Yuya Hattori

Theoretical and evolutionary parameter tuning of neural oscillators with a double-chain structure for generating rhythmic signals

A neural oscillator with a double-chain structure is one of the central pattern generator models used to simulate and understand rhythmic movements in living organisms. However, it is difficult to reproduce desired rhythmic signals by tuning an enormous number of parameters of neural oscillators. In this study, we propose an automatic tuning method consisting of two parts. The first involves tuning rules for both the time constants and the amplitude of the oscillatory outputs based on theoretical analyses of the relationship between parameters and outputs of the neural oscillators. The second involves an evolutionary tuning method with a two-step genetic algorithm (GA), consisting of a global GA and a local GA, for tuning parameters such as neural connection weights that have no exact tuning rule. Using numerical experiments, we confirmed that the proposed tuning method could successfully tune all parameters and generate sinusoidal waves. The tuning performance of the proposed method was less affected by factors such as the number of excitatory oscillators or the desired outputs. Furthermore, the proposed method was applied to the parameter-tuning problem of some types of artificial and biological wave reproduction and yielded optimal parameter values that generated complex rhythmic signals in Caenorhabditis elegans without trial and error.

Cellular automaton-based model for radiation-induced bystander effects.

BackgroundThe radiation-induced bystander effect is a biological response observed in non-irradiated cells surrounding an irradiated cell. The bystander effect is known to be induced by two intercellular signaling pathways, the medium-mediated pathway (MDP) and the gap junctional pathway (GJP). To investigate the relative contribution of each signaling pathway, we have developed a mathematical model of the cellular response through these two pathways, with a particular focus on cell-cycle modification.MethodsThe model is based on a cellular automaton and consists of four components: (1) irradiation, (2) generation and diffusion of intercellular signals, (3) induction of DNA double-strand breaks (DSBs), and (4) cell-cycle modification or cell death. The intercellular signals are generated in and released from irradiated cells. The signals through the MDP and the GJP are modeled independently based on diffusion equations. The irradiation and both signals raise the number of DSBs, which determines transitions of cellular states, such as cell-cycle arrest or cell death.ResultsOur model reproduced fairly well previously reported experimental data on the number of DSBs and cell survival curves. We examined how radiation dose and intercellular signaling dynamically affect the cell cycle. The analysis of model dynamics for the bystander cells revealed that the number of arrested cells did not increase linearly with dose. Arrested cells were more efficiently accumulated by the GJP than by the MDP.ConclusionsWe present here a mathematical model that integrates various bystander responses, such as MDP and GJP signaling, DSB induction, cell-cycle arrest, and cell death. Because it simulates spatial and temporal conditions of irradiation and cellular characteristics, our model will be a powerful tool to predict dynamical radiobiological responses of a cellular population in which irradiated and non-irradiated cells co-exist.

Cell cycle tracking for irradiated and unirradiated bystander cells in a single colony with exposure to a soft X-ray microbeam

Abstract Purpose: To establish a new experimental technique to explore the photoelectric and subsequent Auger effects on the cell cycles of soft X-ray microbeam-irradiated cells and unirradiated bystander cells in a single colony. Materials and methods: Several cells located in the center of a microcolony of HeLa-Fucci cells consisting of 20–80 cells were irradiated with soft X-ray (5.35 keV) microbeam using synchrotron radiation as a light source. All cells in the colony were tracked for 72 h by time-lapse microscopy imaging. Cell cycle progression, division, and death of each cell in the movies obtained were analyzed by pedigree assay. The number of cell divisions in the microcolony was also determined. Results: The fates of these cells were clarified by tracking both irradiated and unirradiated bystander cells. Irradiated cells showed significant cell cycle retardation, explosive cell death, or cell fusion after a few divisions. These serious effects were also observed in 15 and 26% of the bystander cells for 10 and 20 Gy irradiation, respectively, and frequently appeared in at least two daughter or granddaughter cells from a single-parent cell. Conclusions: We successfully tracked the fates of microbeam-irradiated cells and unirradiated bystander cells with live cell recordings, which have revealed the dynamics of soft X-ray irradiated and unirradiated bystander cells for the first time. Notably, cell deaths or cell cycle arrests frequently arose in closely related cells. These details would not have been revealed by a conventional immunostaining imaging method. Our approach promises to reveal the dynamic cellular effects of soft X-ray microbeam irradiation and subsequent Auger processes from various endpoints in future studies.

A mathematical model of radiation-induced responses in a cellular population including cell-to-cell communications

Cell-to-cell communication is an important factor for understanding the mechanisms of radiation-induced responses such as bystander effects. In this study, a new mathematical model of intercellular signalling between individual cells in a cellular population is proposed. The authors considered two types of transmission of signals: via culture medium and via gap junction. They focus on the effects that radiation and intercellular signalling have on cell-cycle modification. The cell cycle is represented as a virtual clock that includes several checkpoint pathways within a cyclic process. They also develop a grid model and set up diffusion equations to model the propagation of signals to and from spatially located cells. The authors have also considered the role that DNA damage plays in the cycle of cells which can progress through the cell cycle or stop at the G1, S, G2 or M-phase checkpoints. Results of testing show that the proposed model can simulate intercellular signalling and cell-cycle progression in individual cells during and after irradiation.

A novel tuning method for neural oscillators with a ladder-like structure based on oscillation analysis

Neural oscillators with a ladder-like structure is one of the central pattern generator (CPG) model that is used to simulate rhythmic movements in living organisms. However, it is not easy to realize rhythmical cycles by tuning many parameters of neural oscillators. In this study, we propose an automatic tuning method. We derive the tuning rules for both the time constants and the coefficients of amplitude by linearizing the nonlinear equations of the neural oscillators. Other parameters such as neural connection weights are tuned using a genetic algorithm (GA). Through numerical experiments, we confirmed that the proposed tuning method can successfully tune all parameters.

Development of ultra-thin chips for immobilization of Caenorhabditis elegans in microfluidic channels during irradiation and selection of buffer solution to prevent dehydration

BACKGROUND Targeted microbeam irradiation of Caenorhabditis elegans allows the effective knockdown of specific regions, thus helping to identify their roles in processes such as locomotion. We previously employed on-chip immobilization of individuals without anesthesia; however, this method was limited by the thickness of the chip, which prevented the detection of ions passing through the animal, and by dehydration of the animals after prolonged immobilization. NEW METHOD We developed ultra-thin, ion-penetrable, polydimethylsiloxane microfluidic chips, referred to as Worm Sheets, with and without wettability (hydrophilicity/hydrophobicity), and identified suitable buffer conditions for maintaining moisture in the microfluidic channels. RESULTS Using a collimating microbeam system, we demonstrated that carbon ions (with a range of ∼1 mm) could pass through the chip, thus allowing the ions to be detected and the applied radiation dose to therefore by measured accurately. We also examined the locomotion of C. elegans following on-chip immobilization in different buffers. Locomotion was decreased in certain buffers on unwettable chips as a result of dehydration due to evaporation, but not on wettable chips. However, locomotion was unaffected on either chip in the presence of a gelatin-based wash buffer. COMPARISON WITH EXISTING METHOD(S) We developed 300-μm-ultra-thin, wettable, ion-penetrable chips for immobilizing C. elegans and provided initial guidance regarding suitable buffer solutions to maintain moisture in microfluidic channels. CONCLUSIONS This improved, wettable chip, together with the identification of suitable buffer conditions, will become a powerful tool for prolonged immobilizing C. elegans, and is widely applicable not only to microbeam irradiation but also to neurobiological assays.

Evaluation of DNA damage induced by Auger electrons from 137Cs.

Abstract Purpose: To understand the biological effect of external and internal exposure from 137Cs, DNA damage spectrum induced by directly emitted electrons (γ-rays, internal conversion electrons, Auger electrons) from 137Cs was compared with that induced by 137Cs γ-rays. Methods: Monte Carlo track simulation method was used to calculate the microscopic energy deposition pattern in liquid water. Simulation was performed for the two simple target systems in microscale. Radiation sources were placed inside for one system and outside for another system. To simulate the energy deposition by directly emitted electrons from 137Cs placed inside the system, the multiple ejections of electrons after internal conversion were considered. In the target systems, induction process of DNA damage was modeled and simulated for both direct energy deposition and the water radical reaction on the DNA. The yield and spatial distribution of simple and complex DNA damage including strand breaks and base lesions were calculated for irradiation by electrons and γ-rays from 137Cs. Results: The simulation showed that the significant difference in DNA damage spectrum was not caused by directly ejected electrons and γ-rays from 137Cs. Conclusions: The result supports the existing perception that the biological effects by internal and external exposure by 137Cs are equivalent.

Modeling of the pharyngeal muscle in Caenorhabditis elegans based on FitzHugh-Nagumo equations

The pharyngeal pumping motion to send food to the bowel is a rhythmic movement in Caenorhabditis elegans. This paper proposes a simulation-based approach to investigate the mechanisms of rhythm phenomena in the pharyngeal pumping motion. To conduct the simulations, first, we developed a pharyngeal muscle model including 29 cell models which simulate the activity of each cell as a membrane potential based on FitzHugh-Nagumo equations. Then, to compare the response of the model with that of C. elegans, we calculated the electropharyngeogram (EPG), which represents the electrophysiological responses of the pharyngeal cells, using the simulated membrane potentials. The results confirmed that our model could generate the EPG similar to that measured from C. elegans. We proposed a computer simulation of the pumping motion to investigate the mechanisms of rhythm phenomena in living organisms.