bioRxiv Science⌕ Search

Biology subjects

Ryzhii, E.

Publications and source records attributed to Ryzhii, E..

3 recordsLinked to original sources

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↗

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↗

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↗