Liquid water radiolysis induced by secondary electrons generated from MeV-energy carbon ions.

Fast ion beams induce damage to deoxyribonucleic acid (DNA) by chemical products, including secondary electrons, produced from interaction with liquid water in living cells. However, the production process of these chemical products in the Bragg peak region used in particle therapy is not fully understood. To investigate this process, we conducted experiments to evaluate the radiolytic yields produced when a liquid water jet in vacuum is irradiated with MeV-energy carbon beams. We used secondary ion mass spectrometry to measure the products, such as hydronium cations (H3O+) and hydroxyl anions (OH-), produced along with ·OH radicals, which are significant inducers of DNA damage formation. In addition, we simulated the ionization process in liquid water by incident ions and secondary electrons using a Monte Carlo code for radiation transport. Our results showed that secondary electrons, rather than incident ions, are the primary cause of ionization in water. We found that the production yield of H3O+ or OH- was linked to the frequency of ionization by secondary electrons in water, with these electrons having energies between 10.9 and 550 eV. These electrons are responsible for ionizing the outer-shell electrons of water molecules. Finally, we present that the elementary processes contribute to advancing radiation biophysics and biochemistry, which study the formation mechanism of DNA damage.

First-principles simulation of an ejected electron produced by monochromatic deposition energy to water at the femtosecond order.

This study uses a time-dependent first-principles simulation code to investigate the transient dynamics of an ejected electron produced in the monochromatic deposition energy from 11 to 19 eV in water. The energy deposition forms a three-body single spur comprising a hydroxyl radical (OH˙), hydronium ion (H3O+), and hydrated electron (eaq-). The earliest formation involves electron thermalization and delocalization dominated by the molecular excitation of water. Our simulation results show that the transient electron dynamics primarily depends on the amount of deposition energy to water; the thermalization time varies from 200 to 500 fs, and the delocalization varies from 3 to 10 nm in this energy range. These features are crucial for determining the earliest single-spur formation and facilitating a sequential simulation from an energy deposition to a chemical reaction in water photolysis or radiolysis. The spur radius obtained from the simulation correlates reasonably with the experimental-based estimations. Our results should provide universalistic insights for analysing ultrafast phenomena dominated by the molecular excitation of water in the femtosecond order.

Initial yield of hydrated electron production from water radiolysis based on first-principles calculation.

Many scientific insights into water radiolysis have been applied for developing life science, including radiation-induced phenomena, such as DNA damage and mutation induction or carcinogenesis. However, the generation mechanism of free radicals due to radiolysis remains to be fully understood. Consequently, we have encountered a crucial problem in that the initial yields connecting radiation physics to chemistry must be parameterized. We have been challenged in the development of a simulation tool that can unravel the initial free radical yields, from physical interaction by radiation. The presented code enables the first-principles calculation of low energy secondary electrons resulting from the ionization, in which the secondary electron dynamics are simulated while considering dominant collision and polarization effects in water. In this study, using this code, we predicted the yield ratio between ionization and electronic excitation from a delocalization distribution of secondary electrons. The simulation result presented a theoretical initial yield of hydrated electrons. In radiation physics, the initial yield predicted from parameter analysis of radiolysis experiments in radiation chemistry was successfully reproduced. Our simulation code helps realize a reasonable spatiotemporal connection from radiation physics to chemistry, which would contribute to providing new scientific insights for precise understanding of underlying mechanisms of DNA damage induction.

Tandemly repeated Fc domain augments binding avidities of antibodies for Fcgamma receptors, resulting in enhanced antibody-dependent cellular cytotoxicity.

Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antibodies exert anti-tumor effects. Here, we show that Fc multimerization augments the binding avidities for all of the low-affinity Fcgamma receptors, increasing ADCC activity very much. A chimeric antibody, designated M-Ab, was constructed with the V regions from mouse anti-CD20 mAb 1F5 and the C regions from human IgG1 and kappa chain. Two or three Fc domains were tandemly repeated downstream of the C-terminus of the M-Ab to give D0-Ab (Fc dimer Ab without a linker), T0-Ab (Fc trimer Ab without a linker), and T3-Ab (Fc trimer Ab with a (GGGGS)(3) linker in front of the second and third hinge regions). HPLC and SDS-PAGE analyses of the purified antibodies indicated that the H and L chains were appropriately linked with interchain disulfide bonds and that the Ab preparations did not contain aggregated molecules. Although flow cytometry indicated that Fc multimerization decreased the binding activity for CD20-bearing cells to 1/3 approximately 1/4, the binding avidities for the extracellular domains of low-affinity Fcgamma receptors were greatly augmented. The avidities were in the order of T3-Ab, T0-Ab, D0-Ab and M-Ab, with T3-Ab showing about 100 times greater avidity than M-Ab not only for FcgammaRIIIA, but also for FcgammaRIIA and FcgammaRIIB. The rank order of ADCC activity with human PBMC was the same, and T3-Ab induced ADCC at a 50-100 times less concentration, compared to M-Ab. These Fc tandem repeat antibodies are promising candidates for anti-tumor therapeutics, and should also be useful as tools to elucidate the biological roles of FcgammaRIIA, FcgammaRIIB, and FcgammaRIIIA.