multifunction data acquisition PCI bus card, due to its relative low cost, high processing capability, versatility and the numerous possibilities offered by such a computer-based system. Four different approaches were tested: using C++ on Microsoft Windows with the manufacturer’s device driver, using a new device driver for Windows, using Linux with real-time application interface; and using LabVIEW for Windows. Experimental and simulation results of the developed controllers are also presented

Direct current control of an active power filter for harmonic elimination, power factor correction and load unbalancing compensation

An active power filter is designed, simulated, implemented, and tested. It can work in different modes: active power filtering, power factor correction, and load unbalance compensation. It is based on a current controlled voltage-source inverter with fixed carrier PWM. The control algorithm generates the source reference currents based on the controlled DC link voltage. The dimensioning criteria of the inductive and capacitive power components is discussed. The implementation is validated with simulated and experimental results obtained in a 5 kVA prototype

New reactive power compensation strategies for railway infrastructure capacity increasing

In AC railway electrification systems, the impact of reactive power flow in the feeding voltage magnitude is one aspect contributing to the quality of supply degradation. Specifically, this issue results in limitations in the infrastructure capacity, either in the maximum number of trains and in maximum train power. In this paper, two reactive power compensation strategies are presented and compared, in terms of the theoretical railway infrastructure capacity. The first strategy considers a static VAR compensator, located in the neutral zone and compensating the substation reactive power, achieving a maximum capacity increase up to 50% without depending on each train active power. The second strategy adapts each train reactive power, achieving also a capacity increase around 50%, only with an increase of the train apparent power below 10%. With a smart metering infrastructure, the implementation of such compensation strategy is viable, satisfying the requirements of real-time knowledge of the railway electrification system state. Specifically, the usage of droop curves to adapt in real time the compensation scheme can bring the operation closer to optimality. Thus, the quality of supply and the infrastructure capacity can be increased with a mobile reactive power compensation scheme, based on a smart metering framework.This research was funded by FCT (Fundação Ciência e Tecnologia) under grant PD/BD/128051/2016.This research is also associated with the Shift2Rail In2Stempo project (grant 777515)

Rail power conditioner based on indirect AC/DC/AC modular multilevel converter using a three-phase V/V power transformer

This paper presents a rail power conditioner (RPC) system based on an indirect AC/DC/AC modular multilevel converter (MMC) where a V/V power transformer is used to feed the main catenary line and the locomotives. The proposed control strategy for this system has been introduced to guarantee a good compensating performance of negative sequence currents (NSCs) and harmonics on the public grid side. This control strategy has also the ability to achieve balanced and equal voltage between the MMC’s submodules (SMs) capacitors. Simulation results for this RPC based on an indirect MMC are presented in this paper to show the main advantages of using this topology. The results show how the proposed system is able to compensate NSCs and harmonics on the public grid side when the V/V power transformer feeds two unequal load sections.Fundação para a Ciência e Tecnologia (FCT)info:eu-repo/semantics/publishedVersio

Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways

AIMS: Cardiac myopathies are the second leading cause of death in patients with Duchenne and Becker muscular dystrophy, the two most common and severe forms of a disabling striated muscle disease. Although the genetic defect has been identified as mutations of the dystrophin gene, very little is known about the molecular and cellular events leading to progressive cardiac muscle damage. Dystrophin is a protein linking the cytoskeleton to a complex of transmembrane proteins that interact with the extracellular matrix. The fragility of the cell membrane resulting from the lack of dystrophin is thought to cause an excessive susceptibility to mechanical stress. Here, we examined cellular mechanisms linking the initial membrane damage to the dysfunction of dystrophic heart. METHODS AND RESULTS: Cardiac ventricular myocytes were enzymatically isolated from 5- to 9-month-old dystrophic mdx and wild-type (WT) mice. Cells were exposed to mechanical stress, applied as osmotic shock. Stress-induced cytosolic and mitochondrial Ca(2+) signals, production of reactive oxygen species (ROS), and mitochondrial membrane potential were monitored with confocal microscopy and fluorescent indicators. Pharmacological tools were used to scavenge ROS and to identify their possible sources. Osmotic shock triggered excessive cytosolic Ca(2+) signals, often lasting for several minutes, in 82% of mdx cells. In contrast, only 47% of the WT cardiomyocytes responded with transient and moderate intracellular Ca(2+) signals. On average, the reaction was 6-fold larger in mdx cells. Removal of extracellular Ca(2+) abolished these responses, implicating Ca(2+) influx as a trigger for abnormal Ca(2+) signalling. Our further experiments revealed that osmotic stress in mdx cells produced an increase in ROS production and mitochondrial Ca(2+) overload. The latter was followed by collapse of the mitochondrial membrane potential, an early sign of cell death. CONCLUSION: Overall, our findings reveal that excessive intracellular Ca(2+) signals and ROS generation link the initial sarcolemmal injury to mitochondrial dysfunctions. The latter possibly contribute to the loss of functional cardiac myocytes and heart failure in dystrophy. Understanding the sequence of events of dystrophic cell damage and the deleterious amplification systems involved, including several positive feed-back loops, may allow for a rational development of novel therapeutic strategies

Deadbeat predictive current control for circulating currents reduction in a modular multilevel converter based rail power conditioner

This paper presents a deadbeat predictive current control methodology to reduce the circulating currents in a modular multilevel converter (MMC) when it operates as a rail power conditioner (RPC) in a conventional railway system-based V/V connection. For this purpose, a half-bridge MMC based on half-bridge submodules, operating as an RPC is explained, and the total system is denominated as a simplified rail power conditioner (SRPC). The SRPC in this study is used to compensate harmonics, reactive power, and the negative sequence component of currents. This paper explains the SRPC system architecture, the key control algorithms, and the deadbeat predictive current control methodology. Mathematical analysis, based on the MMC equivalent circuit, is described and the reference equations are presented. Moreover, simulation results of the deadbeat predictive current control methodology are compared with the results of the conventional proportional-integral (PI) controller. This comparison is to verify the effectiveness of the proposed control strategy. Simulation results of the SRPC show reduced circulating currents in the MMC phases when using the predictive control approach, besides accomplishing power quality improvement at the three-phase power grid side.This work has been supported by the Portuguese Foundation of Science and Technology (FCT), in Portuguese, Fundação para a Ciência e Tecnologia within the R&D Units Project Scope: UIDB/00319/2020 and PTDC/EEI-EEE/28813/2017. The first author Mohamed Tanta is supported by FCT Ph.D. grant with a reference PD/BD/127815/2016

A comprehensive comparison of rail power conditioners based on two-level converters and a V/V power transformer in railway traction power systems

Electric locomotives in the traction power systems represent huge nonlinear single phase loads and they affect adversely the public electrical grid stability and the power quality. Some of such problems are related to the harmonic distortion and the Negative Sequence Components (NSCs). The Rail Power Conditioners (RPCs) are widely used to accomplish harmonics mitigation, besides NSCs compensation, then, maintaining balanced and sinusoidal public electrical grid currents. This paper presents a comprehensive comparison study between three different RPCs based on the two level converters and a V/V power transformer. The Four Wire Rail Power Conditioner (FW RPC), the Three Wire Rail Power Conditioner (TW RPC) and the Half Bridge Rail Power Conditioner (HB RPC) are the main conditioners of interest. The main contribution of this paper is to perform a comprehensive comparison between the aforementioned RPCs, including the control algorithms and the compensating performance regarding the power quality problems. Simulation results with different operation scenarios are presented to establish an appropriate comparison between the aforementioned RPCs topologies.Mohamed Tanta was supported by FCT (Fundação para a Ciência e Tecnologia) PhD grant with a reference PD/BD/127815/2016. This work has been supported by COMPETE: POCI-01-0145–FEDER–007043 and FCT within the Project Scope: UID/CEC/00319/2013.info:eu-repo/semantics/publishedVersio

Efficiency and cost estimation for a static frequency converter and a rail power conditioner based on an indirect modular multilevel converter in railways applications

This paper presents a comparative study between two different power electronics solutions for electrified railway substations to overcome some drawbacks which could appear on the public grid side. These drawbacks or troubles on the public grid side are mainly the harmonics and the negative sequence components (NSCs) of currents, which could become clear in the case of feeding single-phase locomotives or unbalanced loads. The static frequency converters (SFCs) and the rail power conditioners (RPCs) based on an indirect AC/DC/AC modular multilevel converter (MMC) are the main area of interest in this study, taking into consideration the costs estimation analysis between solutions, the efficiency and the power quality on the public grid side. Both systems of SFC and RPC based on an indirect MMC operate on medium voltage levels to feed the catenary line and to solve the problems of harmonics and NSCs. Along the paper are described the system architecture, the control algorithm, the inherent benefits, the estimated cost of implementation, and the operation efficiency based on computational simulation results for each system.This work has been supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT – Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2013. Mohamed Tanta is supported by FCT doctoral scholarship with a reference PD/BD/127815/2016.info:eu-repo/semantics/acceptedVersio