Oleg V. Belov

A quantitative model of the major pathways for radiation-induced DNA double-strand break repair

We have developed a model approach to simulate the major pathways of DNA double-strand break (DSB) repair in mammalian and human cells. The proposed model shows a possible mechanistic explanation of the basic regularities of DSB processing through the non-homologous end-joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA) and two alternative end-joining pathways. It reconstructs the time-courses of radiation-induced foci specific to particular repair processes including the major intermediate stages. The model is validated for ionizing radiations of a wide range of linear energy transfer (0.2-236 keV/µm) including a relatively broad spectrum of heavy ions. The appropriate set of reaction rate constants was suggested to satisfy the kinetics of DSB rejoining for the considered types of exposure. The simultaneous assessment of several repair pathways allows to describe their possible biological relations in response to irradiation. With the help of the proposed approach, we reproduce several experimental data sets on γ-H2AX foci remaining in different types of cells including those defective in NHEJ, HR, or SSA functions. The results produced confirm the hypothesis suggesting existence of at least two alternative Ku-independent end-joining pathways.

Model of SOS-induced mutagenesis in bacteria Escherichia coli under ultraviolet irradiation

A mathematical model of the mutation process in bacteria Escherichia coli induced by ultraviolet radiation is developed. Our model is based on the experimental data characterizing the main processes of the bacterial SOS response. Here we have modeled a whole sequence of the events leading to the fixation of the primary DNA lesion as a point mutation. A quantitative analysis of the key ways of the SOS mutagenesis was performed in terms of modern system biology. The dynamic changes of the basic SOS protein concentrations and the process of the translesion synthesis by the modified replication complex are described quantitatively. We have also demonstrated the applicability of the developed model to the description of the mutagenesis in individual genes. As an example, an estimation of the mutation frequency in E. colis lacI gene is performed.

Radiation damage to neuronal cells: Simulating the energy deposition and water radiolysis in a small neural network

Radiation damage to the central nervous system (CNS) has been an on-going challenge for the last decades primarily due to the issues of brain radiotherapy and radiation protection for astronauts during space travel. Although recent findings revealed a number of molecular mechanisms associated with radiation-induced impairments in behaviour and cognition, some uncertainties exist in the initial neuronal cell injury leading to the further development of CNS malfunction. The present study is focused on the investigation of early biological damage induced by ionizing radiations in a sample neural network by means of modelling physico-chemical processes occurring in the medium after exposure. For this purpose, the stochastic simulation of incident particle tracks and water radiation chemistry was performed in realistic neuron phantoms constructed using experimental data on cell morphology. The applied simulation technique is based on using Monte-Carlo processes of the Geant4-DNA toolkit. The calculations were made for proton, 12C, and 56Fe particles of different energy within a relatively wide range of linear energy transfer values from a few to hundreds of keV/μm. The results indicate that the neuron morphology is an important factor determining the accumulation of microscopic radiation dose and water radiolysis products in neurons. The estimation of the radiolytic yields in neuronal cells suggests that the observed enhancement in the levels of reactive oxygen species may potentially lead to oxidative damage to neuronal components disrupting the normal communication between cells of the neural network.

Estimation of the spatial energy deposition in CA1 pyramidal neurons under exposure to 12C and 56Fe ion beams

Abstract The exposure to heavy charged particles represents a significant risk to the central nervous system. In experiments with rodents, the irradiation with heavy ions induces a prolonged deficit in hippocampus-dependent learning and memory. The exact nature of these violations remains mostly unclear. In this regard, the estimation of radiation effects at the level of single neurons is of our special interest. The present study demonstrates the results of comparative calculations that are performed to clarify the early physical events in single neurons under the exposure to accelerated 12C and 56Fe ions with different parameters. Using the Geant4-based Monte Carlo simulations, the radiation effects are considered in terms of energy and dose deposition. The spatial patterns of energy and dose depositions within a single neural cell are produced. As additional characteristics, the spectra of the specific energy and energy imparted are estimated. Our results show that the cell morphology is an important factor determining the accumulation of radiation dose in neurons under the exposure to heavy ions. The data obtained suggest a possibility of radiation damage to synapses that are considered to play an important role in radiation-induced violations of hippocampus-dependent learning and memory.

Simulation of the charge migration in DNA under irradiation with heavy ions

A computer model to simulate the processes of charge injection and migration through DNA after irradiation by a heavy charged particle was developed. The most probable sites of charge injection were obtained by merging spatial models of short DNA sequence and a single 1 GeV/u iron particle track simulated by the code RITRACKS (Relativistic Ion Tracks). Charge migration was simulated by using a quantum-classical nonlinear model of the DNA-charge system. It was found that charge migration depends on the environmental conditions. The oxidative damage in DNA occurring during hole migration was simulated concurrently, which allowed the determination of probable locations of radiation-induced DNA lesions.

Cluster analysis of HZE particle tracks as applied to space radiobiology problems

A cluster analysis is performed of ionizations in tracks produced by the most abundant nuclei in the charge and energy spectra of the galactic cosmic rays. The frequency distribution of clusters is estimated for cluster sizes comparable to the DNA molecule at different packaging levels. For this purpose, an improved K-meansbased algorithm is suggested. This technique allows processing particle tracks containing a large number of ionization events without setting the number of clusters as an input parameter. Using this method, the ionization distribution pattern is analyzed depending on the cluster size and particle’s linear energy transfer.

The dynamics of monoamine metabolism in rat brain structures in the late period after exposure to accelerated carbon ions

We studied the effect of carbon ions (12C) with an energy of 500 MeV/nucleon at a dose of 1 Gy on monoamine metabolism in the brains of rats of different ages. Neurochemical parameters that characterize the distribution of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and its metabolites were evaluated during 2 months on days 30 and 90 after the exposure to radiation. We studied the prefrontal cortex, hypothalamus, hippocampus, and striatum. The results showed changes in the activities of the NA, DA, and 5-HT systems in rats of different age groups after exposure to radiation. The most prominent differences in the exposed and control animals were observed in the prefrontal cortex and hypothalamus, which indicates the important role of these brain regions in long-term effects of exposure to radiation on the central nervous system. A comparison of animals from different age groups showed a decrease in the intensity of the temporal changes in all analyzed structures except the striatum in the exposed rats. Based on these findings, we assumed that the activation of compensatory and repairing mechanisms occurs in the late post-radiation period. At relatively low linear energy transfer of particles (10.6 keV/µm), it may lead to the partial recovery of brain functions that were impaired by radiation. At higher values of the linear energy transfer, the compensatory and recovery processes are activated to a lesser degree and functional impairment increases with time.

The distribution of monoamines and their metabolites in the brain structures of rats at later periods after exposure to 12C ions

We investigated the levels of monoamines and their metabolites in certain brain structures of rats at 30 and 90 days after exposure to carbon ions (12C) with an energy of 500 MeV/nucleon. The linear energy transfer and radiation dose were 10.6 keV/µm and 1 Gy, respectively. The concentrations of substances were measured in five structures of the brain, including the prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus, and striatum. On day 30 after the exposure, the most pronounced changes in the concentration of monoamines and their metabolites were observed in the nucleus accumbens; the smallest changes were found in the hippocampus and striatum. After 90 days, significant changes were still present in the nucleus accumbens. At the same time, these changes became less evident in other structures. A comparison of our results with the data of similar previous experiments (24 hours after exposure) showed that the most pronounced effect was observed soon after radiation exposure. The induced damage diminished at a later period. Based on the results of our study, we made the hypothesis that the change in the metabolism of monoamines may be compensated if the linear-energy transfer values were relatively low (10.6 keV/μm). At higher values of linear-energy transfer, compensatory and regenerative processes did not occur; the effect increased with time. An increased susceptibility of the nucleus accumbens was found at all the time points after the exposure, which may indicate an important role of this brain structure in the radiation-induced impairment of cognitive functions and emotional and motivational states.

Mathematical model of induced mutagenesis in bacteria Escherichia coli under ultraviolet irradiation

A mathematical model is developed for a mutational process in bacteria Escherichia coli induced by ultraviolet radiation. The dynamics of the basic protein complexes of the SOS-response system is investigated. The probability of mutations during translesion synthesis is estimated.

SOS response dynamics in Escherichia coli bacterial cells upon ultraviolet irradiation

A mathematical model of induced mutations in Escherichia coli bacterial cells upon ultraviolet irradiation is developed. The concentration dynamics of inducible protein complexes synthesized in the course of the SOS response of E. coli is described. The mutation induction at translesion synthesis is studied. The solutions to the model are based on experimental data concerning the expression of the main genes of the SOS system of E. coli bacteria.