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Spectra and frequencies of spontaneous and X-ray-induced somatic mutations were revealed with mouse long-term hematopoietic stem cells (LT-HSCs) by whole-genome sequencing of clonal cell populations propagated in vitro from single isolated LT-HSCs. SNVs and small indels were the most common types of somatic mutations, and increased up to twofold to threefold by whole-body X-irradiation. Base substitution patterns in the SNVs suggested a role of reactive oxygen species in radiation mutagenesis, and signature analysis of single base substitutions (SBS) revealed a dose-dependent increase of SBS40. Most of spontaneous small deletions were shrinkage of tandem repeats, and X-irradiation specifically induced small deletions out of tandem repeats (non-repeat deletions). Presence of microhomology sequences in non-repeat deletions suggested involvement of microhomology mediated end-joining repair mechanisms as well as nonhomologous end-joining in radiation-induced DNA damages. We also identified multisite mutations and structural variants (SV), i.e., large indels, inversions, reciprocal translocations, and complex variants. The radiation-specificity of each mutation type was evaluated from the spontaneous mutation rate and the per-Gy mutation rate estimated by linear regression, and was highest with non-repeat deletions without microhomology, followed by those with microhomology, SV except retroelement insertions, and multisite mutations; these types were thus revealed as mutational signatures of ionizing radiation. Further analysis of somatic mutations in multiple LT-HSCs indicated that large fractions of postirradiation LT-HSCs originated from single LT-HSCs that survived the irradiation and then expanded in vivo to confer marked clonality to the entire hematopoietic system, with varying clonal expansion and dynamics depending on radiation dose and fractionation.

Summary Red blood cell distribution width (RDW), which generally increases with age, is a risk marker for morbidity and mortality in various diseases. We investigated the association between elevated RDW and prior radiation exposure by examining longitudinal RDW changes in 4204 atomic‐bomb survivors over 15 years. A positive association was found between RDW and radiation dose, wherein RDW increased by 0·18%/Gy. This radiation‐associated effect increased as the participants aged. Elevated RDW was also associated with higher all‐cause mortality. The biological mechanisms underlying these observed associations merit further investigation.

Prohydrojasmon (PDJ), an analog of jasmonic acid (JA), was found to induce direct and indirect defenses against herbivores in non-infested plants. To test whether PDJ can be used for pest control in crop production, we conducted experiments in pesticide-free Japanese radish fields from October 4 to December 12 in 2015. Twenty-four Japanese radish plants in three plots were treated with a 100 times-diluted commercial formulation (5%) of PDJ (treated plants), and 24 plants in three different plots were treated with water (control plants) until November 29 every week. Throughout the observation period, the number of aphids, leaf-mining fly larvae, vegetable weevils, and thrips was significantly lower on the treated plants than on the control plants. In contrast, the number of lepidopteran larvae was not significantly different between the treated and control plants throughout the study period. Parasitized aphids (mummies) were also observed in both plots. Poisson regression analyses showed that a significantly higher number of mummies was recorded on the treated plants as compared to that on the control plants when the number of aphids increased. This suggested that PDJ application to Japanese radish plants attracted more parasitoid wasps on the treated plants than on the control plants. We also identified eight terpenoids and methyl salicylate as the PDJ-induced plant volatiles in the headspace of the treated plants. Some of these volatiles might be responsible for attracting aphid-parasitoid wasps in the field. However, for other insect pests, we did not find any natural enemies. Interestingly, the genes of the JA and salicylic acid signaling pathways were differentially upregulated in the treated plants. We also observed that the PDJ treatments induced the expression of the genes related to glucosinolate biosynthesis and the subsequent isothiocyanate formation. Additionally, the weights of both the aboveground and belowground parts of the treated plants were significantly lower than those of the respective parts of the control plants. These results indicated that the treatment of Japanese radish plants with a 100 times-diluted commercial formulation of PDJ induced their direct and indirect defenses against several insect pest species to reduce their numbers, and negatively affected their biomass.

Enhanced inflammatory responses have been suggested decades after radiation exposure in atomic-bomb survivors, but cellular and molecular alterations related to prolonged inflammation remain unclear. This study, utilizing longitudinal haematological data over 50 years for 14 000 persons, investigated whether radiation exposure promoted the relative increase in peripheral myeloid cells, known as an aging-associated indicator of low-grade inflammation. Statistical modelling was performed with a linear mixed-effects model for leucocyte subsets, together with a proportional hazards regression model for all-cause mortality. We found that age trends in lymphocyte, neutrophil and monocyte percentages or counts differed before versus after age 60 years. Radiation dose was associated with monocyte percentages and counts, but not with the lymphoid-myeloid cell ratio. Radiation effects on monocytes were stronger after versus before age 60 years. Increases in monocyte percentages and counts were associated with higher risk of all-cause mortality. Studies of chromosomal aberrations have shown a clonal expansion of haematopoietic stem cells among atomic-bomb survivors. Therefore, radiation exposure might accelerate aging-associated clonal haematopoiesis, which could result in a long-lasting elevation of circulating monocytes.

The objective of this study was to evaluate effects of whole body radiation exposure early in life on influenza vaccination immune responses much later in life. A total of 292 volunteers recruited from the cohort members of ongoing Adult Health Study (AHS) of Japanese atomic bomb (A-bomb) survivors completed this observational study spanning two influenza seasons (2011-2012 and 2012-2013). Peripheral blood samples were collected prior to and three weeks after vaccination. Serum hemagglutination inhibition (HAI) antibody titers were measured as well as concentrations of 25 cytokines and chemokines in culture supernatant from peripheral blood mononuclear cells, with and without in vitro stimulation with influenza vaccine. We found that influenza vaccination modestly enhanced serum HAI titers in this unique cohort of elderly subjects, with seroprotection ranging from 18 to 48% for specific antigen/season combinations. Twelve percent of subjects were seroprotected against all three vaccine antigens post-vaccination. Males were generally more likely to be seroprotected for one or more antigens post-vaccination, with no differences in vaccine responses based on age at vaccination or radiation exposure in early life. These results show that early life exposure to ionizing radiation does not prevent responses of elderly A-bomb survivors to seasonal influenza vaccine.

The elastoplastic deformation behaviors of thin-walled tubes made of pure aluminum and steel were measured under various tension–torsion combined loadings. The ratio between the displacement and rotation of a grip was held constant for the linear-loading experiment. In the nonlinear-loading experiments, a specimen was subjected to uniaxial tension followed by the simultaneous application of tension and torsion. It was determined that the associated flow rule predicts the plastic flow behaviors observed in the experiments with sufficient accuracy, provided that the specimen was subjected to linear loadings. Meanwhile, under nonlinear loadings, the plastic flow behaviors were markedly dissimilar to those in the linear loadings, and the direction of plastic flow rotated toward the direction of the stress/strain rate. By analyzing the experimental results, a linear relationship between the plastic flow direction and strain rate direction was determined. Therefore, the experimental data demonstrated that the stress state and the strain rate direction are essential parameters characterizing a plastic flow rule. Eventually, a pseudo-corner model capable of reproducing experimentally observed plastic deformation behavior was proposed.

Elastoplastic responses of rate-independent polycrystals are simulated under linear and various nonlinear strain paths, and the influence of the loading condition on the plastic flow behavior is investigated. It is observed that the shear components of elastoplastic tangent moduli start decreasing when the plastic deformation occurs, and the direction of the plastic flow depends on the direction of the stress/strain rates. A phenomenological plastic flow rule capable of reproducing these behaviors is developed. The flow rule relates the direction of plastic strain rate to the direction of strain rate, and yields the reduction of shear modulus after plastic yielding. The proposed constitutive model is then integrated into a finite element program, and the plane strain tension and pure bending are analyzed. The advantage of the proposed flow rule for simulating the occurrence of a shear band is demonstrated.

The formability of AZ31 sheets was experimentally measured for uniaxial tension, plane strain stretching, and equi-biaxial stretching modes. The limit strain of the specimen was reasonable under uniaxial tension but was drastically reduced in the biaxial stretching modes. Full-field strain analysis and the observation of the fracture surface revealed that the specimen fractured without the formation of a visible local necking. To predict the fracture behavior using a crystal plasticity-based finite element method, a mean field model was developed to solve the mechanical interplay between the parent and twins. The destabilization of the specimen was simulated by introducing fracture criteria as functions of the accumulated slip inside the contraction twin region. Simulations revealed that strong strain heterogeneity forms in the case of the biaxial stretching modes, and this heterogeneity is apparently reduced under uniaxial tension as a result of the activation of prismatic slip, which produces a uniform strain distribution. Contraction twins nucleate at smaller strain levels in the biaxial stretching modes, and premature failure is predicted in the biaxial stretching modes as a result of the accumulation of slip in the twinned regions. Parametric studies show that even when the volume fraction of twins is small, they have a significant impact on the ductility of AZ31 sheets.

Plastic flow rule is a fundamental equation that describes the plastic behavior of polycrystalline aggregate. To clarify plastic response at the point where the loading mode is suddenly changed, uniaxial tension followed by combined tension–torsion was applied to an A3003-O tube. The loading mode was altered at different plastic strains. It was observed that the direction of the plastic strain rate rotated immediately when the loading mode was changed. The greater the deviation in the subsequent loading mode from the uniaxial tension, the higher is the extent of rotation of the direction of plastic strain rate. The extent of instantaneous rotation of the plastic flow direction was the same regardless of the magnitude of the plastic strain at the alteration of the loading mode. Thus, the experimental results showed that the direction of the plastic flow depended on the direction of the stress/strain rate tensor; however, it was not affected by the magnitude of the plastic strain. Then, the effects of the hardening behavior of a slip system on the direction of the plastic flow were examined through a crystal plasticity simulation that considers the latent and kinematic hardenings. The crystal plasticity simulations reproduced the experimentally observed rotation of the plastic flow direction. Moreover, the simulations showed that the latent and kinematic hardenings did not affect the direction of the macroscopic plastic flow, even though they altered the activities of the slip systems. Therefore, it became clear that the plastic flow behavior of the polycrystal depends on the stress state and the direction of the stress/strain rate, and it is not affected by either the magnitude of the plastic strain or the hardening behavior of a slip system.

Previous immunological studies in atomic bomb survivors have suggested that radiation exposure leads to long-lasting changes, similar to immunological aging observed in T-cell-adaptive immunity. However, to our knowledge, late effects of radiation on dendritic cells (DCs), the key coordinators for activation and differentiation of T cells, have not yet been investigated in humans. In the current study, we hypothesized that numerical and functional decreases would be observed in relationship to radiation dose in circulating conventional DCs (cDCs) and plasmacytoid DCs (pDCs) among 229 Japanese A-bomb survivors. Overall, the evidence did not support this hypothesis, with no overall changes in DCs or functional changes observed with radiation dose. Multivariable regression analysis for radiation dose, age and gender effects revealed that total DC counts as well as subpopulation counts decreased in relationship to increasing age. Further analyses revealed that in women, absolute numbers of pDCs showed significant decreases with radiation dose. A hierarchical clustering analysis of gene expression profiles in DCs after Toll-like receptor stimulation in vitro identified two clusters of participants that differed in age-associated expression levels of genes involved in antigen presentation and cytokine/chemokine production in cDCs. These results suggest that DC counts decrease and expression levels of gene clusters change with age. More than 60 years after radiation exposure, we also observed changes in pDC counts associated with radiation, but only among women.

The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44+ group 3 ILCs (NCR+ILC3s) and conventional NK (cNK) cells from CD34+ hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR+ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry. We demonstrated that Notch signaling in combination with IL-7 induced NCR+ILC3 differentiation, but conversely suppressed IL-15–dependent cNK cell generation in CD45RA+Flt-3−c-Kitlow, a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA−Flt-3+c-Kithigh multipotent HPCs to generate CD34+CD7+CD62Lhigh, the earliest thymic progenitor–like cells, which preserved high cNK/T cell potential, but lost NCR+ILC3 potential. These findings implicate the countervailing functions of Notch signaling in the fate decision between NCR+ILC3 and cNK cell lineages at different maturational stages of human HPCs. Inhibition of Notch functions by Abs specific for either the Notch1 or Notch2 negative regulatory region suggested that both Notch1 and Notch2 signals were involved in the fate decision of innate lymphocyte-committed HPCs and in the generation of earliest thymic progenitor–like cells from multipotent HPCs. Furthermore, the synergistic interaction between Notch and IL-7 in NCR+ILC3 commitment was primarily explicable by the induction of IL-7 receptor expression in the innate lymphocyte–committed HPCs by Notch stimulation, suggesting the pivotal role of Notch in the transcriptional control required for human NCR+ILC3 commitment.

Background: In soccer performance, coordination training is important and there is a high chance of injury due to improper concentration during a performance, but there is little research on the relationship with injury. The aim of this study was to assess the effect of dual-task training on young soccer players' attention distribution ability, physical function and performance, and occurrence of injury. Methods: The subjects were 70 soccer players as intervention group and 52 players were as control group (age of all subjects was 15.9 ± 0.8 years, the height was 168.8 ± 5.3 cm, and the body weight was 59.5 ± 6.2 kg). Agility t-test and an original dual-task agility t-test were measured as indicator of attention distribution ability. The history of subjects’ injuries was interviewed, and a single-leg triple hop for the distance test and a single-leg standing test with closed eyes were measured as physical function. The dual-task training concluded 5 items and the intervention was performed in approximately 20 minutes one time and six times over 3 weeks at a frequency of twice weekly. The number of people with injuries in each group and each measurement value was compared in each group. Results: The control group comprised 10 subjects with injuries before intervention and 7 after intervention, whereas the intervention group comprised 12 subjects with injuries before intervention and 3 after intervention. No significant differences were observed in any of the parameters after the intervention in either of the two groups. Conclusion: Whether this difference was caused by the intervention remains unclear; however, it is possible that the training program in this study was effective for short-term injury prevention. The contents of evaluation and training menu should be reexamined in the future.

Experimental and spectroscopic studies revealed unprecedented reactivity of a “naked” lithium cation with very weakly coordinating anions, including carborane anions. The superactivated lithium cation has greatly enhanced Lewis acidic character and mediates various organic reactions such as carbonyl-ene reaction, NBS-bromination of unactivated aromatics, and Friedel–Crafts alkylation, which are not promoted by conventional lithium salts. Chemical robustness of the counteranion also plays an important role in the chemistry of the strongly activated lithium cation.

The relationships between commitments of dendritic cells (DCs) and T cells in human hematopoietic stem cells are not well understood. In this study, we enumerate and characterize conventional DC and plasmacytoid DC precursors in association with T cell and thymus-derived types of NK cell precursors among CD34+ hematopoietic progenitor cells (HPCs) circulating in human peripheral blood. By limiting-dilution analyses using coculture with stroma cells expressing Notch1 ligand, the precursor frequencies (PFs) of DCs in HPCs were found to significantly correlate with T cell PFs, but not with NK cell PFs, among healthy donors. Clonal analyses showed that the majority of T/NK dual- and T single-lineage precursors—but only a minority of NK single-lineage precursors—were associated with the generation of DC progenies. All clones producing both DC and T cell progenies were found with monocyte and/or granulocyte progenies, suggesting DC differentiation via myeloid DC pathways. Analyses of peripheral blood HPC subpopulations revealed that the lineage split between DC and T/NK cell progenitor occurs at the stage prior to bifurcation into T and NK cell lineages. The findings suggest a strong linkage between DC and T cell commitments, which may be imprinted in circulating lymphoid-primed multipotent progenitors or in more upstream HPCs.

Strain localization of sheet metals subjected to plane-strain stretching was simulated by finite-element analysis based on a crystal plasticity model. The ratio of specimen thickness to grain size, denoted by Ng, is varied from 1 to 70, and its influence on the evolution of surface roughness and the occurrence of sheet necking is investigated. Roughening of the free surface of the specimen is induced by the grain-scale strain heterogeneity associated with local grain misorientation. The magnitude of surface roughness depends mainly on the grain size and is less sensitive to Ng. As Ng decreases while maintaining the thickness, the magnitude of surface roughness becomes large with respect to the thickness. As a result, large geometrical imperfection is generated. Therefore, the formability of sheet metal is reduced as Ng decreases. Such an effect is found to be particularly considerable when Ng is less than 30. It is also found that the localization mode shifts from a sharp shear banding mode to a localized thinning mode as Ng increases.

A thin-walled tubular specimen of A3003-O is subjected to uniaxial, biaxial, and triaxial stress paths using an axial load-internal pressure-torsion type test machine. For linear multiaxial stress paths, the ratios of axial, circumferential, and shear stresses are kept constant, and the stress–strain relations for various stress paths are measured. The work-hardening behavior of the specimen is evaluated based on the plastic work per unit volume, and contours of equal plastic work are constructed. The shape of the contour changes progressively with increasing plastic strain. Therefore, the amount of work hardening of the specimen depends on the plastic work and the applied stress path. In order to clarify the source of such work-hardening behavior, numerical simulations are performed using the crystal plasticity model. Two hardening models are adopted. In one model, the slip resistance is given as a function of accumulated slip, and, in the other model, the slip resistance is given as a function of dislocation density. The evolution of macroscopic flow stress depends only on the plastic work for the accumulated-slip-based model, and this model cannot predict the experimental trend. On the other hand, the dislocation-density-based model reproduces the stress-path dependent work-hardening behavior observed in the experiments, although quantitative agreement is not fully achieved. In the simulation, the evolution rate of the dislocation density varies depending on the stress path, which is identified as the source of the stress-path-dependent work-hardening behavior.

A novel framework to predict the onset of plastic flow localization is presented. The proposed framework combines a classical strain localization analysis with a homogenization-based finite element method, and has high applicability to various types of material with a characteristic microstructure that may have significant heterogeneity as long as its representative volume element can be represented by a finite element discretization. According to the proposed method, a plastic flow localization analysis can be performed taking only one or two material points in macroscopic analysis. This means that localization analysis of materials involving very complex microstructures, which is hard to be satisfactorily treated in a fully micro-macro-coupled finite element analysis with the homogenization approach, can be carried out with a reasonable computational cost. As a practical application of the proposed general framework, a plane stress version, that is, a Marciniak–Kuczynski-type (M–K) approach, is considered, then the forming limit strains of FCC polycrystalline sheets are evaluated. Crystal plasticity theory is adopted as a constitutive model for each crystal grain, and the homogenization-based finite element method is used to evaluate the average material response to be used in M–K-type sheet necking analysis. A numerical convergence analysis is conducted to determine the appropriate size of the representative volume element in the homogenization, and the effect of the geometrical configuration of crystal grains is studied. Then, the forming limit strains of a textured material are evaluated. The computational results are compared with those obtained using the conventional Taylor-type polycrystalline model.

Age-associated changes of T and NK cell (T/NK) potential of human hematopoietic stem cells are unknown. In this study, we enumerate and characterize T/NK precursors among CD34+Lin− cell populations circulating in normal human adult peripheral blood (PB) by a limiting-dilution assay using coculture with OP9-DL1 stroma cells expressing Notch 1 ligand, Delta–like 1. The frequency of T cell precursors in CD34+Lin− cells was found to decrease with donor age, whereas the ratio of NK to T cell precursor frequency (NK/T ratio) increased with age, suggesting that lymphoid differentiation potential of PB progenitors shifts from T to NK cell lineage with aging. Clonal analyses of CD34+Lin− cells showed that differences in the NK/T ratio were attributable to different distributions of single- and dual-lineage T/NK precursor clones. Because nearly all of the clones retained monocyte and/or granulocyte differentiation potentials in coculture with OP9-DL1 cells, T/NK precursors in PB are considered to be contained in the pool of T/NK/myeloid multipotent progenitors. The age-associated increase in NK over T cell commitment might occur in precursor cells with T/NK/myeloid potential.

In a series of studies of atomic bomb survivors, radiation-dose-dependent alterations in peripheral T-cell populations have been reported. For example, reduced size in naïve T-cell pools and impaired proliferation ability of T cells were observed. Because these alterations are also generally observed with human aging, we hypothesized that radiation exposure may accelerate the aging process of the T-cell immune system. To further test this hypothesis, we conducted cross-sectional analyses of telomere length, a hallmark of cellular aging, of naïve and memory CD4 T cells and total CD8 T cells in the peripheral blood of 620 atomic bomb survivors as it relates to age and radiation dose, using fluorescence in situ hybridization with flow cytometry. Since telomere shortening has been recently demonstrated in obesity-related metabolic abnormalities and diseases, the modifying effects of metabolic status were also examined. Our results indicated nonlinear relationships between T-cell telomere length and prior radiation exposure, i.e., longer telomeres with lower dose exposure and a decreasing trend of telomere length with individuals exposed to doses higher than 0.5 Gy. There were associations between shorter T-cell telomeres and higher hemoglobin Alc levels or fatty liver development. In naïve and memory CD4 T cells, radiation dose and high-density lipoprotein (HDL) cholesterol were found to positively interact with telomere length, suggesting that the decreasing trend of telomere length from a higher radiation dose was less conspicuous in individuals with a higher HDL cholesterol. It is therefore likely that radiation exposure perturbs T-cell homeostasis involving telomere length maintenance by multiple biological mechanisms, depending on dose, and that long-term-radiation-induced effects on the maintenance of T-cell telomeres may be modified by the subsequent metabolic conditions of individuals.

Immune system impairments reflected by the composition and function of circulating lymphocytes are still observed in atomic bomb survivors, and metabolic abnormalities including altered blood triglyceride and cholesterol levels have also been detected in such survivors. Based on closely related features of immune and metabolic profiles of individuals, we investigated the hypothesis that long-term effects of radiation exposure on lymphocyte subsets might be modified by metabolic profiles in 3,113 atomic bomb survivors who participated in health examinations at the Radiation Effect Research Foundation, Hiroshima and Nagasaki, in 2000-2002. The lymphocyte subsets analyzed involved T-, B- and NK-cell subsets, and their percentages in the lymphocyte fraction were assessed using flow cytometry. Health examinations included metabolic indicators, body mass index, serum levels of total cholesterol, high-density lipoprotein cholesterol, C-reactive protein and hemoglobin A1c, as well as diabetes and fatty liver diagnoses. Standard regression analyses indicated that several metabolic indicators of obesity/related disease, particularly high-density lipoprotein cholesterol levels, were positively associated with type-1 helper T- and B-cell percentages but were inversely associated with naive CD4 T and NK cells. A regression analysis adjusted for high-density lipoprotein cholesterol revealed a radiation dose relationship with increasing NK-cell percentage. Additionally, an interaction effect was suggested between radiation dose and C-reactive protein on B-cell percentage with a negative coefficient of the interaction term. Collectively, these findings suggest that radiation exposure and subsequent metabolic profile changes, potentially in relationship to obesity-related inflammation, lead to such long-term alterations in lymphocyte subset composition. Because this study is based on cross-sectional and exploratory analyses, the implications regarding radiation exposure, metabolic profiles and circulating lymphocytes warrant future longitudinal and molecular mechanistic studies.

Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations then recovered to a normal range, but accompanying cells derived from hematopoietic stem cells still remain that bear molecular changes possibly caused by past radiation exposure and aging. In the present study, we evaluated radiation-related changes in the frequency of phosphorylated (Ser-139) H2AX (γH2AX) foci formation in circulating CD34-positive/lineage marker-negative (CD34 + Lin−) hematopoietic stem and progenitor cells (HSPCs) among 226Hiroshima A-bomb survivors. An association between the frequency of γH2AX foci formation in HSPCs and the radiation dose was observed, but the γH2AX foci frequency was not significantly elevated by past radiation. We found a negative correlation between the frequency of γH2AX foci formation and the length of granulocyte telomeres. A negative interaction effect between the radiation dose and the frequency of γH2AX foci was suggested in a proportion of a subset of HSPCs as assessed by the cobblestone area-forming cell assay (CAFC), indicating that the self-renewability of HSPCs may decrease in survivors who were exposed to a higher radiation dose and who had more DNA damage in their HSPCs. Thus, although many years after radiation exposure and with advancing age, the effect of DNA damage on the self-renewability of HSPCs may be modified by A-bomb radiation exposure.

Ionizing radiation (IR) is a major source of cellular damage and the immediate cellular response to IR has been well characterized. But the long-term impact of IR on cell function and its relationship with aging are not known. Here, we examined the IR effects on telomere length and other biomarkers 50 to 68 years post-exposure (two time points per person) in survivors of the atomic bombing at Hiroshima during WWII. We found that telomere length of leukocytes was inversely correlated with the dose of IR (p=0.008), and this effect was primarily found in survivors who were exposed at younger ages; specifically those

Past exposure to atomic bomb (A-bomb) radiation has exerted various long-lasting deleterious effects on the health of survivors. Some of these effects are seen even after >60 yr. In this study, we evaluated the subclinical inflammatory status of 442 A-bomb survivors, in terms of 8 inflammation-related cytokines or markers, comprised of plasma levels of reactive oxygen species (ROS), interleukin (IL)-6, tumor necrosis factor α (TNF-α), C-reactive protein (CRP), IL-4, IL-10, and immunoglobulins, and erythrocyte sedimentation rate (ESR). The effects of past radiation exposure and natural aging on these markers were individually assessed and compared. Next, to assess the biologically significant relationship between inflammation and radiation exposure or aging, which was masked by the interrelationship of those cytokines/markers, we used multivariate statistical analyses and evaluated the systemic markers of inflammation as scores being calculated by linear combinations of selected cytokines and markers. Our results indicate that a linear combination of ROS, IL-6, CRP, and ESR generated a score that was the most indicative of inflammation and revealed clear dependences on radiation dose and aging that were found to be statistically significant. The results suggest that collectively, radiation exposure, in conjunction with natural aging, may enhance the persistent inflammatory status of A-bomb survivors.—Hayashi, T., Morishita, Y., Khattree, R., Misumi, M., Sasaki, K., Hayashi, I., Yoshida, K., Kajimura, J., Kyoizumi, S., Imai, K., Kusunoki, Y., Nakachi, K. Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects.

Background The case-cohort study design has received significant methodological attention in the statistical and epidemiological literature but has not been used as widely as other cohort-based sampling designs, such as the nested case-control design. Despite its efficiency and practicality for a wide range of epidemiological study purposes, researchers may not yet be aware of the fact that the design can be analysed using standard software with only minor adjustments. Furthermore, although the large number of options for design and analysis of case-cohort studies may be daunting, they can be reduced to a few simple recommendations. Methods We review conventional methods for the design and analysis of case-cohort studies and describe empirical comparisons based on a study of radiation, gene polymorphisms and cancer in the Japanese atomic bomb survivor cohort. Results Stratified, as opposed to simple, random subcohort selection is recommended, especially for studies of gene-environment interaction, which are notorious for lacking statistical power. Methods based on the score-unbiased exact pseudo-likelihood (or its analogue with stratified case-cohort data) are recommended for use in conjunction with the asymptotic variance estimator. Conclusions We present an example of how to implement case-cohort analysis methods using SPSS, a popular statistical package that lacks some of the features necessary to directly adapt and implement published methods based on other software platforms. We also illustrate case-control analysis using Epicure, which provides greater risk-modelling flexibility than other software. Our conclusions and recommendations should help investigators to better understand and apply the case-cohort design in epidemiological research.

Plastic deformation characteristics and limit strains are simulated for textured face-centered cubic polycrystalline sheets using a generalized Taylor-type crystal plasticity model. The r- values are predicted to be 1.04, 7.74, and 0.17 for the pseudo-random, {1 1 1}〈 uvw 〉, and {0 0 1}〈 uvw 〉 textures, respectively. The {1 1 1}〈 uvw 〉 texture gives limit strains as large as the random texture, whereas the {0 0 1}〈 uvw 〉 texture yields limit strains apparently higher than the other two, even though its r -value is extremely low. Thus, the r -value cannot act as an indicator of the stretchability of sheet metals. For the {0 0 1}〈 uvw 〉 texture, a superior strain-hardening ability under the plane-strain stretching mode is found to be responsible for the increase in the limit strains under plane strain and equi-biaxial stretching modes. It is concluded that the enhancement of the strain hardening ability for the plane-strain stretching mode is one of the key factors of high stretchability sheets.

It is not yet known whether hematopoietic stem and progenitor cells (HSPCs) are compromised in the aging population of atomic bomb (A-bomb) survivors after their exposure nearly 70 years ago. To address this, we evaluated age- and radiation-related changes in different subtypes of circulating HSPCs among the CD34-positive/lineage marker-negative (CD34(+)Lin(-)) cell population in 231 Hiroshima A-bomb survivors. We enumerated functional HSPC subtypes, including: cobblestone area-forming cells; long-term culture-initiating cells; erythroid burst-forming units; granulocyte and macrophage colony-forming units; and T-cell and natural killer cell progenitors using cell culture. We obtained the count of each HSPC subtype per unit volume of blood and the proportion of each HSPC subtype in CD34(+)Lin(-) cells to represent the lineage commitment trend. Multivariate analyses, using sex, age and radiation dose as variables, showed significantly decreased counts with age in the total CD34(+)Lin(-) cell population and all HSPC subtypes. As for the proportion, only T-cell progenitors decreased significantly with age, suggesting that the commitment to the T-cell lineage in HSPCs continuously declines with age throughout the lifetime. However, neither the CD34(+)Lin(-) cell population, nor HSPC subtypes showed significant radiation-induced dose-dependent changes in counts or proportions. Moreover, the correlations of the proportions among HSPC subtypes in the survivors properly revealed the hierarchy of lineage commitments. Taken together, our findings suggest that many years after exposure to radiation and with advancing age, the number and function of HSPCs in living survivors as a whole may have recovered to normal levels.

This study aims to deepen understanding of lymphocyte phenotypes related to the course of hepatitis C virus (HCV) infection and progression of liver fibrosis, in a cohort of atomic-bomb survivors. The study subjects comprise three groups: 162 HCV persistently infected, 145 spontaneously cleared, and 3511 uninfected individuals. We found increased percentages of peripheral blood TH1 and total CD8 T cells and decreased percentages of NK cells in the HCV persistence group, compared with the other two groups, after adjustment for age, gender, and radiation exposure dose. Subsequently, we found that increased TH1 cell percentages in the HCV persistence group were significantly associated with an accelerated time-course reduction in platelet counts―accelerated progression of liver fibrosis―while TC1 and NK cell percentages were inversely associated with the progression. This study suggests that TH1 immunity is enhanced by persistent HCV infection, and that percentages of peripheral TH1, TC1, and NK cells may help predict progression of liver fibrosis., This research was based on RERF Research Protocols 3-09, 4-02, 2-00, 9-92, and was supported in part by the U.S. National Institute of Allergy and Infectious Diseases (NIAID Contract HHSN272200900059C).

Lung cancer is a leading cause of cancer death worldwide. Prevention could be improved by identifying susceptible individuals as well as improving understanding of interactions between genes and etiological environmental agents, including radiation exposure. The epidermal growth factor receptor (EGFR)-signaling pathway, regulating cellular radiation sensitivity, is an oncogenic cascade involved in lung cancer, especially adenocarcinoma. The cytosine adenine (CA) repeat number polymorphism in the first intron of EGFR has been shown to be inversely correlated with EGFR production. It is hypothesized that CA repeat number may modulate individual susceptibility to lung cancer. Thus, we carried out a case-cohort study within the Japanese atomic bomb (A-bomb) survivor cohort to evaluate a possible association of CA repeat polymorphism with lung cancer risk in radiation-exposed or negligibly exposed (5 mGy) A-bomb survivors. First, by dividing study subjects into Short and Long genotypes, defined as the summed CA repeat number of two allelesor = 37 andor = 38, respectively, we found that the Short genotype was significantly associated with an increased risk of lung cancer, specifically adenocarcinoma, among negligibly exposed subjects. Next, we found that prior radiation exposure significantly enhanced lung cancer risk of survivors with the Long genotype, whereas the risk for the Short genotype did not show any significant increase with radiation dose, resulting in indistinguishable risks between these genotypes at a high radiation dose. Our findings imply that the EGFR pathway plays a crucial role in assessing individual susceptibility to lung adenocarcinoma in relation to radiation exposure.

Individual grains in a polycrystal rotate during plastic deformation. This leads to a change in the crystallographic texture, and results in an increase or decrease of the macroscopic flow stress of the material. Such a change of strength as a result of grain rotations is called geometrical or texture hardening/softening. In the present study, for textured aluminum alloy sheets, the geometrical hardening/softening effect in the in-plane plane-strain stretching mode is numerically investigated using a generalized Taylor-type polycrystalline model. It is found that the cube texture ( { 1 0 0 } 〈 0 0 1 〉 ) exhibits significant geometrical hardening when the major stretching direction is inclined at 45° relative to the orthotropic axes, and that a cube texture rotated about the normal direction (ND) shows a notable degree of geometrical hardening for any in-plane orientation of the sheet. Using the Marciniak-Kuczynski-type approach, forming limits for these textured sheets are analyzed. It is found that geometrical hardening definitely enhances the formability. It is, therefore, strongly suggested that texture control guided by the present results may be highly effective in producing aluminum alloy sheets with higher formability.

Forming limit stresses of sheet metals subjected to linear and combined stress paths are analyzed using the M-K model in conjunction with two anisotropic work-hardening models: a work-hardening model which is capable of describing Bauschinger and cross-hardening effects, and a work-hardening model which cannot predict the cross-hardening effect. It is found that the forming limit stress is path-independent when the stress–strain curves for the linear and combined stress paths agree well with each other. On the other hand, the forming limit stress for the combined stress path depends on the strain path when the prestrain changes the subsequent stress–strain relation. We conclude that the stress-based forming limit criterion is efficient only for a material with a work-hardening behavior that is not affected by strain path change. The influence of the work-hardening behavior on the forming limit stress is discussed in detail.