Biophysical phenotypes of SCN5A mutations causing long QT and Brugada syndromes

AbstractLong QT and Brugada syndromes are two hereditary cardiac diseases. Brugada syndrome has so far been associated with only one gene, SCN5A, which encodes the cardiac sodium channel. However, in long QT syndrome (LQTS) at least six genes, including the SCN5A, are implicated. The substitution (D1790G) causes LQTS and the insertion (D1795) induces both LQTS and Brugada syndromes in carrier patients. hH1/insD1795 and hH1/D1790G mutant channels were expressed in the tsA201 human cell line and characterized using the patch clamp technique in whole-cell configuration. Our data revealed a persistent inward sodium current of about 6% at −30 mV for both D1790G and insD1795, and a reduction of 62% of channel expression for the insD1795. Moreover, a shift of steady-state inactivation curve in both mutants was also observed. Our findings uphold the idea that LQT3 is related to a persistent sodium current whereas reduction in the expression level of cardiac sodium channels is one of the biophysical characteristics of Brugada syndrome

A New Cardiac Channelopathy: From Clinical Phenotypes to Molecular Mechanisms Associated With Nav1.5 Gating Pores

Voltage gated sodium channels (NaV) are broadly expressed in the human body. They are responsible for the initiation of action potentials in excitable cells. They also underlie several physiological processes such as cognitive, sensitive, motor, and cardiac functions. The NaV1.5 channel is the main NaV expressed in the heart. A dysfunction of this channel is usually associated with the development of pure electrical disorders such as long QT syndrome, Brugada syndrome, sinus node dysfunction, atrial fibrillation, and cardiac conduction disorders. However, mutations of Nav1.5 have recently been linked to the development of an atypical clinical entity combining complex arrhythmias and dilated cardiomyopathy. Although several Nav1.5 mutations have been linked to dilated cardiomyopathy phenotypes, their pathogenic mechanisms remain to be elucidated. The gating pore may constitute a common biophysical defect for all NaV1.5 mutations located in the channel's VSDs. The creation of such a gating pore may disrupt the ionic homeostasis of cardiomyocytes, affecting electrical signals, cell morphology, and cardiac myocyte function. The main objective of this article is to review the concept of gating pores and their role in structural heart diseases and to discuss potential pharmacological treatments

Editorial: Recent Advances in Voltage-Gated Sodium Channels, their Pharmacology and Related Diseases

No availabl

Regulatory Role of Voltage-Gated Na+ Channel β Subunits in Sensory Neurons

Voltage-gated sodium Na+ channels are membrane-bound proteins incorporating aqueous conduction pores that are highly selective for sodium Na+ ions. The opening of these channels results in the rapid influx of Na+ ions that depolarize the cell and drive the rapid upstroke of nerve and muscle action potentials. While the concept of a Na+-selective ion channel had been formulated in the 1940s, it was not until the 1980s that the biochemical properties of the 260-kDa and 36-kDa auxiliary β subunits (β1, β2) were first described. Subsequent cloning and heterologous expression studies revealed that the α subunit forms the core of the channel and is responsible for both voltage-dependent gating and ionic selectivity. To date, 10 isoforms of the Na+ channel α subunit have been identified that vary in their primary structures, tissue distribution, biophysical properties, and sensitivity to neurotoxins. Four β subunits (β1–β4) and two splice variants (β1A, β1B) have been identified that modulate the subcellular distribution, cell surface expression, and functional properties of the α subunits. The purpose of this review is to provide a broad overview of β subunit expression and function in peripheral sensory neurons and examine their contributions to neuropathic pain

Reliable Data Forwarding in Wireless Sensor Networks: Delay and Energy Trade Off

eliable Data Forwarding in Wireless Sensor Networks: Delay and Energy Trade Of

Cardiac involvement in patient-specific induced pluripotent stem cells of myotonic dystrophy type 1: unveiling the impact of voltage-gated sodium channels

Myotonic dystrophy type 1 (DM1) is a genetic disorder that causes muscle weakness and myotonia. In DM1 patients, cardiac electrical manifestations include conduction defects and atrial fibrillation. DM1 results in the expansion of a CTG transcribed into CUG-containing transcripts that accumulate in the nucleus as RNA foci and alter the activity of several splicing regulators. The underlying pathological mechanism involves two key RNA-binding proteins (MBNL and CELF) with expanded CUG repeats that sequester MBNL and alter the activity of CELF resulting in spliceopathy and abnormal electrical activity. In the present study, we identified two DM1 patients with heart conduction abnormalities and characterized their hiPSC lines. Two differentiation protocols were used to investigate both the ventricular and the atrial electrophysiological aspects of DM1 and unveil the impact of the mutation on voltage-gated ion channels, electrical activity, and calcium homeostasis in DM1 cardiomyocytes derived from hiPSCs. Our analysis revealed the presence of molecular hallmarks of DM1, including the accumulation of RNA foci and sequestration of MBNL1 in DM1 hiPSC-CMs. We also observed mis-splicing of SCN5A and haploinsufficiency of DMPK. Furthermore, we conducted separate characterizations of atrial and ventricular electrical activity, conduction properties, and calcium homeostasis. Both DM1 cell lines exhibited reduced density of sodium and calcium currents, prolonged action potential duration, slower conduction velocity, and impaired calcium transient propagation in both ventricular and atrial cardiomyocytes. Notably, arrhythmogenic events were recorded, including both ventricular and atrial arrhythmias were observed in the two DM1 cell lines. These findings enhance our comprehension of the molecular mechanisms underlying DM1 and provide valuable insights into the pathophysiology of ventricular and atrial involvement

D2WFP: A Novel Protocol for Forensically Identifying, Extracting, and Analysing Deep and Dark Web Browsing Activities

The use of the un-indexed web, commonly known as the deep web and dark web, to commit or facilitate criminal activity has drastically increased over the past decade. The dark web is an in-famously dangerous place where all kinds of criminal activities take place [1-2], despite advances in web forensics techniques, tools, and methodologies, few studies have formally tackled the dark and deep web forensics and the technical differences in terms of investigative techniques and artefacts identification and extraction. This research proposes a novel and comprehensive protocol to guide and assist digital forensics professionals in investigating crimes committed on or via the deep and dark web, The protocol named D2WFP establishes a new sequential approach for performing investigative activities by observing the order of volatility and implementing a systemic approach covering all browsing related hives and artefacts which ultimately resulted into improv-ing the accuracy and effectiveness. Rigorous quantitative and qualitative research has been conducted by assessing D2WFP following a scientifically-sound and comprehensive process in different scenarios and the obtained results show an apparent increase in the number of artefacts re-covered when adopting D2WFP which outperform any current industry or opensource browsing forensics tools. The second contribution of D2WFP is the robust formulation of artefact correlation and cross-validation within D2WFP which enables digital forensics professionals to better document and structure their analysis of host-based deep and dark web browsing artefacts

Ethnic and racial differences in Asian populations with ion channelopathies associated with sudden cardiac death

Cardiovascular diseases are associated with several morbidities and are the most common cause of worldwide disease-related fatalities. Studies show that treatment and outcome-related differences for cardiovascular diseases disproportionately affect minorities in the United States. The emergence of ethnic and racial differences in sudden cardiac death (SCD) and related ion channelopathies complicates cardiovascular disease prevention, diagnosis, management, prognosis, and treatment objectives for patients and physicians alike. This review compiles and synthesizes current research in cardiac ion channelopathies and genetic disorders in Asian populations, an underrepresented population in cardiovascular literature. We first present a brief introduction to SCD, noting relevant observations and statistics from around the world, including Asian populations. We then examined existing differences between Asian and White populations in research, treatment, and outcomes related to cardiac ion channelopathies and SCD, showing progression in thought and research over time for each ion channelopathy. The review also identifies research that explored phenotypic abnormalities, device usage, and risk of death in Asian patients. We touch upon the unique genetic risk factors in Asian populations that lead to cardiac ion channelopathies and SCD while comparing them to White and Western populations, particularly in the United States, where Asians comprise approximately 7% of the total population. We also propose potential solutions such as improving early genetic screening, addressing barriers affecting access to medical care and device utilization, physician training, and patient education on risks

Enhancing WPA2-PSK four-way handshaking after re-authentication to deal with de-authentication followed by brute-force attack a novel re-authentication protocol

The nature of wireless network transmission and the emerging attacks are continuously creating or exploiting more vulnerabilities. Despite the fact that the security mechanisms and protocols are constantly upgraded and enhanced, the Small Office/Home Office (SOHO) environments that cannot afford a separate authentication system, and generally adopt the IEEE 802.11 Wi-Fi-Protected-Access-2/Pre-Shared-Key (WPA2-PSK) are still exposed to some attack categories such as de-authentication attacks that aim to push wireless client to re-authenticate to the Access Point (AP) and try to capture the keys exchanged during the handshake to compromise the network security. This kind of attack is impossible to detect or prevent in spite of having an Intrusion Detection and Prevention System (IDPS) installed on the client or on the AP, especially when the attack is not repetitive and is targeting only one client. This paper proposes a novel method which can mitigate and eliminate the risk of exposing the PSK to be captured during the re-authentication process by introducing a novel re-authentication protocol relying on an enhanced four-way handshake which does not require any hardware upgrade or heavy-weight cryptography affecting the network flexibility and performances