Biology subjects

Ryzhii, E.

Publications and source records attributed to Ryzhii, E..

6 recordsLinked to original sources

bioRxiv2025

Assessment of atrioventricular nodal reentrant tachycardia inducibility with alternative pacing methods: Computer simulation

Background and objectiveIn clinical and experimental electrophysiology, the standard S1S2 stimulation protocol is widely used to assess the inducibility of reciprocal tachycardias. However, this method may lead to over- or under-estimation of atrioventricular nodal reentrant tachycardia (AVNRT) susceptibility. Computational modeling enables a detailed examination of these limitations and the design of more physiologically accurate stimulation approaches. This study evaluates alternative stimulation methods using a compact, multifunctional rabbit AV node model with autonomic nervous system (ANS) control. MethodsThe model, based on experimental data, incorporates dual (fast and slow) pathway conduction and simulates the propagation of nodal electrical excitation. Alternative stimulation protocols were implemented and compared with the standard S1S2 approach at both atrial and His bundle stimulation sites. ResultsSimulations yielded AV node ladder diagrams, effective refractory periods, and echo response zones across the full range of ANS modulation. The proposed methods enabled accurate characterization of nodal pathway refractory periods during retrograde conduction and identified physiological conditions leading to intranodal reentry. Compared with the S1S2 protocol, the alternative approaches reduced misestimation of AVNRT inducibility and provided clearer separation between echo beats and sustained reentry. ConclusionsThe proposed stimulation methods, particularly during His bundle pacing, offer a more accurate and physiologically grounded assessment of AVNRT inducibility than the conventional S1S2 protocol, improving the understanding of nodal conduction dynamics and arrhythmia mechanisms.

physiology↗

bioRxiv2025

KEAP1 retention in phase-separated p62 bodies drives liver damage in autophagy-deficient conditions

Phase-separated p62 bodies activate NRF2, a key transcription factor for antioxidant response, by sequestering KEAP1, which targets NRF2 for degradation. Although p62 bodies containing KEAP1 are degraded by autophagy, they accumulate in various liver disorders. Their precise disease role remains unclear. We show that excessive KEAP1 retention in p62 bodies and NRF2 activation are major causes of liver damage when autophagy is impaired. In mice with weakened or blocked p62-KEAP1 interactions, KEAP1 retention and NRF2 activation under autophagy-deficient conditions were suppressed. Transcriptome and proteome analyses revealed that NRF2 targets upregulated by autophagy suppression normalized in p62 mutants unable to bind KEAP1. Autophagy deficiency caused organelle accumulation, especially of the ER, regardless of p62 mutation. Liver damage and hepatomegaly from autophagy suppression markedly improved in p62 mutants, particularly those with blocked KEAP1 binding. These findings highlight excessive KEAP1 retention in p62 bodies and defective organelle turnover as key drivers of liver pathology, underscoring the significance of phase separation in vivo.

cell biology↗

bioRxiv2024

Atrioventricular nodal reentrant tachycardia onset,sustainability, and spontaneous termination in rabbit atrioventricular node model with autonomic nervous system control

Atrioventricular nodal reentrant tachycardia (AVNRT) is one of the most common types of paroxysmal supraventricular tachycardia. The autonomic nervous system (ANS) activity is known to affect sudden episodes of AVNRT, but the detailed underlying mechanism is not fully understood. In this work, we update our recent compact multifunctional model of the rabbit atrioventricular node (AV) with ANS control to simulate AVNRT. The refractoriness of model cells is modulated by one ANS coefficient, causing a change in the effective refractory periods, conduction delays, and intrinsic frequency of pacemaker cells. Using the model, we examine the onset, sustainability, and spontaneous termination of typical slow-fast and atypical fast-slow forms of AVNRT under ANS modulation. The conditions for the onset and sustainability of AVNRT can occur independently of each other in various combinations. Differences in the effective refractory periods of the slow and fast pathways of the AV node during anterograde and retrograde conduction determine the form of AVNRT. For the first time, the possibility of identifying hidden processes occurring inside the AV node using a computer model is shown, allowing us to come closer to understanding the role of ANS control during AVNRT. The results obtained are consistent with clinical and experimental data and represent a new tool for studying the electrophysiological mechanisms of this type of arrhythmia.

biophysics↗

bioRxiv2023

A compact multifunctional model of the rabbit atrioventricular node with dual pathways

The atrioventricular node (AVN) is considered a "black box", and the functioning of its dual pathways remains controversial and not fully understood. In contrast to numerous clinical studies, there are only a few mathematical models of the node. In this paper, we present a compact, computationally lightweight multi-functional rabbit AVN model based on the Aliev-Panfilov two-variable cardiac cell model. The AVN model includes fast (FP) and slow (SP) pathways, primary pacemaking in the sinoatrial node, subsidiary pacemaking in the SP, and takes into account the asymmetry of coupling between model cells. At the same time, the model is accompanied by a visualization of electrical conduction in the AVN, revealing the interaction between SP and FP in the form of ladder diagrams. The AVN model demonstrates broad functionality, including normal sinus rhythm, AVN automaticity, filtering of high-rate atrial rhythms during atrial fibrillation and atrial flutter with Wenckebach periodicity, direction-dependent properties, and realistic anterograde and retrograde conduction curves in the control case and the cases of FP and SP ablation. To show the validity of the proposed model, we compare the simulation results with the available experimental data. Despite its simplicity, the proposed model can be used both as a stand-alone module and as a part of complex three-dimensional atrial or whole heart simulation systems and can help to understand some puzzling functions of AVN.

biophysics↗

bioRxiv2022

Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox-independent stress response

NRF2 is a transcription factor responsible for antioxidant stress responses that is usually regulated in a redox-dependent manner. p62 bodies formed by liquid-liquid phase separation contain Ser349-phosphorylated p62, which participates in the redox-independent activation of NRF2. However, the regulatory mechanism and physiological significance of phosphorylation remain unclear. Herein, we identify ULK1 as a kinase responsible for phosphorylation of p62. ULK1 co-localizes with p62 bodies, and directly interacts with p62. This phosphorylation allows KEAP1 to be retained within p62 bodies, activating NRF2. p62S351E/+ mice are phosphomimetic knock-in mice in which Ser351 corresponding to human Ser349 is replaced by Glu. These mice, but not phosphodefective p62S351A/S351A mice, exhibit NRF2 hyperactivation and growth retardation, the latter caused by malnutrition and dehydration due to obstruction of the esophagus and forestomach secondary to hyperkeratosis. p62S351E/+ mice are a phenocopy of systemic Keap1-knockout mice. Our results expand our understanding of the physiological importance of the redox-independent NRF2 activation pathway and provide new insight into the role of phase separation in this process.

cell biology↗

bioRxiv2021

Pacemaking function of two simplified cell models

Simplified nonlinear models of biological cells are widely used in computational electrophysiology. The models reproduce qualitatively many of the characteristics of various organs, such as the heart, brain, and intestine. In contrast to complex cellular ion-channel models, the simplified models usually contain a small number of variables and parameters, which facilitates nonlinear analysis and reduces computational load. In this paper, we consider pacemaking variants of the Aliev-Panfilov and Corrado two-variable excitable cell models. We conducted a numerical simulation study of these models and investigated the main nonlinear dynamic features of both isolated cells and 1D coupled pacemaker-excitable systems. Simulations of the 2D sinoatrial node and 3D intestine tissue as application examples of combined pacemaker-excitable systems demonstrated results similar to obtained previously. The uniform formulation for the conventional excitable cell models and proposed pacemaker models allows a convenient and easy implementation for the construction of personalized physiological models, inverse tissue modeling, and development of real-time simulation systems for various organs that contain both pacemaker and excitable cells.

biophysics↗