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- Computational modeling of In vitro swelling of mitochondria: A biophysical approachPublication . Makarov, Vladimir I.; Khmelinskii, Igor; Javadov, SabzaliSwelling of mitochondria plays an important role in the pathogenesis of human diseases by stimulating mitochondria-mediated cell death through apoptosis, necrosis, and autophagy. Changes in the permeability of the inner mitochondrial membrane (IMM) of ions and other substances induce an increase in the colloid osmotic pressure, leading to matrix swelling. Modeling of mitochondrial swelling is important for simulation and prediction of in vivo events in the cell during oxidative and energy stress. In the present study, we developed a computational model that describes the mechanism of mitochondrial swelling based on osmosis, the rigidity of the IMM, and dynamics of ionic/neutral species. The model describes a new biophysical approach to swelling dynamics, where osmotic pressure created in the matrix is compensated for by the rigidity of the IMM, i.e., osmotic pressure induces membrane deformation, which compensates for the osmotic pressure effect. Thus, the effect is linear and reversible at small membrane deformations, allowing the membrane to restore its normal form. On the other hand, the membrane rigidity drops to zero at large deformations, and the swelling becomes irreversible. As a result, an increased number of dysfunctional mitochondria can activate mitophagy and initiate cell death. Numerical modeling analysis produced results that reasonably describe the experimental data reported earlier.
- External control of the Drosophila melanogaster egg to imago development period by specific combinations of 3D low-frequency electric and magnetic fieldsPublication . Makarov, Vladimir I.; Khmelinskii, IgorWe report that the duration of the egg-to-imago development period of the Drosophila melanogaster, and the imago longevity, are both controllable by combinations of external 3-dimensional (3D) low-frequency electric and magnetic fields (LFEMFs). Both these periods may be reduced or increased by applying an appropriate configuration of external 3D LFEMFs. We report that the longevity of D. melanogaster imagoes correlates with the duration of the egg-to-imago development period of the respective eggs. We infer that metabolic processes in both eggs and imago are either accelerated (resulting in reduced time periods) or slowed down (resulting in increased time periods). We propose that external 3D LFEMFs induce electric currents in live systems as well as mechanical vibrations on sub-cell, whole-cell and cell-group levels. These external fields induce media polarization due to ionic motion and orientation of electric dipoles that could moderate the observed effects. We found that the longevity of D. melanogaster imagoes is affected by action of 3D LFEMFs on the respective eggs in the embryonic development period (EDP). We interpret this effect as resulting from changes in the regulation mechanism of metabolic processes in D. melanogaster eggs, inherited by the resulting imagoes. We also tested separate effects of either 3D electric or 3D magnetic fields, which were significantly weaker.
- Photo-activation of mitochondrial ATP synthesisPublication . Khmelinskii, Igor; Makarov, Vladimir I.ATP production by mitochondria isolated from Saccharomyces cerevisiae cells was accelerated upon both direct and indirect mitochondrial photo-activation (MPA). The extent of direct MPA was dependent on the wavelength of excitation light. Direct MPA was created by light in cytochrome c spectral absorption bands (440, 520 and 550 nm), this light was absorbed producing electronically excited cytochrome c, and the excitation energy of the latter was used in the ATP production chain. The activity of cytochrome c was tested with 600 nm light, where cytochrome c does not absorb, and thus ATP production rate remained the same as in darkness. Note that ATP production rates were significantly larger under light at 550, 520 and 440 nm. Therefore, photo-activation of cytochrome c was the first step of MPA synthesis of ATP. Indirect MPA of ATP production also proceeded via electronically excited cytochrome c, by energy transfer from electronically excited Co/BN film to cytochrome c located in the inner mitochondrial membrane (IMM). Co/BN excitons were generated by photons absorbed by the Co/BN film, which was not in contact with the mitochondrial sample. Next, these excitons propagated along the Co/BN film to the part of the film that was in contact with the mitochondrial sample. There the exciton energy was transferred to cytochrome c located in the IMM, producing electronically excited cytochrome c. Thus, excited cytochrome c was generated in a way different from that of direct MPA. Next, the energy of excited cytochrome c was used in activated ATP synthesis, with virtually the same effect for 519 and 427 nm excitation. Thus, the first step of ATP synthesis in indirect MPA was the exciton energy transfer from Co/BN film to cytochrome c located in the IMM, producing an electronically excited cytochrome c molecule. A phenomenological mechanism of direct and indirect MPA was proposed, and the model parameters were obtained by fitting the model to the experimental data. However, more information is needed before the detailed mechanism of ATP synthesis activation by electronically excited cytochrome c could be understood. The present results support the earlier proposed hypothesis of indirect MPA of ATP production in vertebrate retina in daylight.
- Temperature dependence of IR exciton emission spectra in Müller cell intermediate filamentsPublication . Khmelinskii, Igor; Makarov, Vladimir I.Temperature dependences of IR exciton properties in Muller cell (MC) intermediate filaments (IFs) isolated from porcine retina were studied. It was found that the widths of the spectral emission bands in the 2500 cm-1 and 5000 cm-1 energy ranges grow with temperature. It was found that temperature effects on the bandwidth may be described by thermal activation of the low-frequency vibrational modes of the IFs. The average activation energies for the two IR bands were estimated. Considering the dynamics of IR emission, its buildup time was independent on the sample temperature, while its decay time decreased with temperature. Thus, the emission decay rate increased exponentially with the sample temperature. The mechanisms explaining the observed temperature effects were proposed and discussed. Taking into account that MC IFs are capable of transmitting ATP hydrolysis energy within and between cells, with these properties being apparently common for all IFs, these IFs may be used by cells for physical energy transport and communications. As presently reported, temperature effects upon IR exciton spectra should not affect these proposed physiological functions to any significant extent. Therefore, the currently reported data are important for improving our understanding of the physical communication mechanisms operating within and between cells.
- Theoretical approaches used in the modelling of reversible and irreversible mitochondrial swelling in vitroPublication . Khmelinskii, Igor; Makarov, Vladimir I.Existing theoretical approaches were considered that allow modelling of mitochondrial swelling (MS) dynamics. Simple phenomenological kinetic models were reviewed. Simple and extended biophysical and bioenergetic models that ignore mechanical properties of inner mitochondrial membrane (IMM), and similar models that include these mechanical properties were also reviewed. Limitations of these models we considered, as regards correct modelling of MS dynamics. It was found that simple phenomenological kinetic models have significant limitations, due to dependence of the kinetic parameter values estimated by fitting of the experimental data on the experimental conditions. Additionally, such simple models provide no understanding of the detailed mechanisms behind the MS dynamics, nor of the dynamics of various system parameters during MS. Thus, biophysical and bioenergetic models ignoring IMM mechanical properties can't be used to model the transition between reversible and irreversible MS. However, simple and extended biophysical models that include IMM mechanical properties allow modelling the transition to irreversible swelling. These latter models are still limited due to significantly simplified description of biochemistry, compared to those of bioenergetic models. Finally, a strategy of model development is proposed, towards correct interpretation of the mitochondrial life cycle, including the effects of MS dynamics.
- IR exciton activation mechanism of ethanol oxidation by human alcohol dehydrogenase (ADH) 1A enzymePublication . Khmelinskii, Igor; Makarov, Vladimir I.Low-energy (2500 cm(-1)) exciton transfer was explored in Muller cell (MC) intermediate filaments (IFs) isolated from porcine retina and filling a capillary matrix. Excitons were generated by absorption of IR radiation at 4 mu m. The effects of these excitons on ethanol oxidation by human alcohol dehydrogenase (ADH1A) enzyme were quantified. It was found that IR excitons transferred to the enzyme accelerated alcohol oxidation rate, which increased by the factor of 2.76 when exciting the IFs with 2.39 mu W/cm(2) of 4 mu m IR light. Power dependence of the oxidation rate was also explored. These results show that IFs may be transmitting energy to enzyme mole-cules in vivo, facilitating enzymatic reactions. The required excitons may be produced by cells at the cost of adenosine triphosphate (ATP) hydrolysis energy. Therefore, such control mechanism for enzymatic reactions may be operational in living systems. Direct activation of the enzyme by IR radiation with 4 mu m wavelength did not occur; instead, indirect activation of the IF...ADH1A...NAD (nicotinamide adenine dinucleotide)...EtOH complex occurred by energy transfer of the IR exciton to the ADH1A molecule of this complex. Considering that every living cell has a network of IFs, a similar reaction control mechanism may be operational in vivo, providing a much faster energy supply redirection within the cell than ATP diffusion, and justifying a closer inquiry.
- In silico simulation of reversible and irreversible swelling of mitochondria: The role of membrane rigidityPublication . Makarov, Vladimir I.; Khmelinskii, Igor; Khuchua, Zaza; Javadov, SabzaliMitochondria have been widely accepted as the main source of ATP in the cell. The inner mitochondrial membrane (IMM) is important for the maintenance of ATP production and other functions of mitochondria. The electron transport chain (ETC) generates an electrochemical gradient of protons known as the proton-motive force across the IMM and thus produces the mitochondrial membrane potential that is critical to ATP synthesis. One of the main factors regulating the structural and functional integrity of the IMM is the changes in the matrix volume. Mild (reversible) swelling regulates mitochondrial metabolism and function; however, excessive (irreversible) swelling causes mitochondrial dysfunction and cell death. The central mechanism of mitochondrial swelling includes the opening of non-selective channels known as permeability transition pores (PTPs) in the IMM by high mitochondrial Ca2+ and reactive oxygen species (ROS). The mechanisms of reversible and irreversible mitochondrial swelling and transition between these two states are still unknown. The present study elucidates an upgraded biophysical model of reversible and irreversible mitochondrial swelling dynamics. The model provides a description of the PTP regulation dynamics using an additional differential equation. The rigidity tensor was used in numerical simulations of the mitochondrial parameter dynamics with different initial conditions defined by Ca2+ concentration in the sarco/endoplasmic reticulum. We were able to estimate the values of the IMM rigidity tensor components by fitting the model to the previously reported experimental data. Overall, the model provides a better description of the reversible and irreversible mitochondrial swelling dynamics.
- Quantum spin polarization effect in multi-nanolayer structuresPublication . Makarov, Vladimir I.; Khmelinskii, IgorWe studied the spin-polarized state transport in Fe-SnO2-Ag and Fe-BeO-Ag three-nanolayer sandwich structures. The exchange-resonance spectra of these sandwich structures are quite specific and different from those observed earlier in other three-nanolayer structures. The presently recorded spectra comprise a set of discrete lines, their width increasing with the sample temperature and also with the Ag layer thickness, for both samples. The linewidth dependences on temperature and Ag layer thickness were studied in detail. The effect of thickness of the intermediate nanolayers of SnO2 and BeO on the linewidth was also explored. To explain the observed line broadening effects, we proposed and developed the spin-orbit (SO) coupling mechanism of the electron spin relaxation. In the frameworks of this mechanism, we assumed that the electron spin of a bonding electron in one of the layers of the sandwich system is coupled by SO interaction with the other layers. We found that the change in phonon densities affects the linewidths of the exchange resonance spectra. We estimated the values of the model parameters from the analysis of the experimental data. To that end, we continue further development of our earlier theoretical model, using it to interpret the current experimental results, including ab initio calculations of the electronic structure. The exchange resonance spectra were simulated using phenomenological model, where the anisotropy of the g-factor was introduced. We performed ab initio simulations of the exchange resonance spectra and their linewidths, using Gaussian-2000 and a homemade FORTRAN code.
- Quantum confinement in semiconductor nanofilms: Optical spectra and multiple exciton generationPublication . Khmelinskii, Igor; Makarov, Vladimir I.We report optical absorption and photoluminescence (PL) spectra of Si and SnO2 nanocrystalline films in the UV-vis-NIR range, featuring discrete bands resulting from transverse quantum confinement, observed in the optical spectra of nanofilms for the first time ever. The film thickness ranged from 3.9 to 12.2 nm, depending on the material. The results are interpreted within the particle-in-a-box model, with infinite walls. The calculated values of the effective electron mass are independent on the film thickness and equal to 0.17m(o) (Si) and 0.21m(o) (SnO2), with m(o) the mass of the free electron. The second calculated model parameter, the quantum number n of the HOMO (valence band), was also thickness-independent: 8.00 (Si) and 7.00 (SnO2). The transitions observed in absorption all start at the level n and correspond to Delta n =1, 2, 3,.... The photoluminescence bands exhibit large Stokes shifts, shifting to higher energies with increased excitation energy. In effect, nanolayers of Si, an indirect-gap semiconductor, behave as a direct-gap semiconductor, as regards the transverse-quantized level system. A prototype Si-SnO2 nanofilm photovoltaic cell demonstrated photoelectron quantum yields achieving 2.5, showing clear evidence of multiple exciton generation, for the first time ever in a working nanofilm device. (C) 2016 Elsevier B.V. All rights reserved.
- Spin-anticrossing effects in Co-SiO2-Fe and ZnO-SiO2-CuO three-nanolayer devicesPublication . Khmelinskii, Igor; Makarov, Vladimir I.Presently we report measurements of the spin-anticrossing spectra in the Co-SiO2-Fe and ZnO-SiO2-CuO three-nanolayer sandwich structures. The spin-anticrossing spectra in these systems are quite specific, differing from those observed earlier in other similar structures built of different materials. The theoretical model developed earlier is extended and used to interpret the available experimental results. A detailed ab initio analysis of the magnetic-field dependence of the output magnetic moment is also performed. The model predicts a spin-anticrossing spectrum comprising a series of peaks, with the spectral structure determined by several factors, discussed in the paper. Published by Elsevier Ltd.