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Abstract
We show that zinc finger imprinted 3 (Zim3), when used as Zim3-KRAB-dCas9 effector in interference CRISPR, without any guide RNAs, paradoxically up-regulates key cardiac ion channel genes in human-induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs), responsible for healthy resting membrane potential, repolarization of the action potential, and electrical transmission of signals. These were found to yield expected functional enhancements consistent with a more mature iPSC-CM phenotype, with potentially desirable properties.

The human brain is a small organ which uses a disproportional amount of the total metabolic energy pro- duction in the body. While it is well understood that the most significant energy sink is the maintenance of the neuronal membrane potential during the brain signaling activity, the role of astrocytes in the energy balance continues to be the topic of a lot of research. A key function of astrocytes, besides clearing glutamate from the synaptic clefts, is the potassium clearing after neuronal activation. Extracellular potassium plays a significant role in triggering neuronal firing, and elevated concentration of potassium may lead to abnormal firing pattern, e.g., seizures, thus emphasizing the importance of the glial K+ buffering role. The predictive mathematical model proposed in this paper elucidates the role of glial potassium clearing in brain energy metabolism, integrating a detailed model of the ion dynamics which regulates neuronal firing with a three compartment metabolic model. Because of the very different characteristic time scales of electrophysiology and metabolism, care must be taken when coupling the two models to ensure that the predictions, e.g., neuronal firing frequencies and the oxygen- glucose index (OGI) of the brain during activation and rest, are in agreement with empirical observations. The temporal multi-scale nature of the problem requires the design of new computational tools to ensure a stable and accurate numerical treatment of the problem. The model predictions for different protocols, including combinations of elevated activation and ischemic episodes, are in good agreement with experimental observations reported in the literature. ; This work was supported by the Bizkaia Talent and European Commission through CO- FUND under the grant CIPAS: Computational Inverse Problems Across Scales (AYD-000-278, 2015), by the Basque Government through the BERC 2014-2017 program, and by the Spanish Ministry of Economics and Competitive- ness MINECO through the BCAM Severo Ochoa excellence accreditation SEV-2013-0323 and the Spanish "Plan Estatal de Investigacio ́n, Desarrollo e Innovacio ́n Orientada a los Retos de la Sociedad" under Grant BELEMET - Brain ELEctro-METabolic modeling and numerical approximation (MTM2015-69992-R). The work of Daniela Cal- vetti was partly supported by Grant Number 246665 from the Simons Foundation, and the work of Erkki Somersalo was partly supported by NSF Grant DMS 1016183. Daniela Calvetti and Erkki Somersalo were partly supported by NIH, grant 1U01GM111251-01.

[EN] During atrial fibrillation, cardiac tissue undergoes different remodeling processes at different scales from the molecular level to the tissue level. One central player that contributes to both electrical and structural remodeling is the myofibroblast. Based on recent experimental evidence on myofibroblasts' ability to contract, we extended a biophysical myofibroblast model with Ca2+ handling components and studied the effect on cellular and tissue electrophysiology. Using genetic algorithms, we fitted the myofibroblast model parameters to the existing in vitro data. In silico experiments showed that Ca2+ currents can explain the experimentally observed variability regarding the myofibroblast resting membrane potential. The presence of an L-type Ca2+ current can trigger automaticity in the myofibroblast with a cycle length of 799.9 ms. Myocyte action potentials were prolonged when coupled to myofibroblasts with Ca2+ handling machinery. Different spatial myofibroblast distribution patterns increased the vulnerable window to induce arrhythmia from 12 ms in non-fibrotic tissue to 22 & PLUSMN; 2.5 ms and altered the reentry dynamics. Our findings suggest that Ca2+ handling can considerably affect myofibroblast electrophysiology and alter the electrical propagation in atrial tissue composed of myocytes coupled with myofibroblasts. These findings can inform experimental validation experiments to further elucidate the role of myofibroblast Ca2+ handling in atrial arrhythmogenesis. ; We gratefully acknowledge financial support by the Deutsche Forschungsgemeinschaft (DFG) through DO637/22-3 and LO2093/1-1 and by the KIT-Publication Fund of the Karlsruhe Institute of Technology. This work was supported by the European High-Performance Computing Joint Undertaking EuroHPC under grant agreement No 955495 (MICROCARD) co-funded by the Horizon 2020 programme of the European Union (EU), the French National Research Agency ANR, the German Federal Ministry of Education and Research, and the Research Council of Norway. ...

AbstractThe 'informational content' of Earth's electromagnetic signaling is like a set of operating instructions for human life. These environmental cues are dynamic and involve exquisitely low inputs (intensities) of critical frequencies with which all life on Earth evolved. Circadian and other temporal biological rhythms depend on these fluctuating electromagnetic inputs to direct gene expression, cell communication and metabolism, neural development, brainwave activity, neural synchrony, a diversity of immune functions, sleep and wake cycles, behavior and cognition. Oscillation is also a universal phenomenon, and biological systems of the heart, brain and gut are dependent on the cooperative actions of cells that function according to principles of non-linear, coupled biological oscillations for their synchrony. They are dependent on exquisitely timed cues from the environment at vanishingly small levels. Altered 'informational content' of environmental cues can swamp natural electromagnetic cues and result in dysregulation of normal biological rhythms that direct growth, development, metabolism and repair mechanisms. Pulsed electromagnetic fields (PEMF) and radiofrequency radiation (RFR) can have the devastating biological effects of disrupting homeostasis and desynchronizing normal biological rhythms that maintain health. Non-linear, weak field biological oscillations govern body electrophysiology, organize cell and tissue functions and maintain organ systems. Artificial bioelectrical interference can give false information (disruptive signaling) sufficient to affect critical pacemaker cells (of the heart, gut and brain) and desynchronize functions of these important cells that orchestrate function and maintain health. Chronic physiological stress undermines homeostasis whether it is chemically induced or electromagnetically induced (or both exposures are simultaneous contributors). This can eventually break down adaptive biological responses critical to health maintenance; and resilience can be compromised. Electrohypersensitivity can be caused by successive assaults on human bioelectrochemical dynamics from exogenous electromagnetic fields (EMF) and RFR or a single acute exposure. Once sensitized, further exposures are widely reported to cause reactivity to lower and lower intensities of EMF/RFR, at which point thousand-fold lower levels can cause adverse health impacts to the electrosensitive person. Electrohypersensitivity (EHS) can be a precursor to, or linked with, multiple chemical sensitivity (MCS) based on reports of individuals who first develop one condition, then rapidly develop the other. Similarity of chemical biomarkers is seen in both conditions [histamines, markers of oxidative stress, auto-antibodies, heat shock protein (HSP), melatonin markers and leakage of the blood-brain barrier]. Low intensity pulsed microwave activation of voltage-gated calcium channels (VGCCs) is postulated as a mechanism of action for non-thermal health effects.

et al. ; Therapeutic success of treatment of cerebral diseases must be assessed in terms of functional outcome. In experimental stroke studies, this has been limited to behavioral studies combined with morphological evaluations and single time point functional magnetic resonance imaging (fMRI) measurements butlacking the access to understanding underlying mechanisms for alterations in brain activation. Using a recently developed blood oxygenation level-dependent fMRI protocol to study longitudinal and intraindividual profiles of functional brain activation in the somatosensory system, we have demonstrated activation reemergence in the original representation field as the basic principle offunctional recovery from experimental stroke. No plastic reorganization has been observed atany time point during 7 weeks after stroke induction. Applying combined recording of fMRI and somatosensory evoked potentials, we observed a tight coupling ofelectrical brain activity and hemodynamic response atall times, indicating persistentpreservation ofneurovascular coupling. Identification of functional brain recovery mechanisms has important implications for the understanding of brain plasticity after cerebral lesions, whereas preservation of neurovascular coupling is important for the clinical translation of fMRI. ; This work was supported by grants from the Hertie Foundation (Functional Brain Imaging) and through European Union Project LSHB-CT-2006-037526 (StemStroke). ; Peer reviewed

Ventricular fibrillation (VF) during acute myocardial infarction (AMI) is an important contributor to sudden cardiac death. Large animal models are widely used to study AMI-induced arrhythmia, but the mode of AMI induction ranges from thoracotomy and surgical ligation of a coronary vessel (open chest) to minimally invasive techniques, including balloon occlusion (closed chest). How the choice of induction affects arrhythmia development is unclear. The aim of this study was to compare an open-chest and a closed-chest model with regard to hemodynamics, electrophysiology, and arrhythmia development. Forty-two female Danish Landrace pigs (20 open chest, 22 closed chest) were anesthetized, and occlusion of the mid-left anterior descending coronary artery was performed for 60 min. Opening the chest reduced blood pressure and cardiac output (Δ −22 mmHg, Δ −1.5 L/min from baseline, both P < 0.001 intragroup). Heart rate decreased with opening of the chest but increased with balloon placement (P < 0.001). AMI-induced ST elevation was lower in the open-chest group (P < 0.001). Premature ventricular contractions occurred in two distinct phases (0–15 and 15–40 min), the latter of which was delayed in the open-chest group (P = 0.005). VF occurred in 7 out of 20 and 12 out of 22 pigs in the open-chest and closed-chest groups, respectively (P = 0.337), with longer time-to-VF in the open-chest group (23.4 ± 1.2 min in open chest and 17.8 ± 1.4 min in closed chest; P = 0.007). In summary, opening the chest altered hemodynamic parameters and delayed the onset of ventricular arrhythmias. Hence, in the search for mechanisms and novel treatments of AMI-induced arrhythmia, caution should be taken when choosing between or comparing the results from these two models. ; This work was funded by Novo Nordisk Foundation Synergy program (to T. Jespersen and J. Tfelt-Hansen); Hjertecenterts Forskningsudvalg (to S. M. Sattler); and the European Union's Horizon 2020 Research and Innovation Program (ESCAPE-NET) Grant 733381 (to J. ...

BACKGROUND: Brugada syndrome (BrS) is an inherited electroclinical syndrome and can be occasionally precipitated by fever. The prevalence of Brugada-type electrocardiographic patterns (BTEP) due to febrile illnesses have not been previously studied in India. MATERIALS AND METHODS: Between June 2014 and December 2015, 525 consecutive patients admitted to a government hospital with acute febrile illness were retrospectively enrolled. In addition to their investigations for workup of fever, ECGs were analyzed and BTEP types 1 and 2 were noted. Daily ECGs if available were perused to document reversal. RESULTS: BTEP was seen in 23 (4% 95%CI: 2.9–6.5%): BTEP type 1 (Brugada syndrome) in 11 patients (2%; 95%CI 1.2–3.7%) and BTEP type 2 in 12. All patients with BrS (BTEP type1) were males; mean age and temperature were 37.7 years (SD: 17.6) and 38.8 °C (SD: 0.6), respectively. There were no significant differences in age, temperature or ECG parameters between patients with BTEP and those without. These patients neither had cardiac symptoms nor family history of sudden cardiac deaths. Bacterial infections were the commonest cause of fever in patients with BrS. All BTEP changes resolved with defervesence of fever except in one. CONCLUSION: The prevalence of the fever induced BrS is higher in our study group and is comparable to estimates in Southeast Asian populations. An ECG should be considered in all febrile patients. Further studies are required for better characterization and risk stratification of these patients.

Health care in the United States (US) is undergoing major changes. Although high end health care is probably the best in the world, primary care has been badly lacking, not to mention that in 2010, there were approximately 50 million Americans without health insurance. In 2014, The Commonwealth Fund ranked the US last among the developed countries including Canada and Australia; however we were the first in expenditure. Medicare and Health accounts for 27% of the Federal Budget, and the annual US Health care spending by households, businesses, and the government is due to reach over 3 trillion dollars in 2015. This article reviews and suggests cost containment strategies, the pros and cons of consolidation of health care, and the future of computerized medicine.

1. Dosimetry in bioelectromagnetics / Marko Markov -- 2. Uncertainty sources associated with low-frequency electric and magnetic field experiments on cell cultures / Lucas A. Portelli -- 3. Potential causes for nonreplication of EMF bioeffect results, and what to do about it / Carl F. Blackman -- 4. Physical dynamics : the base for the development of biophysical treatments / Ruggero Cadossi. [et al.] -- 5. Dose and exposure in bioelectromagnetics / Kjell Hansson Mild and Mats-Olof Mattsson -- 6. Physical aspects of radiofrequency radiation dosimetry / Marko S. Andjelkovic and Goran S. Ristic -- 7. Necessary characteristics of quality bioelectromagnetic experimental research / Ben Greenebaum -- 8. External electric and magnetic fields as a signaling mechanism for biological systems / Frank S. Barnes -- 9. Duration of exposure and dose in assessing nonthermal biological effects of microwaves / Igor Belyaev -- 10. Practical principles of dosimetry in studying biological effects of extremely high-frequency electromagnetic fields / Andrew B. Gapeyev -- 11. Experimental approaches for local heating and absorption measurement / Andrei G. Pakhomov -- 12. Dosimetry in electroporation-based technologies and treatments / Eva Pirc, Matej Rebersek, and Damijan Miklavcic -- 13. Quantifying in bioelectromagnetics / Pawel Bienkowski and Hubert Trzaska -- 14. Blood and vascular targets for magnetic field dosing / Harvey N. Mayrovitz -- 15. Methodology of standards development for EMF RF in Russia and by international commissions : distinctions in approaches / Yury G. Grigoriev -- 16. The intracellular signaling system controlling cell hydration as a biomarker for EMF dosimetry / Sinerik Ayrapetyan -- 17. Clinical dosimetry of extremely low-frequency pulsed electromagnetic fields / William Pawluk -- 18. Enhancement of nerve regeneration by selected electromagnetic signals / Betty F. Sisken -- 19. The conundrum of dosimetry : its applications to pharmacology and biophysics are distinct / Wayne Miller.

Myocardial slices are widely used for cardiac electrophysiology research but correspondence of electrophysiological properties between the cardiac slices and the whole heart has not been studied in details. The aim of this study is to investigate the differences in electrophysiological properties between the left ventricle and the longitudinal ventricular slice passing through the apex using mathematical models. ECG signals and the time of activation and repolarization, repolarization dispersion and dispersion of action potential duration were compared. We have shown that the electrophysiological processes in the ventricle and the longitudinal ventricular slice are quite similar, so we believe that cardiac slices can be used to evaluate global electrophysiological properties of the ventricles. The local differences obtained can be explained by differences in geometry and fiber orientation locally affecting depolarization and repolarization in the myocardium. © 2018 Creative Commons Attribution. ; Russian Foundation for Basic Research, RFBR: 16-31-60015, 18-31-00401 ; This work was supported by IIF UrB RAS theme #AAAA-A18-118020590031-8, RFE Government Act #211 of March 16, 2013, the Program of the Presidium RAS #27 and RFBR (#16-31-60015, 18-31-00401).

Via de ogen krijgen mensen een enorme hoeveelheid gegevens binnen. Het blijkt dat veel van deze informatie niet doorgestuurd wordt naar de hersenen en dus verborgen blijft voor waarneming. Het netvlies, een zeer compact netwerk van neuronen dat de binnenkant van ons oog bekleedt, selecteert al wat van belang is en wat niet. Maar welke informatie geselecteerd wordt en wat de onderliggende neuronale mechanismen zijn, is slecht bekend. Er lijkt echter wel een algemeen principe te zijn: onvoorspelbare stimuli worden beter doorgegeven. Zowel zeer globale als zeer gespecialiseerde neurale netwerken

Comunicació presentada a la 9th international conference on Functional Imaging and Modeling of the Heart (FIMH 2017), celebrada els dies 11 a 13 de juny de 2017 a Toronto, Canadà. ; Finite element methods (FEM) are generally used in cardiac 3D-electromechanical modeling. For FEM modeling, a step of a suitable mesh construction is required, which is non-trivial and time-consuming for complex geometries. A meshless method is proposed to avoid meshing. The smoothed particle hydrodynamics (SPH) method was used to solve an electrophysiological model on a left ventricle extracted from medical imaging straightforwardly, without any need of a complex mesh. The proposed method was compared against FEM in the same left-ventricular model. Both FEM and SPH methods provide similar solutions of the models in terms of depolarization times. Main differences were up to 10.9% at the apex. Finally, a pathological application of SPH is shown on the same ventricular geometry with an added scar on the heart wall. ; The work is supported by the European Union Horizon 2020 research and innovation programme under grant agreement No 642676 (CardioFunXion).