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 p62 phosphorylation remain unclear. Here, we identify ULK1 as a kinase responsible for the phosphorylation of p62. ULK1 colocalizes with p62 bodies, directly interacting with p62. ULK1-dependent phosphorylation of p62 allows KEAP1 to be retained within p62 bodies, thus activating NRF2. p62S351E/+ mice are phosphomimetic knock-in mice in which Ser351, corresponding to human Ser349, is replaced by Glu. These mice, but not their phosphodefective p62S351A/S351A counterparts, exhibit NRF2 hyperactivation and growth retardation. This retardation is caused by malnutrition and dehydration due to obstruction of the esophagus and forestomach secondary to hyperkeratosis, a phenotype also observed in systemic Keap1-knockout mice. Our results expand our understanding of the physiological importance of the redox-independent NRF2 activation pathway and provide new insights into the role of phase separation in this process.

Corrigendum: A compact multi-functional model of the rabbit atrioventricular node with dual pathways.

[This corrects the article DOI: 10.3389/fphys.2023.1126648.].

A compact multi-functional 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 one-dimensional AVN model includes fast (FP) and slow (SP) pathways, primary pacemaking in the sinoatrial node, and subsidiary pacemaking in the SP. To obtain the direction-dependent conduction properties of the AVN, together with gradients of intercellular coupling and cell refractoriness, we implemented the asymmetry of coupling between model cells. We hypothesized that the asymmetry can reflect some effects related to the complexity of the real 3D structure of AVN. In addition, 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.

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.

Computer simulation of atypical Brugada syndrome.

Recently, the so-called atypical Brugada syndrome (BS) has been reported in few cases in literature. The typical BS is characterized by ST-segment elevation in the right precordial leads, whereas atypical forms of the disease are distinguished by electrocardiogram abnormalities of the J wave, and ST-segment elevation appeared in the inferior and lateral leads. In this work, we report a simulation of atypical BS based on a 3-dimensional whole-heart model. By setting the action potentials of Brugada model cells in different epicardial regions, we calculated 12-lead electrocardiogram and body surface potentials that are in good agreement with clinical data. Applying additional electrical stimuli, we obtained the induction of ventricular fibrillation in both typical and atypical BS forms. The calculated results confirm possibility of similar electrophysiological basis in both cases and suggest that BS can also be observed in inferior and lateral precordial leads.

Cardiac Conduction Model for Generating 12 Lead ECG Signals With Realistic Heart Rate Dynamics.

We present an extended heterogeneous oscillator model of cardiac conduction system for generation of realistic 12 lead ECG waveforms. The model consists of main natural pacemakers represented by modified van der Pol equations, and atrial and ventricular muscles, in which the depolarization and repolarization processes are described by modified FitzHugh-Nagumo equations. We incorporate an artificial RR-tachogram with the specific statistics of a heart rate, the frequency-domain characteristics of heart rate variability produced by Mayer and respiratory sinus arrhythmia waves, normally distributed additive noise and a baseline wander that couple the respiratory frequency. The standard 12 lead ECG is calculated by means of a weighted linear combination of atria and ventricle signals and thus can be fitted to clinical ECG of real subject. The model is capable to simulate accurately realistic ECG characteristics including local pathological phenomena accounting for biophysical properties of the human heart. All these features provide significant advantages over existing nonlinear cardiac models. The proposed model constitutes a useful tool for medical education and for assessment and testing of ECG signal processing software and hardware systems.

Formation of second-degree atrioventricular blocks in the cardiac heterogeneous oscillator model.

We study formation of second-degree atrioventricular blocks (Wenckebach and Mobitz types) with reduction of coupling between nodes in the heterogeneous oscillator model of cardiac conduction system. We demonstrate that maximal possible number of physiological mode lock patterns in both cases appears at a particular value of coupling coefficient. For the type II atrioventricular block total conduction ratio at high sinus rates might be represented by a product of conduction ratios of atrioventricular nodal and infrahisian blocks.