The main achievements of the Institute
It has been shown that in the human population there are from 2% to 12% percent of X-people possessing an unusual combination of receptor systems that allow constructing a virtual world of new images inside the brain. This phenomenon is called synesthesia.
Back in the early twentieth century, academician P.P. Lazarev intuitively put forward the postulate that such a unification is possible, having considered only one particular version of synesthesia. At that time, this discovery was not understood and declared a lie. Half a century later, it was proved that synesthesia exists, today interest in its study has increased greatly.
The influence of synesthesia on a significant decrease in the characteristic time of memorizing and analyzing large amounts of information has been proven.
It is not a pathology and can have both a genetic basis and be acquired in the process of intensive purposeful work in creative processes (artists, scientists, architects, etc.).
The emergence of synesthesia is associated with the restructuring of the cerebral structures of the cerebral cortex, stimulated by waves of the hippocampus, which leads to the formation, based on a combinatorial enhancement, of connections in the cerebral cortex between the display areas of the receptor systems (see Fig.). The result of rearrangements in the connections of the brain makes it possible to transform multiparameter phenomena observed by a person in the external world into the form of generalized virtual images in the form of shapes that differ from each other in their topology or color. (FGBUN Institute for Theoretical and Experimental Biophysics of the Russian Academy of Sciences (ITEB RAS), Corresponding Member of the RAS Ivanitsky G.R.)
Reconstruction of the cerebral structures of the cerebral cortex, stimulated by waves of the hippocampus, which leads to the formation on the basis of a combinatorial enhancement of connections in the cerebral cortex between the display areas of the receptor systems.
Obtaining strains of superproducers of mutant forms of nickase BspD6I. The work was aimed at studying a new phenomenon - DNA polymerase synthesis of new genetic information from free dNTPs (DNA synthesis ab initio). A method has been developed to prevent calcification and degeneration of vascular and heart valve grafts. Were cloned and synthesized recombinant proteins of particularly dangerous pathogens and obtained monoclonal antibodies to them.
Our study continues the research of the mechanisms of epilepsy, one of the most widespread and heterogeneous neurological disorders. A decrease in brain glucose consumption is an early common symptom of all major neurodegenerative diseases, including acquired epilepsy. However, the mechanisms for this inhibition of glucose metabolism remain unclear. In the work, we showed that ictal activity leads to oxidative stress in the brain tissue, followed by rapid and prolonged inhibition of glucose utilization. Thus, seizure activity maintains and aggravates glucose hypometabolism in the brain, creating a vicious circle of epileptogenesis. It was shown that such a pathological cycle might be ripped by normalization of glucose metabolism in the brain by using of exogenous energy substrates. The current study may serve as the basis for the effective treatment of seizure disorders. The work was carried out within the international collaboration with Unite 751 of the French National Institute of Health and Medical Research (INSERM UMR1106, Institut de Neurosciences des Systèmes, Aix-Marseille University, Marseille, France). (ITEB RAS, Ph.D. Malkov A.E.)
Results published in the journal Neurobiology of Disease:
Malkov A, Ivanov AI, Buldakova S, Waseem T, Popova I, Zilberter M, Zilberter Y. Seizure-induced reduction in glucose utilization promotes brain hypometabolism during epileptogenesis. Neurobiol Dis. 2018 Aug;116:28-38. doi: 10.1016/j.nbd.2018.04.016.
It is shown that low-amplitude transcranial stimulation with electric current (tDCS) affects cognitive activity: solving logical, geometric and arithmetic problems. The result depends on the polarity of the stimulus: anodic stimulation improves cognitive performance, while with cathodic stimulation, the effect is subtle. Anodic stimulation increases electrical activity of the cortex, increases efficiency of cognitive activity and optimizes the autonomous activation of resources during cognitive load. Cathodic stimulation affects the spectral power of the EEG, depending on the individual balance of excitation and inhibition in the brain and increases the influence of the parasympathetic branch of the autonomic nervous system. Thus, low-amplitude transcranial stimulation with electric current, being a promising non-invasive method, can be used to improve cognitive performance. (ITEB RAS, Doctor of Physical and Mathematical Sciences Aliev R.R.).
For the first time it was shown that in case of chronic hyperammonemia caused by portacaval shunting, the accumulation of ammonia in different parts of the animal brain was associated with the activation of ammonia-forming reactions, which, regardless of its concentration in the blood, independently contributed to the development of convulsive seizures and coma. A direct correlation between the concentration of ammonia in non-synaptic mitochondria of the brain and the rate of formation of a superoxide radical that initiated the development of oxidative stress was also revealed. In addition, it was shown that the cerebellum (unlike the hippocampus, striatum, neocortex) was more sensitive to ammonium-induced oxidative stress. The results obtained show that there are fundamental differences between the mechanisms of regulation of ammonia homeostasis in different parts of the brain and provide a better understanding of the causes of degeneration and death of cerebellar neurons observed in diseases that are associated with chronic hyperammonemia (ITEB RAS, Dr. E.A. Kosenko, DSc (Biology).
The role of cerebellar mitochondria in the development of oxidative stress under the action of ammonia which is formed in the brain during portacaval shunting (PCS - portacaval shunting; O2• - - superoxide radical; NOS - NO-synthase; Mn2+ - SOD - Mn2+ - form of superoxide dismutase.
Results published in the journal Free Radical Biology & Medicine
Kosenko E.A., Tikhonova LA, Alilova GA, Montoliu C, Barreto GE, Aliev G, Kaminsky YG. Portacaval shunting causes differential mitochondrial superoxide production in brain regions. Free Radic Biol Med. 2017, 28 (113), 109-118.
It is known that cell membranes, due to the energy of interfacial interactions in lipids and proteins, form a three-dimensional cellular network in the cytoplasm. In experiments with living cells, as well as on model systems, the influence of both chemical and physical agents on the energy of interfacial interactions and the stability of phases was studied. In particular, the influence of polyphenolic compounds of plant origin on the phase state of biological membranes and formation of a network of fibrillar proteins was studied. It has been shown that the flavonoids taxifolin and kaempferol can accelerate the formation of a network of collagen protein fibrils, while quercetin and myricetin can prevent the formation of these fibrils. The kinetics of interfacial interactions can be controlled using the action of not only chemical but also physical agents, including electromagnetic irradiation, temperature and pressure changes. We have developed a kinetic model that covers the main molecular events in cellular regulatory networks with feedback, including protein-protein interactions, activation and deactivation of GTPases, phosphorylation and dephosphorylation. The methods for increasing / decreasing the energy of interphase barriers that determine the stability of proteins and membranes are of practical importance and can be used as tools in modern medicine, cell and tissue engineering, as well as in artificial insemination, used to preserve endangered species of animals, as it was shown in our study on amphibians. (ITEB RAS, Corr. Member of RAS Ivanitsky G.R.).
Using the set of methods, including fluorescence analysis, spectrophotometry, circular dichroism, dynamic light scattering, X-ray diffraction, confocal, electron and atomic force microscopy, amyloid properties of giant muscle protein titin were studied. It has been shown that titin of striated and smooth muscles forms in vitro amyloid aggregates. The toxic effect of titin amyloids on the culture of smooth muscle cells was revealed. The results indicate a possible participation of titin in the formation of cytotoxic aggregates in vivo during the development of amyloidosis. (ITEB RAS, Dr. Vikhlyantsev I.M., DSc (Biology).
The study of the neuroprotective effect of the anti-inflammatory cytokine IL-10 on hypoxia-induced neuronal damage showed that, unlike the cells of the immune system, IL-10 implements its protective effect in neurons without the participation of the intracellular signaling pathway PI3K / Akt. This confirms the non-canonical effect of this interleukin on neurons, indicating the need to determine other intracellular mediators of IL-10 effects.
Under conditions of excitotoxic damage to hippocampal neurons caused by kainate, a reciprocal relationship was shown between the activity of metabotropic glutamate receptors (mGluR) and their level of expression. This makes it possible to predict the effectiveness of pre- and postsynaptic mGluR ligands as neuroprotectors under conditions of glutamate excitotoxicity. (ITEB RAS, Dr. Arkhipov V.I., DSc (Biology).
In 2016, based on the data of the thermodynamic parameters of proteins, the parameters of hydration at a temperature of 298 K were used and the numerical values of the enthalpy, free energy, and entropy of these proteins in the gas phase were estimated. Statistical studies of the dependence of the frequency of bond breaks on the nucleotide sequence of DNA have been carried out, which makes it possible to estimate the errors of experimental procedures in determining the primary structures of DNA. The growth of cells on various polymers and the detachment of cell layers from them were studied. Experiments on long-term synchronous monitoring of minute pulse values and blood biochemical parameters were performed; the essential role of a number of biochemical factors in the development of the process of adaptation of the organism to variations in the geomagnetic field is described. A comparative study of the method of all combinations and the method of minimum coverage, as well as the histogram method was carried out. The intraday periods in time series of fluctuations of the alpha decay rate are investigated, and their relationship with the long-wave part of the spectrum of the Earth's natural oscillations is shown. New aspects of solving the problem of refraction of autowave fronts at the interface between two homogeneous sections of the active medium are described. Manifestations of the universal period-tripling system have been found in a wide range of natural and technical systems. The character of genetic variation in P. pica from Europe, the Far East, Japan, Korea and Taiwan is described. The analysis of bioacoustic parameters of P. pica signals in comparison with genetic results was performed. The mechanisms of isolation in closely related Acrocephalus dumetorum and Acrocephalus orinus have been determined.
On the basis of the created database and the found rules for the recognition of specific DNA regions by the protein, drugs can be designed for the treatment of genetic diseases.
Within the framework of the IDEA-2016 competition, the values of effective frequencies for magnetotherapy and UHF therapy, obtained as a result of studying the universal period-tripling system, were sent to a Russian enterprise producing medical devices.
(ITEB RAS, Doctor of Physical and Mathematical Sciences Polozov R.V.)
Back in the early twentieth century, academician P.P. Lazarev intuitively put forward the postulate that such a unification is possible, having considered only one particular version of synesthesia. At that time, this discovery was not understood and declared a lie. Half a century later, it was proved that synesthesia exists, today interest in its study has increased greatly.
The influence of synesthesia on a significant decrease in the characteristic time of memorizing and analyzing large amounts of information has been proven.
It is not a pathology and can have both a genetic basis and be acquired in the process of intensive purposeful work in creative processes (artists, scientists, architects, etc.).
The emergence of synesthesia is associated with the restructuring of the cerebral structures of the cerebral cortex, stimulated by waves of the hippocampus, which leads to the formation, based on a combinatorial enhancement, of connections in the cerebral cortex between the display areas of the receptor systems (see Fig.). The result of rearrangements in the connections of the brain makes it possible to transform multiparameter phenomena observed by a person in the external world into the form of generalized virtual images in the form of shapes that differ from each other in their topology or color. (FGBUN Institute for Theoretical and Experimental Biophysics of the Russian Academy of Sciences (ITEB RAS), Corresponding Member of the RAS Ivanitsky G.R.)
Reconstruction of the cerebral structures of the cerebral cortex, stimulated by waves of the hippocampus, which leads to the formation on the basis of a combinatorial enhancement of connections in the cerebral cortex between the display areas of the receptor systems.
Obtaining strains of superproducers of mutant forms of nickase BspD6I. The work was aimed at studying a new phenomenon - DNA polymerase synthesis of new genetic information from free dNTPs (DNA synthesis ab initio). A method has been developed to prevent calcification and degeneration of vascular and heart valve grafts. Were cloned and synthesized recombinant proteins of particularly dangerous pathogens and obtained monoclonal antibodies to them.
Our study continues the research of the mechanisms of epilepsy, one of the most widespread and heterogeneous neurological disorders. A decrease in brain glucose consumption is an early common symptom of all major neurodegenerative diseases, including acquired epilepsy. However, the mechanisms for this inhibition of glucose metabolism remain unclear. In the work, we showed that ictal activity leads to oxidative stress in the brain tissue, followed by rapid and prolonged inhibition of glucose utilization. Thus, seizure activity maintains and aggravates glucose hypometabolism in the brain, creating a vicious circle of epileptogenesis. It was shown that such a pathological cycle might be ripped by normalization of glucose metabolism in the brain by using of exogenous energy substrates. The current study may serve as the basis for the effective treatment of seizure disorders. The work was carried out within the international collaboration with Unite 751 of the French National Institute of Health and Medical Research (INSERM UMR1106, Institut de Neurosciences des Systèmes, Aix-Marseille University, Marseille, France). (ITEB RAS, Ph.D. Malkov A.E.)
Decrease in glucose consumption after induction of convulsive discharges in surviving brain slices of experimental animals
Results published in the journal Neurobiology of Disease:
Malkov A, Ivanov AI, Buldakova S, Waseem T, Popova I, Zilberter M, Zilberter Y. Seizure-induced reduction in glucose utilization promotes brain hypometabolism during epileptogenesis. Neurobiol Dis. 2018 Aug;116:28-38. doi: 10.1016/j.nbd.2018.04.016.
It is shown that low-amplitude transcranial stimulation with electric current (tDCS) affects cognitive activity: solving logical, geometric and arithmetic problems. The result depends on the polarity of the stimulus: anodic stimulation improves cognitive performance, while with cathodic stimulation, the effect is subtle. Anodic stimulation increases electrical activity of the cortex, increases efficiency of cognitive activity and optimizes the autonomous activation of resources during cognitive load. Cathodic stimulation affects the spectral power of the EEG, depending on the individual balance of excitation and inhibition in the brain and increases the influence of the parasympathetic branch of the autonomic nervous system. Thus, low-amplitude transcranial stimulation with electric current, being a promising non-invasive method, can be used to improve cognitive performance. (ITEB RAS, Doctor of Physical and Mathematical Sciences Aliev R.R.).
Distribution of the electric field caused by active (red) and reference (blue) electrode placement during low-amplitude transcranial stimulation procedure
Results published in the journal Brain Stimulation
Ashikhmin A. V., Shishelova A. Y., Aliev R. R. tDCS provokes sustainable changes in EEG and reorganizes autonomic modulation of heart rate //Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 2017. 10 (№. 2). 484-486.
For the first time it was shown that in case of chronic hyperammonemia caused by portacaval shunting, the accumulation of ammonia in different parts of the animal brain was associated with the activation of ammonia-forming reactions, which, regardless of its concentration in the blood, independently contributed to the development of convulsive seizures and coma. A direct correlation between the concentration of ammonia in non-synaptic mitochondria of the brain and the rate of formation of a superoxide radical that initiated the development of oxidative stress was also revealed. In addition, it was shown that the cerebellum (unlike the hippocampus, striatum, neocortex) was more sensitive to ammonium-induced oxidative stress. The results obtained show that there are fundamental differences between the mechanisms of regulation of ammonia homeostasis in different parts of the brain and provide a better understanding of the causes of degeneration and death of cerebellar neurons observed in diseases that are associated with chronic hyperammonemia (ITEB RAS, Dr. E.A. Kosenko, DSc (Biology).
The role of cerebellar mitochondria in the development of oxidative stress under the action of ammonia which is formed in the brain during portacaval shunting (PCS - portacaval shunting; O2• - - superoxide radical; NOS - NO-synthase; Mn2+ - SOD - Mn2+ - form of superoxide dismutase.
Results published in the journal Free Radical Biology & Medicine
Kosenko E.A., Tikhonova LA, Alilova GA, Montoliu C, Barreto GE, Aliev G, Kaminsky YG. Portacaval shunting causes differential mitochondrial superoxide production in brain regions. Free Radic Biol Med. 2017, 28 (113), 109-118.
It is known that cell membranes, due to the energy of interfacial interactions in lipids and proteins, form a three-dimensional cellular network in the cytoplasm. In experiments with living cells, as well as on model systems, the influence of both chemical and physical agents on the energy of interfacial interactions and the stability of phases was studied. In particular, the influence of polyphenolic compounds of plant origin on the phase state of biological membranes and formation of a network of fibrillar proteins was studied. It has been shown that the flavonoids taxifolin and kaempferol can accelerate the formation of a network of collagen protein fibrils, while quercetin and myricetin can prevent the formation of these fibrils. The kinetics of interfacial interactions can be controlled using the action of not only chemical but also physical agents, including electromagnetic irradiation, temperature and pressure changes. We have developed a kinetic model that covers the main molecular events in cellular regulatory networks with feedback, including protein-protein interactions, activation and deactivation of GTPases, phosphorylation and dephosphorylation. The methods for increasing / decreasing the energy of interphase barriers that determine the stability of proteins and membranes are of practical importance and can be used as tools in modern medicine, cell and tissue engineering, as well as in artificial insemination, used to preserve endangered species of animals, as it was shown in our study on amphibians. (ITEB RAS, Corr. Member of RAS Ivanitsky G.R.).
Using the set of methods, including fluorescence analysis, spectrophotometry, circular dichroism, dynamic light scattering, X-ray diffraction, confocal, electron and atomic force microscopy, amyloid properties of giant muscle protein titin were studied. It has been shown that titin of striated and smooth muscles forms in vitro amyloid aggregates. The toxic effect of titin amyloids on the culture of smooth muscle cells was revealed. The results indicate a possible participation of titin in the formation of cytotoxic aggregates in vivo during the development of amyloidosis. (ITEB RAS, Dr. Vikhlyantsev I.M., DSc (Biology).
The study of the neuroprotective effect of the anti-inflammatory cytokine IL-10 on hypoxia-induced neuronal damage showed that, unlike the cells of the immune system, IL-10 implements its protective effect in neurons without the participation of the intracellular signaling pathway PI3K / Akt. This confirms the non-canonical effect of this interleukin on neurons, indicating the need to determine other intracellular mediators of IL-10 effects.
Under conditions of excitotoxic damage to hippocampal neurons caused by kainate, a reciprocal relationship was shown between the activity of metabotropic glutamate receptors (mGluR) and their level of expression. This makes it possible to predict the effectiveness of pre- and postsynaptic mGluR ligands as neuroprotectors under conditions of glutamate excitotoxicity. (ITEB RAS, Dr. Arkhipov V.I., DSc (Biology).
In 2016, based on the data of the thermodynamic parameters of proteins, the parameters of hydration at a temperature of 298 K were used and the numerical values of the enthalpy, free energy, and entropy of these proteins in the gas phase were estimated. Statistical studies of the dependence of the frequency of bond breaks on the nucleotide sequence of DNA have been carried out, which makes it possible to estimate the errors of experimental procedures in determining the primary structures of DNA. The growth of cells on various polymers and the detachment of cell layers from them were studied. Experiments on long-term synchronous monitoring of minute pulse values and blood biochemical parameters were performed; the essential role of a number of biochemical factors in the development of the process of adaptation of the organism to variations in the geomagnetic field is described. A comparative study of the method of all combinations and the method of minimum coverage, as well as the histogram method was carried out. The intraday periods in time series of fluctuations of the alpha decay rate are investigated, and their relationship with the long-wave part of the spectrum of the Earth's natural oscillations is shown. New aspects of solving the problem of refraction of autowave fronts at the interface between two homogeneous sections of the active medium are described. Manifestations of the universal period-tripling system have been found in a wide range of natural and technical systems. The character of genetic variation in P. pica from Europe, the Far East, Japan, Korea and Taiwan is described. The analysis of bioacoustic parameters of P. pica signals in comparison with genetic results was performed. The mechanisms of isolation in closely related Acrocephalus dumetorum and Acrocephalus orinus have been determined.
On the basis of the created database and the found rules for the recognition of specific DNA regions by the protein, drugs can be designed for the treatment of genetic diseases.
Within the framework of the IDEA-2016 competition, the values of effective frequencies for magnetotherapy and UHF therapy, obtained as a result of studying the universal period-tripling system, were sent to a Russian enterprise producing medical devices.
(ITEB RAS, Doctor of Physical and Mathematical Sciences Polozov R.V.)
The hippocampus plays a critical role in the processes of attention and memory. When processing new information by the brain in the hippocampus, theta rhythm is oscilations of local field potential with a frequency of 4 to 12 Hz. A mathematical model of the neural network of one of the hippocampal regions (fields СА1) in the theta rhythm generation mode was proposed. The model takes into account the main neural groups of the hippocampus and the arrival of signals on external inputs. In computational experiments, the model reproduces the synchronization parameters of neural populations and the main electrophysiological characteristics of theta rhythm described in the experimental literature. The obtained results make it possible to make conclusions about the contribution of external inputs and neurons of the СА1 field to the formation of oscilations. In particular, it has been shown that the exciting input to the СА1 field from another region of the hippocampus, the СА3 field, plays the most important role in the generation of theta rhythm. It should be noted that the proposed model allows not only to reproduce the characteristics of the theta rhythm, but also indicates which neural groups of the hippocampus and at what time the information is transmitted.
The results are published in Mysin I.E., Kitchigina V.F., Kazanovich Y.B. Phase relations of theta oscillations in a computer model of the hippocampal CA1 field: Key role of Schaffer collaterals. Neural Network. 2019, 116, 119-138. https://www.sciencedirect.com/science/article/pii/S0893608019301029?via%3Dihub
The results are published in Mysin I.E., Kitchigina V.F., Kazanovich Y.B. Phase relations of theta oscillations in a computer model of the hippocampal CA1 field: Key role of Schaffer collaterals. Neural Network. 2019, 116, 119-138. https://www.sciencedirect.com/science/article/pii/S0893608019301029?via%3Dihub
A sample of multienzyme sensors and microreactors has been fabricated, which is combination of oppositely charged polyelectrolytes layers and microcapsules with an enzyme. The possibilities of multienzyme systems that determine substances in biological fluids (blood, urine) have been investigated. A program was developed and tested for numerically displaying the determined concentrations of two blood metabolites.
(ITEB RAS, Ph.D. Fomkina M.G., t. 739-181)
The design of novel, effective drug delivery systems is one of the most promising ways to improve the treatment of socially important diseases. This article reports on an innovative approach to the production of composite microcontainers (microcapsules) bearing advanced protective functions. Cerium oxide (CeO2) nanoparticles were incorporated into layer-by-layer polyelectrolyte microcapsules as a protective shell for an encapsulated enzyme (luciferase of Photinus pyralis), preventing its oxidation by hydrogen peroxide, the most abundant type of reactive oxygen species (ROS). The protective effect depends on CeO2 loading in the shell: at a low concentration, CeO2 nanoparticles only scavenge ROS, whereas a higher content leads to a decrease in access for both ROS and the substrate to the enzyme in the core. By varying the nanoparticle concentration in the microcapsule, it is possible to control the level of core shielding, from ROS filtering to complete blocking. The approach demonstrated that the active protection of microencapsulated substances by CeO2 nanoparticles can be used in the development of new drug delivery and diagnostic systems. (A.L.Popov)
Results published in the journal ACS Applied Materials & Interfaces serves: Popov A., Popova, N., Gould D., Shcherbakov A.; Sukhorukov G.; Ivanov V. Ceria nanoparticles-decorated microcapsules as a smart drug delivery/protective system: Protection of encapsulated P. pyralis luciferase» ACS Appl. Mater. Interfaces, 2018, 10, 17, 14367-14377
___________________
The method of immunochemical analysis on microarrays, which allows to detect protein biomarkers in femtogram quantities, has been modified and fundamentally improved. This qualitative immunochemical analysis was transformed into a quantitative method by: (i) employing parallel titration of analytes by measuring signal response to a series of sample dilutions with increasing analyte concentration, (ii) internally normalizing the signal (by relating signal intensity to that of positive controls on the same microarray) and (iii) taking measurements in the linear range of the calibration curve at concentrations close to the limit of detection. The method may form the basis of a new non-invasive diagnostics of pulmonary diseases (eg, tuberculosis) by analyzing the exhaled breath for the presence of antigens and specific antibodies (ITEB RAS, prof. Morozov VN).
