Neurological disorders in patients with long COVID syndrome and cell therapy methods for their correction a literature review

The review presents the current understanding of the incidence and nature of neurological disorders in patients with the so-called long COVID syndrome. Symptoms, putative pathophysiological mechanisms, risk factors, search for methods of treatment and rehabilitation of patients using the patient's own hematopoietic cells are discussed. A search was carried out for scientific articles, including those published in peer-reviewed journals indexed in PubMed, Web of Science, Scopus and RSCI. The inclusion of stem cells (SC) in rehabilitation programs for patients with various injuries and diseases of the central nervous system (CNS) is a promising area of research. The mechanisms of CNS damage therapy based on the use of adult-type pluripotent stem cells, including CD34+, consist of many aspects. On the background of SC transplantation, damaged nerve cells and surrounding tissues, including neurons and glial cells, can be restored, which helps to ensure the integrity of the nerve conduction pathway and, thus, restore nerve function. SC therapy can suppress genes involved in inflammation and apoptosis, as well as activate genes with neuroprotective action, thereby protecting spinal neurons from secondary damage. This line of cell therapy can be used to treat long COVID syndrome.

Hoop-like role of the cytosolic interface helix in Vibrio PomA, an ion-conducting membrane protein, in the bacterial flagellar motor

Vibrio has a polar flagellum driven by sodium ions for swimming. The force-generating stator unit consists of PomA and PomB. PomA contains four-transmembrane regions and a cytoplasmic domain of approximately 100 residues which interacts with the rotor protein, FliG, to be important for the force generation of rotation. The three-dimensional structure of the stator shows that the cytosolicinterface (CI) helix of PomA is located parallel to the inner membrane. In this study, we investigated the function of CI helix and its role as stator. Systematic proline mutagenesis showed that residues K64, F66, and M67 were important for this function. The mutant stators did not assemble around the rotor. Moreover, the growth defect caused by PomB plug deletion was suppressed by these mutations. We speculate that the mutations affect the structure of the helices extending from TM3 and TM4 and reduce the structural stability of the stator complex. This study suggests that the helices parallel to the inner membrane play important roles in various processes, such as the hoop-like function in securing the stability of the stator complex and the ion conduction pathway, which may lead to the elucidation of the ion permeation and assembly mechanism of the stator.

Endocardial and epicardial activation maps for three-dimensional-perimitral flutter using a three-dimensional mapping system: A case report

Background Perimitral flutter (PMF) is a macro-reentrant tachycardia, and mitral isthmus (MI) linear ablation is considered to be the preferable mode of treatment. Additionally, PMF can sometimes develop via epicardial connections, including coronary sinus and vein of Marshall. However, there are no reports of three-dimensional (3 D) atrial tachycardia (AT) via the intramural tissue. Case summary A 78-year-old man underwent catheter ablation for paroxysmal atrial fibrillation and AT, including pulmonary vein isolation, left atrial posterior wall isolation, superior vena cava isolation, and MI linear ablation in a total of four procedures. However, AT reoccurred, and he underwent a fifth procedure for AT. Although the MI block line was complete in both the endocardial and epicardial voltage maps, AT indicated PMF. The total activation time did not cover all phases of tachycardia cycle length due to the conduction pathway through the intramural muscle/bundles that could not be mapped with the addition of epicardial mapping. The tachycardia was terminated by ablation at the mitral valve annulus in the 2 o'clock position, where the bundles might have been attached. Discussion Both endocardial and epicardial activation maps indicated 3 D-PMF, whose circuit included the intramural muscle and bundles in a tachycardia circuit. It is necessary to recognise AT, which is involved via intramural tissues.

Ion currents through Kir potassium channels are gated by anionic lipids

Ion currents through potassium channels are gated. Constriction of the ion conduction pathway at the inner helix bundle, the textbook ‘gate’ of Kir potassium channels, has been shown to be an ineffective permeation control, creating a rift in our understanding of how these channels are gated. Here we present the first evidence that anionic lipids act as interactive response elements sufficient to gate potassium conduction. We demonstrate the limiting barrier to K+ permeation lies within the ion conduction pathway and show that this ‘gate’ is operated by the fatty acyl tails of lipids that infiltrate the conduction pathway via fenestrations in the walls of the pore. Acyl tails occupying a surface groove extending from the cytosolic interface to the conduction pathway provide a potential means of relaying cellular signals, mediated by anionic lipid head groups bound at the canonical lipid binding site, to the internal gate.

Two-pore domain potassium channels (K2P) in GtoPdb v.2021.3

The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two-pore domain, or K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the More detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below.

Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP

Mutations in the voltage sensor domain (VSD) of CaV1.1, the α1S subunit of the L-type calcium channel in skeletal muscle, are an established cause of hypokalemic periodic paralysis (HypoPP). Of the 10 reported mutations, 9 are missense substitutions of outer arginine residues (R1 or R2) in the S4 transmembrane segments of the homologous domain II, III (DIII), or IV. The prevailing view is that R/X mutations create an anomalous ion conduction pathway in the VSD, and this so-called gating pore current is the basis for paradoxical depolarization of the resting potential and weakness in low potassium for HypoPP fibers. Gating pore currents have been observed for four of the five CaV1.1 HypoPP mutant channels studied to date, the one exception being the charge-conserving R897K in R1 of DIII. We tested whether gating pore currents are detectable for the other three HypoPP CaV1.1 mutations in DIII. For the less conserved R1 mutation, R897S, gating pore currents with exceptionally large amplitude were observed, correlating with the severe clinical phenotype of these patients. At the R2 residue, gating pore currents were detected for R900G but not R900S. These findings show that gating pore currents may occur with missense mutations at R1 or R2 in S4 of DIII and that the magnitude of this anomalous inward current is mutation specific.

Cryo-EM structure of the human TACAN channel in a closed state

TACAN is an ion channel involved in sensing mechanical pain. It has recently been shown to represent a novel and evolutionarily conserved class of mechanosensitive channels. Here, we present the cryoelectron microscopic structure of human TACAN (hTACAN). hTACAN forms a dimer in which each protomer consists of a transmembrane globular domain (TMD) that is formed of six helices and an intracellular domain (ICD) that is formed of two helices. Molecular dynamic simulations suggest that a putative ion conduction pathway is located inside each protomer. Single point mutation of the key residue Met207 significantly increased the surface tension activated currents. Moreover, cholesterols were identified at the flank of each subunit. Our data show the molecular assembly of hTACAN and suggest that the wild type hTACAN is in a closed state, providing a basis for further understanding the activation mechanism of the hTACAN channel.

Analog Transmission of Action Potential Fine Structure in Spiral Ganglion Axons

Action potential waveforms generated at the axon initial segment (AIS) are specialized between and within neuronal classes. But is the fine structure of each electrical event retained when transmitted along myelinated axons or is it rapidly and uniformly transmitted to be modified again at the axon terminal? To address this issue action potential axonal transmission was evaluated in a class of primary sensory afferents that possess numerous types of voltage-gated ion channels underlying a complex repertoire of endogenous firing patterns. In addition to their signature intrinsic electrophysiological heterogeneity, spiral ganglion neurons are uniquely designed. The bipolar, myelinated somata of type I neurons are located within the conduction pathway, requiring that action potentials generated at the first heminode must be conducted through their electrically excitable membrane. We utilized this unusual axonal-like morphology to serve as a window into action potential transmission to compare locally-evoked action potential profiles to those generated peripherally at their glutamatergic synaptic connections with hair cell receptors. These comparisons showed that the distinctively-shaped somatic action potentials were highly correlated with the nodally-generated, invading ones for each neuron. This result indicates that the fine structure of the action potential waveform is maintained axonally, thus supporting the concept that analog signaling is incorporated into each digitally-transmitted action potential in the specialized primary auditory afferents.