Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp

Anatomical model of rat ventricles to study cardiac arrhythmias under infarction injury

Species-specific computer models of the heart are a novel powerful tool in studies of life-threatening cardiac arrhythmias. Here, we develop such a model aimed at studying infarction injury in a rat heart, the most common experimental system to investigate the effects of myocardial damage. We updated the Gattoni2016 cellular ionic model by fitting its parameters to experimental data using a population modeling approach. Using four selected cellular models, we studied 2D spiral wave dynamics and found that they include meandering and break-up. Then, using an anatomically realistic ventricular geometry and fiber orientation in the rat heart, we built a model with a post-infarction scar to study the electrophysiological effects of myocardial damage. A post-infarction scar was simulated as an inexcitable obstacle surrounded by a border zone with modified cardiomyocyte properties. For cellular models, we studied the rotation of scroll waves and found that, depending on the model, we can observe different types of dynamics: anchoring, self-termination or stable rotation of the scroll wave. The observed arrhythmia characteristics coincide with those measured in the experiment. The developed model can be used to study arrhythmia in rat hearts with myocardial damage from ischemia reperfusion and to examine the possible arrhythmogenic effects of various experimental interventions.Cardiolog

Anatomical Model of Rat Ventricles to Study Cardiac Arrhythmias under Infarction Injury

Species-specific computer models of the heart are a novel powerful tool in studies of life-threatening cardiac arrhythmias. Here, we develop such a model aimed at studying infarction injury in a rat heart, the most common experimental system to investigate the effects of myocardial damage. We updated the Gattoni2016 cellular ionic model by fitting its parameters to experimental data using a population modeling approach. Using four selected cellular models, we studied 2D spiral wave dynamics and found that they include meandering and break-up. Then, using an anatomically realistic ventricular geometry and fiber orientation in the rat heart, we built a model with a postinfarction scar to study the electrophysiological effects of myocardial damage. A post-infarction scar was simulated as an inexcitable obstacle surrounded by a border zone with modified cardiomyocyte properties. For cellular models, we studied the rotation of scroll waves and found that, depending on the model, we can observe different types of dynamics: anchoring, self-termination or stable rotation of the scroll wave. The observed arrhythmia characteristics coincide with those measured in the experiment. The developed model can be used to study arrhythmia in rat hearts with myocardial damage from ischemia reperfusion and to examine the possible arrhythmogenic effects of various experimental interventions. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.This study has been supported by a grant from the Ministry of Science and Higher Education of the Russian Federation (agreement № 075-15-2020-800)

The BLLAST field experiment: Boundary-Layer Late Afternoon and Sunset Turbulence

Due to the major role of the sun in heating the earth's surface, the atmospheric planetary boundary layer over land is inherently marked by a diurnal cycle. The afternoon transition, the period of the day that connects the daytime dry convective boundary layer to the night-time stable boundary layer, still has a number of unanswered scientific questions. This phase of the diurnal cycle is challenging from both modelling and observational perspectives: it is transitory, most of the forcings are small or null and the turbulence regime changes from fully convective, close to homogeneous and isotropic, toward a more heterogeneous and intermittent state. These issues motivated the BLLAST (Boundary-Layer Late Afternoon and Sunset Turbulence) field campaign that was conducted from 14 June to 8 July 2011 in southern France, in an area of complex and heterogeneous terrain. A wide range of instrumented platforms including full-size aircraft, remotely piloted aircraft systems, remote-sensing instruments, radiosoundings, tethered balloons, surface flux stations and various meteorological towers were deployed over different surface types. The boundary layer, from the earth's surface to the free troposphere, was probed during the entire day, with a focus and intense observation periods that were conducted from midday until sunset. The BLLAST field campaign also provided an opportunity to test innovative measurement systems, such as new miniaturized sensors, and a new technique for frequent radiosoundings of the low troposphere. Twelve fair weather days displaying various meteorological conditions were extensively documented during the field experiment. The boundary-layer growth varied from one day to another depending on many contributions including stability, advection, subsidence, the state of the previous day's residual layer, as well as local, meso- or synoptic scale conditions. Ground-based measurements combined with tethered-balloon and airborne observations captured the turbulence decay from the surface throughout the whole boundary layer and documented the evolution of the turbulence characteristic length scales during the transition period. Closely integrated with the field experiment, numerical studies are now underway with a complete hierarchy of models to support the data interpretation and improve the model representations

Role of the residual layer and large-scale subsidence on the development and evolution of the convective boundary layer

Observations, mixed-layer theory and the Dutch Large-Eddy Simulation model (DALES) are used to analyze the dynamics of the boundary layer during an intensive operational period (1 July 2011) of the Boundary Layer Late Afternoon and Sunset Turbulence campaign. Continuous measurements made by remote sensing and in situ instruments in combination with radio soundings, and measurements done by remotely piloted aircraft systems and two manned aircrafts probed the vertical structure and the temporal evolution of the boundary layer during the campaign. The initial vertical profiles of potential temperature, specific humidity and wind, and the temporal evolution of the surface heat and moisture fluxes prescribed in the models runs are inspired by some of these observations. The research focuses on the role played by the residual layer during the morning transition and by the large-scale subsidence on the evolution of the boundary layer. By using DALES, we show the importance of the dynamics of the boundary layer during the previous night in the development of the boundary layer at the morning. DALES numerical experiments including the residual layer are capable of modeling the observed sudden increase of the boundary-layer depth during the morning transition and the subsequent evolution of the boundary layer. These simulations show a large increase of the entrainment buoyancy flux when the residual layer is incorporated into the mixed layer. We also examine how the inclusion of the residual layer above a shallow convective boundary layer modifies the turbulent kinetic energy budget. Large-scale subsidence mainly acts when the boundary layer is fully developed, and, for the studied day, it is necessary to be considered to reproduce the afternoon observations. Finally, we also investigate how carbon dioxide (CO2) mixing ratio stored the previous night in the residual layer plays a fundamental role in the evolution of the CO2 mixing ratio during the following day

Study of a prototypical convective boundary layer observed during BLLAST: contributions by large-scale forcings

We study the influence of the large-scale atmospheric contribution to the dynamics of the convective boundary layer (CBL) in a situation observed during the Boundary Layer Late Afternoon and Sunset Turbulence (BLLAST) field campaign. We employ two modeling approaches, the mixed-layer theory and large-eddy simulation (LES), with a complete data set of surface and upper-air atmospheric observations, to quantify the contributions of the advection of heat and moisture, and subsidence. We find that by only taking surface and entrainment fluxes into account, the boundary-layer height is overestimated by 70 %. Constrained by surface and upper-air observations, we infer the large-scale vertical motions and horizontal advection of heat and moisture. Our findings show that subsidence has a clear diurnal pattern. Supported by the presence of a nearby mountain range, this pattern suggests that not only synoptic scales exert their influence on the boundary layer, but also mesoscale circulations. LES results show a satisfactory correspondence of the vertical structure of turbulent variables with observations. We also find that when large-scale advection and subsidence are included in the simulation, the values for turbulent kinetic energy are lower than without these large-scale forcings. We conclude that the prototypical CBL is a valid representation of the boundary-layer dynamics near regions characterized by complex topography and small-scale surface heterogeneity, provided that surface- and large-scale forcings are representative for the local boundary layer

Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

<p>Abstract</p> <p>Background</p> <p>In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized.</p> <p>Methods</p> <p>COX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis.</p> <p>Results</p> <p>Three unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of <it>POLG </it>were subsequently found in both the 2nd and 3rd patients.</p> <p>Conclusion</p> <p>Histoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent than observed until now. A novel pathogenic mutation in <it>POLG </it>is reported.</p> <p>Tentative explanations for the mitochondrial mosaics are, in one patient, unequal partition of mutated mitochondria during mitoses, and in two others, an interaction between products of several genes required for mtDNA maintenance.</p