New Mathematical Model of Electromechanical Coupling in Rat Cardiomyocytes

The rat is one of the most widely used laboratory animal species. Therefore development of mathematical models aimed to analyze electromechanical coupling in the rat myocardium is a matter of top interest. We have developed a novel model of excitation-contraction coupling in the rat cardiomyocyte. This model combines equations from the Pandit electrophysiological model and Hinch model of calcium handling with equations describing myofilament mechanical activity from the 'Ekaterinburg-Oxford' mathematical model. The model reproduces both fast and slow responses to mechanical interventions in rat myocardium. © 2018 Creative Commons Attribution.Russian Foundation for Basic Research, RFBR: 18-01-00059The work is performed in the frameworks of IIP UrB RAS projects (Nos. AAAA-A18-118020590031-8, АААА-А18-118020590134-6), and supported by RFBR (No. 18-01-00059), by Act 211 Government of the Russian Federation, contract No. 02.A03.21.0006

The Effects of Mechanical Preload on Transmural Differences in Mechano-Calcium-Electric Feedback in Single Cardiomyocytes: Experiments and Mathematical Models

Transmural differences in ventricular myocardium are maintained by electromechanical coupling and mechano-calcium/mechano-electric feedback. In the present study, we experimentally investigated the influence of preload on the force characteristics of subendocardial (Endo) and subepicardial (Epi) single ventricular cardiomyocytes stretched by up to 20% from slack sarcomere length (SL) and analyzed the results with the help of mathematical modeling. Mathematical models of Endo and Epi cells, which accounted for regional heterogeneity in ionic currents, Ca2+ handling, and myofilament contractile mechanisms, showed that a greater slope of the active tension–length relationship observed experimentally in Endo cardiomyocytes could be explained by greater length-dependent Ca2+ activation in Endo cells compared with Epi ones. The models also predicted that greater length dependence of Ca2+ activation in Endo cells compared to Epi ones underlies, via mechano-calcium-electric feedback, the reduction in the transmural gradient in action potential duration (APD) at a higher preload. However, the models were unable to reproduce the experimental data on a decrease of the transmural gradient in the time to peak contraction between Endo and Epi cells at longer end-diastolic SL. We hypothesize that preload-dependent changes in viscosity should be involved alongside the Frank–Starling effects to regulate the transmural gradient in length-dependent changes in the time course of contraction of Endo and Epi cardiomyocytes. Our experimental data and their analysis based on mathematical modeling give reason to believe that mechano-calcium-electric feedback plays a critical role in the modulation of electrophysiological and contractile properties of myocytes across the ventricular wall. © Copyright © 2020 Khokhlova, Konovalov, Iribe, Solovyova and Katsnelson.AAAA-A18-118020590031-8Russian Foundation for Basic Research, RFBR: 18-01-00059Russian Science Foundation, RSF: 18-74-10059Funding. Wet experiments were supported by the Russian Science Foundation (#18-74-10059). The development of mouse ventricular cardiomyocyte model was supported by the Russian Foundation for Basic Research (#18-01-00059), IIF UrB RAS theme (AAAA-A18-118020590031-8), and by RF Government Act #211 of March 16, 2013 (agreement 02.A03.21.0006)

Синдром VEXAS: на рубеже смены представлений об известных заболеваниях

This article presents the first case of VEXAS syndrome identified in the Russian Federation as well as characteristics of currently known clinical manifestations and treatment approaches. The clinical observation described is an impressive example of how the identification of a new pathogenic mutation can change the understanding of the classification, diagnosis and treatment of previously known immunoinflammatory diseases. Thus, in refractory forms of relapsing polychondritis, neutrophilic dermatosis, atypical forms of vasculitis, inflammatory joint diseases or undifferentiated systemic inflammatory syndrome, especially when associated with macrocytic anemia and myelodysplastic syndrome, VEXAS syndrome should be suspected and genetic testing should be performed to exclude the autoinflammatory nature of the existing condition.В статье приведен первый случай синдрома VEXAS, выявленный в Российской Федерации, а также характеристика известных на настоящий момент клинических проявлений и подходов к его терапии. Описанное клиническое наблюдение является ярким примером того, как выявление новой патогенной мутации может изменить представление о классификации, диагностике и терапии ранее известных иммуновоспалительных заболеваний. Так, при рефрактерных формах рецидивирующего полихондрита, нейтрофильного дерматоза, нетипичных формах васкулита, воспалительных заболеваний суставов или недифференцированном системном воспалительном синдроме, особенно при ассоциации с макроцитарной анемией и миелодиспластическим синдромом, необходима настороженность в отношении синдрома VEXAS и проведение генетического исследования для исключения аутовоспалительной природы имеющегося состояния

Experimental assessments of metallic and metal oxide nanoparticles toxicity

Nanoparticles of metals and their oxides (Me-NPs) are of special interest in the light of health risks assessment and management, because, along with engineered Me-NPs, there exists usually a substantial fraction of nanoscale ("ultrafine") particles of the same substances within the particle size distribution of condensation aerosols generated by arc-welding, metallurgical, and some chemical technologies. The nonspecific responses of the organism to the impact of Me-NP included: changes in the cytological and some biochemical characteristics of the bronchoalveolar lavage fluid caused by the deposition of particles in the lower airways, various manifestations of systemic toxicity including significant damage to the liver and kidneys, moderate neurological disturbances associated with possible penetration of Me-NP into the brain from the blood as well as from the nasal mucous membrane along the olfactory pathway, a paradoxically low manifestation of pulmonary pathology due to low chronic retention of nanoparticles in the lungs, and a genotoxic effect on the organism level. The toxicity and even genotoxicity of Me-NPs can be significantly attenuated by adequately composed combinations of some bioactive agents in innocuous doses. © Published under licence by IOP Publishing Ltd.Government Council on Grants, Russian FederationMinistry of Science and Higher Education of the Russian Federation: 3.9534.2017/8.9The research was partially supported by the Ministry of Science and Higher Education of the Russian Federation (project 3.9534.2017/8.9) and by Government of the Russian Federation (Act 211, Agreement 02.A03.21.0006). The equipment of the Ural Centre for Shared Use “Modern Nanotechnology” UrFU was used

A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies

A multilaboratory comparison of calibration accuracy and the performance of external references in analytical ultracentrifugation.

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies