Dynamic Thermal Imaging for Intraoperative Monitoring of Neuronal Activity and Cortical Perfusion

Neurosurgery is a demanding medical discipline that requires a complex interplay of several neuroimaging techniques. This allows structural as well as functional information to be recovered and then visualized to the surgeon. In the case of tumor resections this approach allows more fine-grained differentiation of healthy and pathological tissue which positively influences the postoperative outcome as well as the patient's quality of life. In this work, we will discuss several approaches to establish thermal imaging as a novel neuroimaging technique to primarily visualize neural activity and perfusion state in case of ischaemic stroke. Both applications require novel methods for data-preprocessing, visualization, pattern recognition as well as regression analysis of intraoperative thermal imaging. Online multimodal integration of preoperative and intraoperative data is accomplished by a 2D-3D image registration and image fusion framework with an average accuracy of 2.46 mm. In navigated surgeries, the proposed framework generally provides all necessary tools to project intraoperative 2D imaging data onto preoperative 3D volumetric datasets like 3D MR or CT imaging. Additionally, a fast machine learning framework for the recognition of cortical NaCl rinsings will be discussed throughout this thesis. Hereby, the standardized quantification of tissue perfusion by means of an approximated heating model can be achieved. Classifying the parameters of these models yields a map of connected areas, for which we have shown that these areas correlate with the demarcation caused by an ischaemic stroke segmented in postoperative CT datasets. Finally, a semiparametric regression model has been developed for intraoperative neural activity monitoring of the somatosensory cortex by somatosensory evoked potentials. These results were correlated with neural activity of optical imaging. We found that thermal imaging yields comparable results, yet doesn't share the limitations of optical imaging. In this thesis we would like to emphasize that thermal imaging depicts a novel and valid tool for both intraoperative functional and structural neuroimaging

Novel miniaturised and highly versatile biomechatronic platforms for the characterisation of melanoma cancer cells

There has been an increasing demand to acquire highly sensitive devices that are able to detect and characterize cancer at a single cell level. Despite the moderate progress in this field, the majority of approaches failed to reach cell characterization with optimal sensitivity and specificity. Accordingly, in this study highly sensitive, miniaturized-biomechatronic platforms have been modeled, designed, optimized, microfabricated, and characterized, which can be used to detect and differentiate various stages of melanoma cancer cells. The melanoma cell has been chosen as a legitimate cancer model, where electrophysiological and analytical expression of cell-membrane potential have been derived, and cellular contractile force has been obtained through a correlation with micromechanical deflections of a miniaturized cantilever beam. The main objectives of this study are in fourfold: (1) to quantify cell-membrane potential, (2) correlate cellular biophysics to respective contractile force of a cell in association with various stages of the melanoma disease, (3) examine the morphology of each stage of melanoma, and (4) arrive at a relation that would interrelate stage of the disease, cellular contractile force, and cellular electrophysiology based on conducted in vitro experimental findings. Various well-characterized melanoma cancer cell lines, with varying degrees of genetic complexities have been utilized. In this study, two-miniaturized-versatile-biomechatronic platforms have been developed to extract the electrophysiology of cells, and cellular mechanics (mechanobiology). The former platform consists of a microfluidic module, and stimulating and recording array of electrodes patterned on a glass substrate, forming multi-electrode arrays (MEAs), whereas the latter system consists of a microcantilever-based biosensor with an embedded Wheatstone bridge, and a microfluidic module. Furthermore, in support of this work main objectives, dedicated microelectronics together with customized software have been attained to functionalize, and empower the two-biomechatronic platforms. The bio-mechatronic system performance has been tested throughout a sufficient number of in vitro experiments.Open Acces

Developmental delays and subcellular stress as downstream effects of sonoporation

Posters: no. 2Control ID: 1672434OBJECTIVES: The biological impact of sonoporation has often been overlooked. Here we seek to obtain insight into the cytotoxic impact of sonoporation by gaining new perspectives on anti-proliferative characteristics that may emerge within sonoporated cells. We particularly focused on investigating the cell-cycle progression kinetics of sonoporated cells and identifying organelles that may be stressed in the recovery process. METHODS: In line with recommendations on exposure hardware design, an immersion-based ultrasound platform has been developed. It delivers 1 MHz ultrasound pulses (100 cycles; 1 kHz PRF; 60 s total duration) with 0.45 MPa peak negative pressure to a cell chamber that housed HL-60 leukemia cells and lipid-shelled microbubbles at a 10:1 cell-tobubble ratio (for 1e6/ml cell density). Calcein was used to facilitate tracking of sonoporated cells with enhanced uptake of exogenous molecules. The developmental trend of sonoporated cells was quantitatively analyzed using BrdU/DNA flow cytometry that monitors the cell population’s DNA synthesis kinetics. This allowed us to measure the temporal progression of DNA synthesis of sonoporated cells. To investigate whether sonoporation would upset subcellular homeostasis, post-exposure cell samples were also assayed for various proteins using Western blot analysis. Analysis focus was placed on the endoplasmic reticulum (ER): an important organelle with multi-faceted role in cellular functioning. The post-exposure observation time spanned between 0-24 h. RESULTS: Despite maintaining viability, sonoporated cells were found to exhibit delays in cell-cycle progression. Specifically, their DNA synthesis time was lengthened substantially (for HL-60 cells: 8.7 h for control vs 13.4 h for the sonoporated group). This indicates that sonoporated cells were under stress: a phenomenon that is supported by our Western blot assays showing upregulation of ER-resident enzymes (PDI, Ero1), ER stress sensors (PERK, IRE1), and ER-triggered pro-apoptotic signals (CHOP, JNK). CONCLUSIONS: Sonoporation, whilst being able to facilitate internalization of exogenous molecules, may inadvertently elicit a cellular stress response. These findings seem to echo recent calls for reconsideration of efficiency issues in sonoporation-mediated drug delivery. Further efforts would be necessary to improve the efficiency of sonoporation-based biomedical applications where cell death is not desirable.postprin

A study on the change in plasma membrane potential during sonoporation

Posters: no. 4Control ID: 1680329OBJECTIVES: There has been validated that the correlation of sonoporation with calcium transients is generated by ultrasound-mediated microbubbles activity. Besides calcium, other ionic flows are likely involved in sonoporation. Our hypothesis is the cell electrophysiological properties are related to the intracellular delivery by ultrasound and microbubbles. In this study, a real-time live cell imaging platform is used to determine whether plasma membrane potential change is related to the sonoporation process at the cellular level. METHODS: Hela cells were cultured in DMEM supplemented with 10% FBS in Opticell Chamber at 37 °C and 5% CO2, and reached 80% confluency before experiments. The Calcein Blue-AM, DiBAC4(3) loaded cells in the Opticell chamber filled with PI solution and Sonovue microbubbles were immerged in a water tank on a inverted fluorescence microscope. Pulsed ultrasound (1MHz freq., 20 cycles, 20Hz PRF, 0.2-0.5MPa PNP) was irradiated at the angle of 45° to the region of interest for 1s.The real-time fluorescence imaging for different probes was acquired by a cooled CCD camera every 20s for 10min. The time-lapse fluorescence images were quantitatively analyzed to evaluate the correlation of cell viability, intracellular delivery with plasma membrane potential change. RESULTS: Our preliminary data showed that the PI fluorescence, which indicated intracellular delivery, was immediately accumulated in cells adjacent to microbubbles after exposure, suggesting that their membranes were damaged by ultrasound-activated microbubbles. However, the fluorescence reached its highest level within 4 to 6 minutes and was unchanged thereafter, indicating the membrane was gradually repaired within this period. Furthermore, using DIBAC4(3), which detected the change in the cell membrane potential, we found that the loss of membrane potential might be associated with intracellular delivery, because the PI fluorescence accumulation was usually accompanied with the change in DIBAC4 (3) fluorescence. CONCLUSIONS: Our study suggests that there may be a linkage between the cell membrane potential change and intracellular delivery mediated by ultrasound and microbubbles. We also suggest that other ionic flows or ion channels may be involved in the cell membrane potential change in sonoporation. Further efforts to explore the cellular mechanism of this phenomenon will improve our understanding of sonoporation.postprin

How sonoporation disrupts cellular structural integrity: morphological and cytoskeletal observations

Posters: no. 1Control ID: 1672429OBJECTIVES: In considering sonoporation for drug delivery applications, it is essential to understand how living cells respond to this puncturing force. Here we seek to investigate the effects of sonoporation on cellular structural integrity. We hypothesize that the membrane morphology and cytoskeletal behavior of sonoporated cells under recovery would inherently differ from that of normal viable cells. METHODS: A customized and calibrated exposure platform was developed for this work, and the ZR-75-30 breast carcinoma cells were used as the cell model. The cells were exposed to either single or multiple pulses of 1 MHz ultrasound (pulse length: 30 or 100 cycles; PRF: 1kHz; duration: up to 60s) with 0.45 MPa spatial-averaged peak negative pressure and in the presence of lipid-shelled microbubbles. Confocal microscopy was used to examine insitu the structural integrity of sonoporated cells (identified as ones with exogenous fluorescent marker internalization). For investigations on membrane morphology, FM 4-64 was used as the membrane dye (red), and calcein was used as the sonoporation marker (green); for studies on cytoskeletal behavior, CellLight (green) and propidium iodide (red) were used to respectively label actin filaments and sonoporated cells. Observation started from before exposure to up to 2 h after exposure, and confocal images were acquired at real-time frame rates. Cellular structural features and their temporal kinetics were quantitatively analyzed to assess the consistency of trends amongst a group of cells. RESULTS: Sonoporated cells exhibited membrane shrinkage (decreased by 61% in a cell’s cross-sectional area) and intracellular lipid accumulation (381% increase compared to control) over a 2 h period. The morphological repression of sonoporated cells was also found to correspond with post-sonoporation cytoskeletal processes: actin depolymerization was observed as soon as pores were induced on the membrane. These results show that cellular structural integrity is indeed disrupted over the course of sonoporation. CONCLUSIONS: Our investigation shows that the biophysical impact of sonoporation is by no means limited to the induction of membrane pores: e.g. structural integrity is concomitantly affected in the process. This prompts the need for further fundamental studies to unravel the complex sequence of biological events involved in sonoporation.postprin

Real-time imaging of cellular dynamics during low-intensity pulsed ultrasound exposure

Control ID: 1671584Oral Session 5 - Bioeffects of therapeutic ultrasoundOBJECTIVE: Although the therapeutic potential of low-intensity pulsed ultrasound is unquestionable, the wave-matter interactions involved in the process remain to be vaguely characterized. Here we seek to undertake a series of in-situ cellular imaging studies that aim to analyze the mechanical impact of low-intensity pulsed ultrasound on attached fibroblasts from three different aspects: membrane, cytoskeleton, and nucleus. METHODS: Our experimental platform comprised an in-house ultrasound exposure hardware that was coupled to a confocal microscopy system. The waveguided ultrasound beam was geometrically aligned to the microscope’s fieldof-view that corresponds to the center of a polystyrene dish containing fibroblasts. Short ultrasound pulses (5 cycles; 2 kHz PRF) with 0.8 MPa peak acoustic pressure (0.21 W/cm2 SPTA intensity) were delivered over a 10 min period. Live imaging was performed on both membrane (CellMask) and cytoskeleton (actin-GFP, tubulin-RFP) over the entire observation period (up to 30 min after end of exposure). Also, pre- and post-exposure fixed-cell imaging was conducted on the nucleus (Hoechst 33342) and two cytoskeleton components related to stress fibers: F-actin (phalloidin-FITC) and vincullin (Alexa Fluor 647 conjugated). To study whether mechanotransduction was responsible in mediating ultrasound-cell interactions, some experiments were conducted with the addition of gadolinium that blocks stretch-sensitive ion channels. RESULTS: Cell shrinkage was evident over the course of low-intensity pulsed ultrasound exposure. This was accompanied with contraction of actin and tubulin. Also, an increase in central stress fibers was observed at the end of exposure, while the nucleus was found to have decreased in size. Interestingly, after the exposure, a significant rebound in cell volume was observed over a 30 min. period. These effects were not observed in cases with gadolinium blockage of mechanosensitive ion channels. CONCLUSIONS: Our results suggest that low-intensity pulsed ultrasound would transiently induce remodeling of a cell’s membrane and cytoskeleton, and it will lead to repression of nucleus. This indicates that ultrasound after all represents a mechanical stress on cellular membrane. The post-exposure outgrowth phenomenon is also of practical relevance as it may be linked to the stimulatory effects that have been already observed in low-intensity pulsed ultrasound treatments.postprin

Experimental and computational biomedicine : Russian Conference with International Participation in memory of Professor Vladimir S. Markhasin : abstract book

Toward 100 Anniversary of I. P. Pavlov's Physiological Society.The volume contains the presentations that were made during Russian conference with international participation "Experimental and Computational Biomedicine" dedicated to corresponding member of RAS V.S. Markhasin (Ekaterinburg, April 10‒12, 2016). The main purpose of the conference is the discussion of the current state of experimental and theoretical research in biomedicine. For a wide range of scientists, as well as for lecturers, students of the biological and medical high schools.Сборник содержит тезисы докладов, представленных на российской конференции с международным участием «Экспериментальная и компьютерная биомедицина», посвященной памяти члена‐корреспондента РАН В. С. Мархасина (г. Екатеринбург, 10‒12 апреля 2016 г.). Основной целью конференции является обсуждение современного состояния экспериментальных и теоретических исследований в области биомедицины. Сборник предназначен для ученых, преподавателей, студентов и аспирантов биологического и медицинского профиля.МАРХАСИН ВЛАДИМИР СЕМЕНОВИЧ (1941-2015)/ MARKHASIN VLADIMIR SEMENOVICH (1941-2015). [3] PROGRAMM COMMITTEE. [5] ORGANIZING COMMITTEE. [6] KEYNOTE SPEAKERS. [7] CONTENTS. [9] PLENARY LECTURES. [10] Fedotov S. Non-Markovian random walks and anomalous transport in biology. [10] Hoekstra A. Multiscale modelling in vascular disease. [10] Kohl P. Systems biology of the heart: why bother? [10] Meyerhans A. On the regulation of virus infection fates. [11] Panfilov A.V., Dierckx H., Kazbanov I., Vandersickel N. Systems approach to studying mechanisms of ventricular fibrillationusing anatomically accurate modeling. [11] Revishvili A.S. Atrial fibrillation. Noninvasive diagnostic and treatment:from fundamental studies to clinical practice. [12] Rice J. Life sciences research at IBM. [12] Roshchevskaya I.M., Smirnova S., Roshchevsky M.P. Regularities of the depolarization of an atria:an experimental comparative-physiological study. [12] Rusinov V.L., Chupahin O.N., Charushin V.N Scientific basis for development of antiviral drugs. [13] Solovyova O.E. Tribute Lecture. Mechano-electric heterogeneity of the myocardiumas a paradigm of its function. [13] Veksler V. Myocardial energy starvation in chronic heart failure:perspectives for metabolic therapy. [13] Wladimiroff J.W. Fetal cardiac assessment using new methodsof ultrasound examination. [14] Yushkov B.G., Chereshnev V.A. The important questions of regeneration theory. [14] EXPERIMENTAL AND COMPUTATIONAL MODELS IN CARDIOVASCULARPHYSIOLOGY AND CARDIOLOGY. [15] EXPERIMENTAL AND COMPUTATIONAL MODELS IN CARDIOVASCULARPHYSIOLOGY AND CARDIOLOGY. [15] Arteyeva N. T-wave area along with Tpeak-Tend interval is the most accurateindex of the dispersion of repolarization. [15] Borodin N., Iaparov B.Y., Moskvin A. Mathematical modeling of the calmodulin effect on the RyR2 gating. [15] Dokuchaev A., Katsnelson L.B., Sulman T.B., Shikhaleva E.V., Vikulova N.A. Contribution of cooperativity to the mechano-calcium feedbacksin myocardium. Experimental discrepancy and mathematicalapproach to overcome it. [16] Elman K.A., Filatova D.Y., Bashkatova Y.V., Beloschenko D.V. The stochastic and chaotic estimation of parametersof cardiorespiratory system of students of Ugra. [16] Erkudov V.O., Pugovkin A.P., Verlov N.A., Sergeev I.V., Ievkov S.A., Mashood S., Bagrina J.V. Characteristics of the accuracy of calculation of values of systemic blood pressure using transfer functions in experimental blood loss and its compensation. [16] Ermolaev P., Khramykh T.Mechanisms of cardiodepression after 80% liver resection in rats. [17] Filatova O.E., Rusak S.N., Maystrenko E.V., Dobrynina I.Y. Aging dynamics of cardio-vascular parameters аboriginal systemand alien population of the Russian North. [17] Frolova S., Agladze K.I., Tsvelaya V., Gaiko O. Photocontrol of voltage-gated ion channel activity by azobenzenetrimethylammonium bromide in neonatal rat cardiomyocytes. [18] Gorbunov V.S., Agladze K.I., Erofeev I.S. The application of C-TAB for excitation propagation photocontrolin cardiac tissue. [18] Iribe G. Localization of TRPC3 channels estimated by in-silicoand cellular functional experiments. [19] Kachalov V.N., Tsvelaya V., Agladze K.I. Conditions of the spiral wave unpinning from the heterogeneitywith different boundary conditions in a model of cardiac tissue. [19] Kalita I., Nizamieva A.A., Tsvelaya V., Kudryashova N., Agladze K.I. The influence of anisotropy on excitation wave propagationin neonatal rat cardiomyocytes monolayer. [19] Kamalova Y. The designing of vectorcardiograph prototype. [20] Kapelko V., Shirinsky V.P., Lakomkin V., Lukoshkova E., Gramovich V.,Vyborov O., Abramov A., Undrovinas N., Ermishkin V. Models of chronic heart failure with acute and gradual onset. [20] Khassanov I., Lomidze N.N., Revishvili A.S. Remote Patient Monitoring and Integration of Medical Data. [20] Kislukhin V. Markov chain for an indicator passing throughoutcardio-vascular system (CVS). [21] Konovalov P.V., Pravdin S., Solovyova O.E., Panfilov A.V. Influence of myocardial heterogeneity on scroll wave dynamicsin an axisymmetrical anatomical model of the left ventricle of thehuman heart. [21] Koshelev A., Pravdin S., Ushenin K.S., Bazhutina A.E. An improved analytical model of the cardiac left ventricle. [22] Lookin O., Protsenko Y.L. Sex-related effects of stretch on isometric twitch and Ca2+ transientin healthy and failing right ventricular myocardiumof adult and impuberal rats. [22] Moskvin A. Electron-conformational model of the ligand-activated ion channels. [22] Nezlobinsky T., Pravdin S., Katsnelson L.B. In silico comparison of the electrical propagation wave alongmyocardium fibers in the left ventricle wall vs. isolation. [23] Nigmatullina R.R., Zemskova S.N., Bilalova D.F., Mustafin A.A., Kuzmina O.I., Chibireva M.D., Nedorezova R.S. Valid method for estimation of pulmonary hypertention degreein children. [23] Parfenov A. Mathematical modeling of the cardiovascular systemunder the influence of environmental factors. [24] Pimenov V.G., Hendy A. Adaptivity of the alternating direction method for fractional reactiondiffusion equation with delay effects in electrocardiology. [24] Podgurskaya A.D., Krasheninnikova A., Tsvelaya V., Kudryashova N., Agladze K.I. Influence of alcohols on excitation wave propagationin neonatal rat ventricular cardiomyocyte monolayer. [24] Pravdin S. A mathematical model of the cardiac left ventricle anatomy and morphology. [24] Seemann G. Cause and effects of cardiac heterogeneity:insights from experimental and computational models. [25] Seryapina A.A., Shevelev O.B. Basic metabolomic patterns in early hypertensive rats: MRI study. [25] Shestakov A.P., Vasserman I.N., Shardakov I.N. Modeling of cardiac arrhythmia generation caused bypathological distribution of myocardial conductivity. [26] Shutko A.V., Gorbunov V.S., Nizamieva A.A., Guriya K.G., Agladze K.I. Contractile micro-constructs from cardiac tissue culturefor the research of autowave propagation in excitable systems. [26] Simakov S., Gamilov T., Kopylov Ph. Computational study of the haemodynamic significanceof the stenosis during multivessel coronary disease. [27] Syomin F., Zberiya M.V. A numerical simulation of changes in the performance of the leftventricle of the heart under various hemodynamic conditions. [27] Tsaturyan A. A simple model of cardiac muscle:mechanics, actin-myosin interaction and Ca-activation. [27] Tsvelaya V., Krasheninnikova A., Kudryashova N., Agladze K.I. Calcium-current dominated upstroke in severe hyperkalemia. [28] Ushenin K.S., Pravdin S., Chumarnaya T.V., Alueva Y.S., Solovyova O.E. Dynamics of scroll wave filaments in personalized modelsof the left ventricle of the human heart. [28] Vasserman I.N., Shardakov I.N., Shestakov A.P. Deriving of macroscopic intracellular conductivity of deformedmyocardium based on its microstructure. [28] Vassilevski Y.V., Pryamonosov R., Gamilov T. Personalized 3D models and applications. [29] Zun P.S., Hoekstra A., Anikina T.S. First results of fully coupled 3D models of in-stent restenosis. [29] BIOMECHANICS. EXPERIMENTAL AND MATHEMATICAL MODELSSBIOMECHANICS. EXPERIMENTAL AND MATHEMATICAL MODELS. EXPERIMENTAL AND MATHEMATICAL MODELS. [30] Balakin A., Kuznetsov D., Protsenko Y.L. The ‘length-tension’ loop in isolated myocardial preparations of theright ventricle of normal and hypertrophied hearts of male rats. [30] Belousova M.D., Kruchinina A.P., Chertopolokhov V.A. Automatic control model of the three-tier arm type manipulatorin the aimed-movement task. [30] Berestin D.K., Bazhenova A.E., Chernikov N.A., Vokhmina Y.V. Mathematical modeling of dynamics of development of Parkinson'sdisease on the tremor parameters. [31] Dubinin A.L., Nyashin Y.I., Osipenko M.A. Development of the biomechanical approach to tooth movementunder the orthodontic treatment. [31] Galochkina T., Volpert V. Reaction-diffusion waves in mathematical model of bloodcoagulation. [31] Golov A.V., Simakov S., Timme E.A. Mathematical modeling of alveolar ventilationand gas exchange during treadmill stress tests. [32] Gurev V., Rice J. Strain prediction in 3D finite element models of cardiac mechanics. [32] Kamaltdinov M.R. Simulation of digestion processes in antroduodenum:food particles dissolution in consideration of functional disorders. [33] Khamzin S., Kursanov A., Solovyova O.E. Load-dependence of the electromechanical function of myocardiumin a 1D tissue model. [33] Khokhlova A., Iribe G., Solovyova O.E Transmural gradient in mechanical properties of isolatedsubendocardial and subepicardial cardiomyocytes. [33] Kruchinin P.A. Optimal control problem and indexesof stabilometric "test with the visual step input". [34] Kruchinina A.P., Yakushev A.G. A study of the edge segments of saccadic eye trajectory. [34] Kursanov A., Khamzin S., Solovyova O.E. Load-dependence of intramyocardial slow force responsein heterogeneous myocardium. [35] Lisin R.V., Balakin A., Protsenko Y.L. Experimental study of the intramyocardial slow force response. [35] Melnikova N.B., Hoekstra A. The mechanics of a discrete multi-cellular model of arterial in‐stent restenosis. [35] Murashova D.S., Murashov S.A., Bogdan O.P., Muravieva O.V., Yugova S.O. Modelling of soft tissue deformation for static elastometry. [36] Nikitin V.N., Tverier V.M., Krotkikh A.A. Occlusion correction based on biomechanical modelling. [36] Nyashin Y.I., Lokhov V.A. Development of the “Virtual physiological human” concept. [37] Shulyatev A.F., Akulich Y.V., Akulich A.Y., Denisov A.S. 3D FEA simulation of the proximal human femur. [37] Smoluk A.T., Smoluk L.T., Balakin A., Protsenko Y.L., Lisin R.V. Modelling viscoelastic hysteresis of passive myocardial sample. [37] Svirepov P.I. Mathematical modeling of the left atria mechanical actionwith mitral regurgitation. [38] Svitenkov A., Rekin O., Hoekstra A. Accuracy of 1D blood flow simulations in relation to level of detailof the arterial tree model. [38] Tsinker M. Mathematical modelling of airflow in human respiratory tract. [39] Wilde M.V. Influence of artificial initial and boundary conditionsin biomechanical models of blood vessels. [39] ELECTROPHYSIOLOGY. EXPERIMENTAL AND COMPUTATIONAL MODELS. CLINICAL STUDIES. [40] Agladze K.I., Agladze N.N. Arrhythmia modelling in tissue culture. [40] Golovko V., Gonotkov M.A. Pharmacological analysis of transmembrane action potential'smorphology of myoepitelial cells in the spontaneously beating heartof ascidia Styela rustica. [40] Gonotkov M.A., Golovko V. The crucial role of the rapidly activating component of outwarddelayed rectifier K-current (IKr) in pig sinoauricular node (SAN). [40] Danilov A.A. Numerical methods for electrocardiography modelling. [41] Kolomeyets N.L., Roshchevskaya I.M. The electrical resistivity of a segment of the tail, lungs, liver,intercostal muscles of grass snakes during cooling. [41] Kharkovskaia E., Zhidkova N., Mukhina I.V., Osipov G.V. Role of TRPC1 channels in the propagation of electrical excitationin the isolated rat heart. [42] Lubimceva T.A., Lebedeva V.K., Trukshina M.A., Lyasnikova E.A., Lebedev D.S. Ventricular lead position and mechanical dyssynchronyin response to cardiac resynchronization therapy. [42] Poskina T.Y., Shakirova L.S., Klyus L.G., Eskov V.V. Stochastics and chaotic analysis of electromyogramand electroencefalogramm. [42] Prosheva V.I. New insights into the pacemaker and conduction systemcells organization in the adult avian heart. [43] Suslonova O., Smirnova S., Roshchevskaya I.M. Cardioelectric field in rats with experimental pulmonaryhypertension during ventricular depolarization. [43] Syunyaev R.A., Karpaev A.A., Aliev R.R. Simulation of the fibroblasts effect on synchronizationand rhythmogenesis in the sinoatrial node. [44] Zorin N.M., Ryvkin A.М., Moskvin A. Cooperation of membrane and calcium oscillatorsin sinoatrial node cells. [44] EXPERIMENTAL AND COMPUTATIONAL MODELS IN IMMUNOLOGY. [45] Bocharov G. Systems approach to modelling the "virus-host organism" interactionin infectious diseases. [45] Brilliant S.A. Impact of immobilization stress on change of protein fractionshemoglobin of bone marrow in rats. [45] Bykova M. The features of biochemical properties of extracellular matrix of bonemarrow in rats in conditions which stimulate granulocytopoiesis. [45] Chigvintsev V.M. A mathematical model of the functioning and mutual regulation ofthe immune and neuroendocrine systems in response to viralexposure under the impact of environmental factors, taking intoaccount the evolution of synthetic function impairment. [46] Khramtsova Y. The role of mast cells in the regulation of repair testicles. [46] Novikov M.Y., Kim A.V. Simulation of immune processes using Bio-Medical Software Package. [47] Polevshchikov A.V., Bondar A.V., Gumovskaya J.P. Modelling of t cell extravasation into a lymph node:from morphological basics towards clonal selection theory. [47] Tuzankina I.A., Sarkisyan N., Bolkov M., Tihomirov L.B., Bass E.A. Oral and maxillofacial manifestationsof primary immunodeficiency syndroms. [47] Zaitsev S.V., Polevshchikov A.V. Evaluation of probabilities of antigen recognition by T-lymphocytesin the lymph node: a mathematical model. [48] MOLECULAR BASIS OF BIOLOGICAL MOTILITY. [49] Bershitsky S.Y., Nabiev S., Kopylova G., Shchepkin D., Matyushenko A.M., Koubassova N.A., Levitsky D.I., Tsaturyan A. Mutations in the central part of tropomyosin molecule affectthe actomyosin interaction. [49] Borovkov D.I., Kopylova G., Shchepkin D., Nabiev S., Matyushenko A.M., Levitsky D.I. Functional studies of tropomyosin mutations associatedwith dilated and hypertrophic cardiomyopathy. [49] Fatkhrakhmanova M.R., Mukhutdinova K.A., Kasimov M.R., Petrov A.M. The role of glutamate NMDA-receptor-NO synthase axis in the effectof 24-hydroxycholesterolon synaptic vesicle exocytosis at the mouseneuromuscular junctions. [50] Gritsyna Y., Vikhlyantsev I.M., Salmov N., Bobylev A.G., Podlubnaya Z.A. Increasing μ-calpain activity in striated muscles of alcohol-fed rats. [50] Kochubey P.V., Bershitsky S.Y. Study of biphasic tension rise in contracting muscle fiberduring ramp stretch. [51] Kopylova G., Shchepkin D., Nabiev S., Nikitina L., Bershitsky S.Y. The Ca2+ regulation of actin-myosin interactionin atrium and ventricle. [51] Nabiev S., Bershitsky S.Y., Tsaturyan A. Measurements of the bending stiffnessof reconstructed thin filament with the optical trap. [51] Shchepkin D., Kopylova G., Matyushenko A.M., Popruga K.E., Pivovarova A.V., Levitsky D.I. Structural and functional studies of tropomyosin species withcardiomyopathic mutations in the areaof tropomyosin-troponin contact. [52] Shenkman B., Nemirovskaya T.L., Lomonosova Y.N., Lyubimova K.A., Ptitsyn K.G. Nitric oxide in uloaded muscle: powerless guard of stability. [52] Shirinsky V.P., Kazakova O.A., Samsonov M.V., Khalisov M.M., Khapchaev A.Yu., Penniyaynen V.A., Ankudinov A.V., Krylov B.V.Spatiotemporal activity profiling of key myosin regulators inendothelial cells with regard to control of cell stiffnessand barrier dysfunction. [53] Yakupova E.I., Bobylev A.G., Vikhlyantsev I.M., Podlubnaya Z.A. Smooth muscle titin forms aggregates with amyloid-likedye-binding properties. [53] MEDICAL BIOINFORMATICS. [54] Eskov V.M., Khadartsev A.A., Gavrilenko T.V., Filatov M.A. Homeostasis and the evolution of complex biological systems. [54] Gorbunov D.V., Garaeva G.R., Sinenko D.V., Grigorenko V.V. Limit of applicability the theorem of Glansdorf-Prigoginein the describing homeostatic systems. [54] Iaparov B.Y., Moskvin A., Solovyova O.E. Electron-conformational transformations governthe temperature dependence of the RYR2 gating. [54] Lookin N. Towards to the bio-computer: from serial von Neumann architectureto systolic computer system in one chip. [55] Obesnyuk V.F. Hybrid technology of cohort rate of conditionallifetime risk trend assessment. [55] Parshin D.V., Cherevko A., Chupakhin A., Orlov K., Ufimtseva I., Krivoshapkin A. Analytical methods for diagnostics of cerebral aneurysms. [56] Rudenko E., Shchegolev B. Parathyroid hypertensive factor (PHF) - β2-adrenergic receptorpotential antagonist. [56] Ryvkin A.М., Moskvin A. Probabilistic theory of ions binding to RYR-channelwithin the improved electron-conformational model. [56] Shadrin K.V., Pakhomova V., Rupenko A. Stoichiometric modeling of oxygen transport through the surfaceof the isolated perfused rat liver at various oxygenation conditions. [57] Zubarev A.Y. Theoretical modelling of magnetic hyperthermia. [57] TRANSLATIONAL MEDICINE. FROM BASIC SCIENCE TO CLINICAL PRACTICE. [58] Blinkova N.B., Danilova I.G., Gette I.F., Abidov M.T., Pozdina V.A. Features of the regenerative processesin the rat liver exposed to alloxan diabetes with stimulationof macrophages functional activity. [58] Bulavintseva T.S., Danilova I.G., Brilliant S.A. The response of macrophage to chronic hyperglycemiabefore and after modulation of macrophage functional phenotype. [58] Chumarnaya T.V., Alueva Y.S., Kochmasheva V.V., Mikhailov S.P., Ostern O.V., Sopov O.V., Solovyova O.E. Specific features of the functional geometryof the left ventricle in myocardial diseases. [59] Kolobov A.V., Kuznetsov M.B., Simakov S., Gorodnova N. Multiscale modeling of angiogenic tumor growth and progression. [59] Maryakhina V.S., Ovechkin M.V., Spirina V.I. Laser flash photolysis in investigation of breast cancerat different stages of tumor development. [59] Nikitina E.A., Zhuravlev A.V., Zakharov G.A., Medvedeva A.V., Dolgaya Y.F., Ivanova P.N., Tokmacheva E.V., Savvateeva-Popova E.V. Genetic and epigenetic aspectsof neurodegenerative diseases etiopathogenesis. [60] Pichugova S.V., Komarova S.Y., Beykin Y.B. Electron microscopy in the diagnosis of male infertility. [60] Pyankova Z.A., Medvedeva S.Y., Gette I.F., Belousova A.V. Influence of the pericellular microenvironmentto the functional liver cells damaged by toxin. [61] Smirnyh S.E., Chereshneva M.V., Danilova I.G.The dynamics of the regenerative processes in the retina in rats withalloxan diabetes and after injectionof tetrahydrophthalazine derivatives. [61] Solodushkin S.; Stolyar A. Mathematical modelling of the kidney transplant outcomes. [62] Tsyvian P.B. Hemodynamics and regulation of angiogenesis in human embryoconceived by in vitro fertilization. [62] Zotova N. Methodological approaches to identificationof Systemic Inflammation under sepsis. [62] MEDICAL CHEMISTRY[64] Bozhko Y., Bakhtin V.M., Belokonova N.A. On correction and prevention of magnesium deficiency. [64] Chernaya L.V., Kovalchuk L.A., Nokhrina E.S., Nikonov G.I. Biological active trace elements of medicinal leeches Hirudomedicinalis L., 1758 and Hirudo verbana Carena, 1820, grown inartificial conditions of regional biofactories in Russia. [64] Emelianov V.V., Savateeva E.A., Sidorova L.P., Tseitler T.A., Gette I.F., Bulavintseva T.S., Smirnyh S.E., Danilova I.G., Maksimova N.E., Mochulskaya N.N., Chupakhin O.N., Chereshnev V.A. 1,3,4-thiadiazine derivates – antioxidants and protein glycationblockers – for correction of experimental diabetes mellitus. [65] Gagarin I., Tonkushina M.O., Ostroushko A.A., Grzhegorzhevskii K.V. Modelling of {Mo72Fe30} electrophoresis. [65] Kurgina T.A., Anarbaev R.O., Lavrik O.I. Poly(ADP-ribose)polymerase 1 is one of the targetsfor the anti-cancer drugs search. [66] Sapozhnikova I.M., Deeva E.G., Konovalova N.I. Synthesis and antiviral activity of nitrile-containing1,2,4-triazolo [5,1-c]-1,2,4-triazines. [66] Savateev K. New perspective series of adenosine receptors inhibitors. [66] Tarkhanova A.E., Kovalchuk L.A. The estimate of the concentrations of macroelements and traceelements in the biological system of obese pregnant women: (bloodof mother – placenta – blood of newborn babies). [67] Tonkushina M.O., Ostroushko A.A., Gagarin I. Associates of Mo72Fe30. [67] Trebukhov A.V., Shirmanova E.A., Trebuhov A.V. The study of the effects of L-arginine and taurine-contains drugs onplatelet aggregation performance and lipid metabolism in patientswith heart diseases. [68] Voinkov E. Nitroacetonitrile is the intermediatefor the synthesis of azolo-6-azapurines. [68] BIOMEDICAL TECHNOLOGY. [69] Balashov V.A., Agladze K.I., Agapov I.I., Efimov A.E. The study of cardiomyocyte structureby scanning probe nanotomography. [69] Chibireva M.D. Development of the way of early diagnosticof essential arterial hypertension different forms in adolescents. [69] Ivanov V.Y., Antsygin I.N., Sedunova I.Н., Myshkina A.V Training for biomedical engineering at the Ural Federal University. [70] Klyueva Y. CD45RA+ T-lymphocytes levels evaluation

Micro/nanofluidic and lab-on-a-chip devices for biomedical applications

Micro/Nanofluidic and lab-on-a-chip devices have been increasingly used in biomedical research [1]. Because of their adaptability, feasibility, and cost-efficiency, these devices can revolutionize the future of preclinical technologies. Furthermore, they allow insights into the performance and toxic effects of responsive drug delivery nanocarriers to be obtained, which consequently allow the shortcomings of two/three-dimensional static cultures and animal testing to be overcome and help to reduce drug development costs and time [2–4]. With the constant advancements in biomedical technology, the development of enhanced microfluidic devices has accelerated, and numerous models have been reported. Given the multidisciplinary of this Special Issue (SI), papers on different subjects were published making a total of 14 contributions, 10 original research papers, and 4 review papers. The review paper of Ko et al. [1] provides a comprehensive overview of the significant advancements in engineered organ-on-a-chip research in a general way while in the review presented by Kanabekova and colleagues [2], a thorough analysis of microphysiological platforms used for modeling liver diseases can be found. To get a summary of the numerical models of microfluidic organ-on-a-chip devices developed in recent years, the review presented by Carvalho et al. [5] can be read. On the other hand, Maia et al. [6] report a systematic review of the diagnosis methods developed for COVID-19, providing an overview of the advancements made since the start of the pandemic. In the following, a brief summary of the research papers published in this SI will be presented, with organs-on-a-chip, microfluidic devices for detection, and device optimization having been identified as the main topics.info:eu-repo/semantics/publishedVersio

Action potentials as indicators of metabolic perturbations for temporal proteomic analysis

The single largest cause of compound attrition during drug development is due to inadequate tools capable of predicting and identifying protein interactions. Several tools have been developed to explore how a compound interferes with specific pathways. However, these tools lack the potential to chronically monitor the time dependent temporal changes in complex biochemical networks, thus limiting our ability to identify possible secondary signaling pathways that could lead to potential toxicity. To overcome this, we have developed an in silico neuronal-metabolic model by coupling the membrane electrical activity to intracellular biochemical pathways that would enable us to perform non-invasive temporal proteomics. This model is capable of predicting and correlating the changes in cellular signaling, metabolic networks and action potential responses to metabolic perturbation. The neuronal-metabolic model was experimentally validated by performing biochemical and electrophysiological measurements on NG108-15 cells followed by testing its prediction capabilities for pathway analysis. The model accurately predicted the changes in neuronal action potentials and the changes in intracellular biochemical pathways when exposed to metabolic perturbations. NG108-15 cells showed a large effect upon exposure to 2DG compared to cyanide and malonate as these cells have elevated glycolysis. A combinational treatment of 2DG, cyanide and malonate had a much higher and faster effect on the cells. A time-dependent change in neuronal action potentials occurred based on the inhibited pathway. We conclude that the experimentally validated in silico model accurately predicts the changes in neuronal action potential shapes and proteins activities to perturbations, and would be a powerful tool for performing proteomics facilitating drug discovery by using action potential peak shape analysis to determine pathway perturbation from an administered compound